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Sample records for mammary tumor angiogenesis

  1. Mast cells and angiogenesis in canine mammary tumor Mastócitos e angiogênese nos tumores mamários caninos

    OpenAIRE

    Lavalle, G. E.; Bertagnolli, A. C.; Tavares, W. L. F.; Ferreira, M. A. N. D.; Cassali, G. D.

    2010-01-01

    The correlation between microvessel density and mast cells density in canine mammary tumors was studied. Sixty-five samples of canine mammary tumors, being 24 benign and 41 malignant, were analyzed. The routine Toluidine Blue staining method was used to assess the mast cells. To evaluate angiogenesis, the immunohistochemical expression of CD31 was assessed. There was no significant difference in either mast cells (P=0.44) or microvessel density (P=0.77) between malignant and benign tumors. A ...

  2. Mast cells and angiogenesis in canine mammary tumor / Mastócitos e angiogênese nos tumores mamários caninos

    Scientific Electronic Library Online (English)

    G.E, Lavalle; A.C, Bertagnolli; W.L.F, Tavares; M.A.N.D, Ferreira; G.D, Cassali.

    1348-13-01

    Full Text Available Estimou-se a correlação entre a densidade de microvasos e a densidade de mastócitos em tumores mamários caninos. Sessenta e cinco amostras de tumores mamários caninos - 24 benignos e 41 malignos - foram analisadas, pela técnica rotineira de coloração com Azul de Toluidina para avaliação da densidade [...] de mastócitos. Para a avaliação da angiogênese, foi utilizada a técnica de imunoistoquímica para expressão de CD31. Não foram observadas diferenças significativas de mastócitos (P=0.44) ou densidade microvascular (P=0.77) entre tumores malignos e benignos. A correlação entre densidade microvascular e densidade de mastócitos foi positiva (r=0,39; P=0,011) em tumores malignos. Estes resultados sugerem que os mastócitos podem exercer um importante papel no desenvolvimento de tumores mamários malignos caninos mediante promoção da angiogênese, similarmente a alguns tumores descritos na espécie humana Abstract in english The correlation between microvessel density and mast cells density in canine mammary tumors was studied. Sixty-five samples of canine mammary tumors, being 24 benign and 41 malignant, were analyzed. The routine Toluidine Blue staining method was used to assess the mast cells. To evaluate angiogenesi [...] s, the immunohistochemical expression of CD31 was assessed. There was no significant difference in either mast cells (P=0.44) or microvessel density (P=0.77) between malignant and benign tumors. A positive correlation was observed between microvessel density and mast cells (r=0.39; P=0.011) in malignant tumors. These results suggest that mast cells may play a role in canine mammary malignant tumors development, promoting angiogenesis, similar to some tumors described in the human species

  3. Mast cells and angiogenesis in canine mammary tumor Mastócitos e angiogênese nos tumores mamários caninos

    Directory of Open Access Journals (Sweden)

    G.E Lavalle

    2010-12-01

    Full Text Available The correlation between microvessel density and mast cells density in canine mammary tumors was studied. Sixty-five samples of canine mammary tumors, being 24 benign and 41 malignant, were analyzed. The routine Toluidine Blue staining method was used to assess the mast cells. To evaluate angiogenesis, the immunohistochemical expression of CD31 was assessed. There was no significant difference in either mast cells (P=0.44 or microvessel density (P=0.77 between malignant and benign tumors. A positive correlation was observed between microvessel density and mast cells (r=0.39; P=0.011 in malignant tumors. These results suggest that mast cells may play a role in canine mammary malignant tumors development, promoting angiogenesis, similar to some tumors described in the human speciesEstimou-se a correlação entre a densidade de microvasos e a densidade de mastócitos em tumores mamários caninos. Sessenta e cinco amostras de tumores mamários caninos - 24 benignos e 41 malignos - foram analisadas, pela técnica rotineira de coloração com Azul de Toluidina para avaliação da densidade de mastócitos. Para a avaliação da angiogênese, foi utilizada a técnica de imunoistoquímica para expressão de CD31. Não foram observadas diferenças significativas de mastócitos (P=0.44 ou densidade microvascular (P=0.77 entre tumores malignos e benignos. A correlação entre densidade microvascular e densidade de mastócitos foi positiva (r=0,39; P=0,011 em tumores malignos. Estes resultados sugerem que os mastócitos podem exercer um importante papel no desenvolvimento de tumores mamários malignos caninos mediante promoção da angiogênese, similarmente a alguns tumores descritos na espécie humana

  4. Mammary tumors

    International Nuclear Information System (INIS)

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported

  5. Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study

    Directory of Open Access Journals (Sweden)

    Broggini-Tenzer Angela

    2011-06-01

    Full Text Available Abstract Background The combined treatment modality of ionizing radiation (IR with inhibitors of angiogenesis (IoA is a promising treatment modality based on preclinical in vivo studies using heterotopic xeno- and allograft tumor models. Nevertheless reservations still exist to translate this combined treatment modality into clinical trials, and more advanced, spontaneous orthotopic tumor models are required for validation to study the efficacy and safety of this treatment modality. Findings We therefore investigated the combined treatment modality of IR in combination with the clinically relevant VEGF receptor (VEGFR tyrosine kinase inhibitor PTK787 in the MMTV/c-neu induced mammary carcinoma model and a syngenic allograft tumor model using athymic nude mice. Mice were treated with fractionated IR, the VEGFR-inhibitor PTK787/ZK222584 (PTK787, or in combination, and efficacy and mechanistic-related endpoints were probed in both tumor models. Overall the treatment response to the IoA was comparable in both tumor models, demonstrating minimal tumor growth delay in response to PTK787 and PTK787-induced tumor hypoxia. Interestingly spontaneously growing tumors were more radiosensitive than the allograft tumors. More important combined treatment of irradiation with PTK787 resulted in a supraadditive tumor response in both tumor models with a comparable enhancement factor, namely 1.5 and 1.4 in the allograft and in the spontaneous tumor model, respectively. Conclusions These results demonstrate that IR in combination with VEGF-receptor tyrosine kinase inhibitors is a valid, promising treatment modality, and that the treatment responses in spontaneous mammary carcinomas and syngenic allografts tumor models are comparable.

  6. Vasculogenic Mimicry and Tumor Angiogenesis

    OpenAIRE

    Folberg, Robert; Hendrix, Mary J. C.; Maniotis, Andrew J.

    2000-01-01

    Tumors require a blood supply for growth and hematogenous dissemination. Much attention has been focused on the role of angiogenesis—the recruitment of new vessels into a tumor from pre-existing vessels. However, angiogenesis may not be the only mechanism by which tumors acquire a microcirculation. Highly aggressive and metastatic melanoma cells are capable of forming highly patterned vascular channels in vitro that are composed of a basement membrane that stains positive with the periodic ...

  7. Compensatory angiogenesis and tumor refractoriness.

    Science.gov (United States)

    Gacche, R N

    2015-01-01

    Since the establishment of tumor angiogenesis as a therapeutic target, an excitement in developing the anti-angiogenic agents was resulted in tailoring a humanized monoclonal antibody (Bevacizumab) against vascular endothelial growth factor (VEGF): a key factor in recruiting angiogenesis. The past three decades' research in the area of angiogenesis also invented a series of novel and effective anti-angiogenic agents targeting the VEGF signaling axis. Despite the demonstrable clinical benefits of anti-angiogenic therapy, the preclinical and clinical data of the current therapeutic settings clearly indicate the transient efficacy, restoration of tumor progression and aggressive recurrence of tumor invasion after the withdrawal of anti-angiogenic therapy. Therefore, the impact of this therapeutic regime on improving overall survival of patients has been disappointing in clinic. The recent advances in pathophysiology of tumor angiogenesis and related molecular and cellular underpinnings attributed the conspiracy of compensatory angiogenic pathways in conferring evasive and intrinsic tumor resistance to anti-angiogenic agents. The understandings of how these pathways functionally cross-talk for sustaining tumor angiogenesis during VEGF blockade is essential and perhaps may act as a basic prerequisite for designing novel therapeutic strategies to combat the growing arrogance of tumors toward anti-angiogenic agents. The present review offers a discourse on major compensatory angiogenic pathways operating at cellular and molecular levels and their attributes with resistance to anti-angiogenic agents along with strategic opinions on future setting in targeting tumor angiogenesis. PMID:26029827

  8. Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study

    OpenAIRE

    Broggini-Tenzer Angela; Jochum Wolfram; Oehler-Jänne Christoph; Riesterer Oliver; Vuong, Van; Pruschy Martin

    2011-01-01

    Abstract Background The combined treatment modality of ionizing radiation (IR) with inhibitors of angiogenesis (IoA) is a promising treatment modality based on preclinical in vivo studies using heterotopic xeno- and allograft tumor models. Nevertheless reservations still exist to translate this combined treatment modality into clinical trials, and more advanced, spontaneous orthotopic tumor models are required for validation to study the efficacy and safety of this treatment modality. Finding...

  9. Canine mammary tumors - clinical survey

    Directory of Open Access Journals (Sweden)

    Elena Atanaskova Petrov

    2014-10-01

    Full Text Available Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs’ age, reproductive cycle and sterilization. The survey was used to retrieve the information in the period of two years from the patient data base of the University Veterinary Hospital at the Faculty of Veterinary medicine in Skopje. Patients included in this survey were subjected to routine clinical investigation and additional laboratory tests (cytological examination, x-rays imaging, CBC and biochemical profile, histopathology of the tumor samples. Aged female patients (12 – 13 years are the most susceptible category for development of mammary tumours. The reproductive history showed that five of the patients with malignant mammary tumourshave never whelped and were not treated with any exogenous hormones. Malignant tumours (adenocarcinoma were diagnosed in 90% of the patients. Three patients died due to lung metastasis. Late diagnosis is one of the major problems that results in lethal outcome due to lung metastases. Since ovarian steroids play an important role in the aetiology, the most effective prevention of mammary tumoursis elective ovariectomy of the bitch at an early age.

  10. Preclinical Molecular Imaging of Tumor Angiogenesis

    OpenAIRE

    Zhu, Lei; Niu, Gang; Fang, Xuexun; Chen, Xiaoyuan

    2010-01-01

    Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging ...

  11. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

    OpenAIRE

    Maria Isabel Carvalho; Isabel Pires; Justina Prada; Queiroga, Felisbina L.

    2014-01-01

    Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both speci...

  12. Angiogenesis in canine mammary tumours: a morphometric and prognostic study.

    Science.gov (United States)

    Sleeckx, N; Van Brantegem, L; Van den Eynden, G; Fransen, E; Casteleyn, C; Van Cruchten, S; Veldhuis Kroeze, E; Van Ginneken, C

    2014-01-01

    Angiogenesis in canine mammary tumours (CMTs) has been described previously; however, only the intratumoural (IT) region has been studied and information on peritumoural (PT) angiogenesis is lacking. In this study, the blood vessel density (BVD), blood vessel perimeter (BVP) and blood vessel area (BVA) in IT and PT regions of 56 benign CMTs, 55 malignant CMTs and 13 samples of normal mammary gland tissue were analyzed. In addition, the blood endothelial cell proliferation (BECP) as an indicator of ongoing angiogenesis was investigated. The prognostic value of each parameter was also examined. Blood vessels and proliferating blood endothelial cells were present in IT and PT regions of both benign and malignant tumours. The vessels in the PT region had a significantly higher area and perimeter compared with those in the IT region. Malignant tumours showed significantly more vessels with a smaller total BVA and a higher BECP compared with benign tumours and control tissue. In the PT regions there was a significantly higher BVD, BVA and BVP compared with the vessels in control tissue. Only the IT and PT BVD and PT BECP in benign tumours allowed prediction of survival. The morphology of blood vessels in CMTs shows similarities with those in human breast cancer, which strengthens the case for the use of dogs with CMTs in comparative oncology trials. PMID:24231306

  13. Targeting the Tumor Microenvironment: Focus on Angiogenesis

    OpenAIRE

    Fengjuan Fan; Alexander Schimming; Dirk Jaeger; Klaus Podar

    2011-01-01

    Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has...

  14. Targeting tumor angiogenesis with Histone Deacetylase Inhibitors

    OpenAIRE

    Ellis, Leigh; Hammers, Hans; Pili, Roberto

    2008-01-01

    Solid tumor malignancies including breast, lung and prostate carcinomas are considered to be angiogenesis dependent. Tumor angiogenesis is often mediated by hypoxia secondary to tumor growth or by increased oncogenic signaling. Both mechanisms result in increased hypoxia-inducible factor-1 alpha (HIF-1?) signaling and its transcriptional target vascular endothelial growth factor (VEGF). Critical to HIF-1? signaling are post translational modifications including acetylation mediated by histo...

  15. Imaging Key Biomarkers of Tumor Angiogenesis

    Directory of Open Access Journals (Sweden)

    Marina V. Backer, Joseph M. Backer

    2012-01-01

    Full Text Available Angiogenesis is a fundamental requirement for tumor growth and therefore it is a primary target for anti-cancer therapy. Molecular imaging of angiogenesis may provide novel opportunities for early diagnostic and for image-guided optimization and management of therapeutic regimens. Here we reviewed the advances in targeted imaging of key biomarkers of tumor angiogenesis, integrins and receptors for vascular endothelial growth factor (VEGF. Tracers for targeted imaging of these biomarkers in different imaging modalities are now reasonably well-developed and PET tracers for integrin imaging are currently in clinical trials. Molecular imaging of longitudinal responses to anti-angiogenic therapy in model tumor systems revealed a complex pattern of changes in targeted tracer accumulation in tumor, which reflects drug-induced tumor regression followed by vascular rebound. Further work will define the competitiveness of targeted imaging of key angiogenesis markers for early diagnostic and image-guided therapy.

  16. Canine mammary tumors - clinical survey

    OpenAIRE

    Elena Atanaskova Petrov; Ksenija Ilievska; Plamen Trojacanec; Irena Celeska; Goran Nikolovski; Ivica Gjurovski; Toni Dovenski

    2014-01-01

    Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs’ age, reproductive cycle and sterilization. The survey was used to retrieve the information in t...

  17. Classification and grading of canine malignant mammary tumors

    OpenAIRE

    Abbas Tavasoly; Hannaneh Golshahi; Annahita Rezaie; Mohammad Farhadi

    2013-01-01

    Histological grading is a good parameter to stratify tumors according to their biological aggressiveness. The Elston and Ellis grading method in humans, invasive ductal breast carcinomas and other invasive tumors are routinely used. The aims of this study were classification of mammary gland tumors and also application of a human grading method in canine mammary carcinoma. The samples included 37 tumors of mammary glands. Mammary tumors were carcinomas (n = 32) and sarcomas (n = 5). The carci...

  18. Prevention of radiation-induced mammary tumors

    International Nuclear Information System (INIS)

    The radiation-induced rat mammary tumor model is useful for studying tumor prevention by treatment in the initiation or promotion stage. In anti-initiation experiments, the administration of radical scavengers or spin-trapping agents before or immediately after irradiation reduced the incidence of mammary tumors, suggesting that free radicals produced by exposure are a potent initiator. To evaluate the role of nitric oxide (NO) in the initiation, NO-specific scavengers or NO synthase inhibitors were administered during the initiation. These agents partially prevented the tumorigenesis, suggesting that radiation-induced NO contributes to tumor initiation. The administration of curcumin during irradiation reduced the incidence of the tumors in the presence of tumor promotor. In anti-promotion experiments on preventing diethylstilbestrol (DES)-dependent tumor development from mammary primodial cells exposed to radiation, tamoxifen decreased the tumor incidence. From the results, estrogen itself or prolactin induced by estrogen may be a promoter for the tumorigenesis. Bezafibrate and simvastatin, agents inducing hypolipidemia and hypocholesterolemia respectively, cause a decrease in the DES-dependent promotion of radiation-induced tumorigenesis. The simultaneous administration of curcumin and DES significantly reduces the development of mammary tumors in irradiated rats. In this review, the endocrinologic and pharmacologic significance of the anti-initiation and anti-promcance of the anti-initiation and anti-promotion is discussed

  19. Mouse Mammary Tumor Virus-Like Nucleotide Sequences in Canine and Feline Mammary Tumors?

    OpenAIRE

    Hsu, Wei-li; Lin, Hsing-yi; Chiou, Shyan-song; Chang, Chao-chin; Wang, Szu-pong; Lin, Kuan-hsun; Chulakasian, Songkhla; Wong, Min-liang; Chang, Shih-chieh

    2010-01-01

    Mouse mammary tumor virus (MMTV) has been speculated to be involved in human breast cancer. Companion animals, dogs, and cats with intimate human contacts may contribute to the transmission of MMTV between mouse and human. The aim of this study was to detect MMTV-like nucleotide sequences in canine and feline mammary tumors by nested PCR. Results showed that the presence of MMTV-like env and LTR sequences in canine malignant mammary tumors was 3.49% (3/86) and 18.60% (16/86), respectively. Fo...

  20. Salicylate inhibition of rat mammary carcinogenesis and angiogenesis in female rat compatible with misoprostol administration

    OpenAIRE

    Di Carlo, Francesco; Pirro, Elisa; Ghezzo, Franco; Berta, Giovanni Nicolao; Mognetti, Barbara

    2005-01-01

    Epidemiological data suggest that non-steroidal anti-inflammatory drugs prevent colon cancer. The evidence for other types of tumour is less conclusive, though animal and in vitro studies indicate that they may be effective against mammary cancer cells. We assessed the effect of dietary acetylsalicylic and salicylic acid against dimethylbenzanthracene-induced rat tumours. Tumour angiogenesis was also investigated to explore the mechanism responsible for salicylate effect. Mammary tumours were...

  1. Evaluation of Tumor Angiogenesis with a Second-Generation US Contrast Medium in a Rat Breast Tumor Model

    International Nuclear Information System (INIS)

    Tumor angiogenesis is an important factor for tumor growth, treatment response and prognosis. Noninvasive imaging methods for the evaluation of tumor angiogenesis have been studied, but a method for the quantification of tumor angiogenesis has not been established. This study was designed to evaluate tumor angiogenesis in a rat breast tumor model by the use of a contrast enhanced ultrasound (US) examination with a second-generation US contrast agent. The alkylating agent 19N-ethyl-N-nitrosourea (ENU) was injected into the intraperitoneal cavity of 30-day-old female Sprague-Dawley rats. Three to four months later, breast tumors were detected along the mammary lines of the rats. A total of 17 breast tumors larger than 1 cm in nine rats were evaluated by gray-scale US, color Doppler US and contrast-enhanced US using SonoVue. The results were recorded as digital video images; time-intensity curves and hemodynamic parameters were analyzed. Pathological breast tumor specimens were obtained just after the US examinations. The tumor specimens were stained with hematoxylin and eosin (H and E) and the expression of CD31, an endothelial cell marker, was determined by immunohistochemical staining. We also evaluated the pathological diagnosis of the tumors and the microvessel density (MVD). Spearman's correlation and the Kruskal-Wallis test were used for the analysis. The pathological diagnoses were 11 invasive ductal carcinomas and six benign intraductal epithelial proliferationsnign intraductal epithelial proliferations. The MVD did not correlate with the pathological diagnosis. However, blood volume (BV) showed a statistically significant correlation with MVD (Spearman's correlation, p < 0.05). Contrast-enhanced US using a second-generation US contrast material was useful for the evaluation of tumor angiogenesis of breast tumors in the rat

  2. A role for T-lymphocytes in human breast cancer and in canine mammary tumors.

    Science.gov (United States)

    Carvalho, Maria Isabel; Pires, Isabel; Prada, Justina; Queiroga, Felisbina L

    2014-01-01

    Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology. PMID:24672781

  3. Human adenovirus type 9-induced rat mammary tumors.

    OpenAIRE

    Javier, R.; Raska, K.; Macdonald, G. J.; Shenk, T.

    1991-01-01

    Following subcutaneous inoculation of newborn Wistar-Furth rats with human adenovirus type 9 (Ad9), 16 of 16 female and 0 of 11 male rats developed mammary tumors. Tumor-positive animals usually developed tumors in multiple glands. Histopathological analyses indicated that three general categories of tumor could be identified. Mammary fibroadenomas were the most common tumor type encountered, but phyllodeslike tumors and solid sarcomas were also frequently found. In situ hybridization and imm...

  4. Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis

    Directory of Open Access Journals (Sweden)

    Susan R. Ross

    2010-09-01

    Full Text Available Mouse mammary tumor virus (MMTV, which was discovered as a milk?transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer.

  5. Classification and grading of canine malignant mammary tumors

    Directory of Open Access Journals (Sweden)

    Abbas Tavasoly

    2013-03-01

    Full Text Available Histological grading is a good parameter to stratify tumors according to their biologicalaggressiveness. The Elston and Ellis grading method in humans, invasive ductal breastcarcinomas and other invasive tumors are routinely used. The aims of this study wereclassification of mammary gland tumors and also application of ahuman grading methodincanine mammary carcinoma. The samples included 37 tumors of mammary glands.Mammary tumors were carcinomas (n=32 and sarcomas (n=5. The carcinomas wereclassified as simple carcinoma 56.8% (n= 21, complex carcinoma13.5% (n= 5, carcinomaarising from benign tumor 10.8% (n= 4 and special type of carcinoma 5.4% (n= 2. Out of 32carcinomas studied, 37.5% (n= 12 grade I, 46.9% (n=15 grade II and 15.6% (n= 5 gradeIII. This study demonstrated that the Elston and Ellis method of histological grading in caninemammary tumor is a reliable prognostic factorwhichis correlated with histopathologicalclassification.

  6. Hybrid modeling of tumor-induced angiogenesis

    CERN Document Server

    Bonilla, L L; Alvaro, M; Carretero, M

    2014-01-01

    When modeling of tumor-driven angiogenesis, a major source of analytical and computational complexity is the strong coupling between the kinetic parameters of the relevant stochastic branching-and-growth of the capillary network, and the family of interacting underlying fields. To reduce this complexity, we take advantage of the system intrinsic multiscale structure: we describe the stochastic dynamics of the cells at the vessel tip at their natural mesoscale, whereas we describe the deterministic dynamics of the underlying fields at a larger macroscale. Here, we set up a conceptual stochastic model including branching, elongation, and anastomosis of vessels and derive a mean field approximation for their densities. This leads to a deterministic integro-partial differential system that describes the formation of the stochastic vessel network. We discuss the proper capillary injecting boundary conditions and include the results of relevant numerical simulations.

  7. Plasma free amino acid profiles of canine mammary gland tumors

    OpenAIRE

    Azuma, Kazuo; Osaki, Tomohiro; Tsuka, Takeshi; Imagawa, Tomohiro; Minami, Saburo; Okamoto, Yoshiharu

    2012-01-01

    The purpose of this study was to elucidate the relationship between plasma free amino acid (PFAA) levels and the clinical stages of mammary gland tumors (MGT) in dogs. PFAA levels in canines with malignant mammary tumors were decreased compared to those of healthy animals. The levels of aspartate and ornithine, in the dogs with tumor metastasis were significantly decreased when compared to those of dogs that did not have metastases. Results of this study indicate that PFAA levels could be a r...

  8. Experimental studies on mammary tumors in rats

    International Nuclear Information System (INIS)

    The purpose of this study was to assess the effects of dietary fat components in radiation-induced rat mammary carcinogenesis, and the response of chemically- or radiation-induced rat mammary tumors (MT) to experimental radiotherapy. Female rats of F344 strain were fed, for 400 days after neutron irradiation, with a synthetic diet containing various fat components with different proportion. Transplanted MTs were tested for their response to radiotherapy in terms of their hormone dependency and antigenicity. An incidence rate of MT was significantly higher in rats given 20% corn oil than in those given 5% or 1% corn oil (61.5% vs 23.0% and 23.8%). In giving diet composed of different fat components with a constant rate of 20%, fish oil significantly inhibited the incidence of MT (16.7%) as compared with lard oil (77.0%) and corn oil (61.5%). In the case of corn oil, an MT incidence rate of 61.5% was reduced to 16.7% when the total caloric intake was decreased by 70%. No association was found between the MT incidence and serum levels of estrogen or prolactin in groups of different fat components. In rats transplanted with 7, 12-dimethylbenz(a)anthracene (DMBA), some of DMBA-induced MTs were spontaneously reduced, suggesting a high antigenicity. Other DMBA-induced MTs were rejected by syngeneic recipients upon cellular transplantation. A high antigenicity may be explained by tumor take and growth with a short latency upon transplantation into immunosuppressed syngeneic rantation into immunosuppressed syngeneic recipients. Ovarian hormone-dependent MTs tended to have a higher radiosensitivity than hormone-independent autonomous MTs. DMBA-induced MTs began to reduce 10 days and were completely destroyed 30 days after irradiation, irrespective of whether they were directly exposed to or shielded from neutron. This abscopal effect can be explained by immunological reaction of the host. (Namekawa, K) 87 refs

  9. Genes affected by mouse mammary tumor virus (MMTV) proviral insertions in mouse mammary tumors are deregulated or mutated in primary human mammary tumors.

    Science.gov (United States)

    Callahan, Robert; Mudunur, Uma; Bargo, Sharon; Raafat, Ahmed; McCurdy, David; Boulanger, Corinne; Lowther, William; Stephens, Robert; Luke, Brian T; Stewart, Claudia; Wu, Xiaolin; Munroe, David; Smith, Gilbert H

    2012-11-01

    The accumulation of mutations is a contributing factor in the initiation of premalignant mammary lesions and their progression to malignancy and metastasis. We have used a mouse model in which the carcinogen is the mouse mammary tumor virus (MMTV) which induces clonal premalignant mammary lesions and malignant mammary tumors by insertional mutagenesis. Identification of the genes and signaling pathways affected in MMTV-induced mouse mammary lesions provides a rationale for determining whether genetic alteration of the human orthologues of these genes/pathways may contribute to human breast carcinogenesis. A high-throughput platform for inverse PCR to identify MMTV-host junction fragments and their nucleotide sequences in a large panel of MMTV-induced lesions was developed. Validation of the genes affected by MMTV-insertion was carried out by microarray analysis. Common integration site (CIS) means that the gene was altered by an MMTV proviral insertion in at least two independent lesions arising in different hosts. Three of the new genes identified as CIS for MMTV were assayed for their capability to confer on HC11 mouse mammary epithelial cells the ability for invasion, anchorage independent growth and tumor development in nude mice. Analysis of MMTV induced mammary premalignant hyperplastic outgrowth (HOG) lines and mammary tumors led to the identification of CIS restricted to 35 loci. Within these loci members of the Wnt, Fgf and Rspo gene families plus two linked genes (Npm3 and Ddn) were frequently activated in tumors induced by MMTV. A second group of 15 CIS occur at a low frequency (2-5 observations) in mammary HOGs or tumors. In this latter group the expression of either Phf19 or Sdc2 was shown to increase HC11 cells invasion capability. Foxl1 expression conferred on HC11 cells the capability for anchorage-independent colony formation in soft agar and tumor development in nude mice. The published transcriptome and nucleotide sequence analysis of gene expression in primary human breast tumors was interrogated. Twenty of the human orthologues of MMTV CIS associated genes are deregulated and/or mutated in human breast tumors. PMID:23131872

  10. Protein Kinase C beta in the tumor microenvironment promotes mammary tumorigenesis

    Directory of Open Access Journals (Sweden)

    GinaMSizemore

    2014-04-01

    Full Text Available Protein kinase C beta (PKC? expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKC? is pro-tumorigenic in this disease is still unclear. Interestingly, while it is known that PKC? mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME, no study to date has investigated whether stromal PKC? is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT induced mammary tumorigenesis in the presence and absence of PKC?. We utilize two model systems: one where PKC? is deleted in both the epithelial and stromal compartments to test the global requirement for PKC? on tumor formation, and second, where PKC? is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKC? live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKC? is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors. These experiments reveal for the first time a tumor promoting role for stromal PKC? in MMTV-PyMT tumorigenesis. In corroboration with these results, PKC? mRNA (Prkcb is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKC? in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer.

  11. Malignant mammary tumor in female dogs: environmental contaminants

    OpenAIRE

    Bissacot Denise Z; Ro, Bersano Paulo; Figueiroa Fernanda C; He, Andrade Fa?bio; Rocha Noeme S

    2010-01-01

    Abstract Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethr...

  12. Isolation of a pathogenic clone of mouse mammary tumor virus.

    OpenAIRE

    Morris, D.W.; Bradshaw, H D; Billy, H T; Munn, R J; CARDIFF, R.D.

    1989-01-01

    Exogenous mouse mammary tumor virus (MMTV) was cloned from a GR mammary tumor. Clone lambda GRT39 contained a full-length integrated MMTV(GR) provirus and both 5' and 3' host flanking DNA. The lambda GRT39 provirus had no apparent structural changes associated with cloning and retained the exogenous MMTV gag gene poison sequence. When introduced into rat mammary adenocarcinoma LA7 cells, the lambda GRT39 provirus was fully expressed. lambda GRT39-transfected LA7 cells made MMTV RNA, had gp52 ...

  13. Netrin-4 Delays Colorectal Cancer Carcinomatosis by Inhibiting Tumor Angiogenesis

    OpenAIRE

    Eveno, Clarisse; Broqueres-You, Dong; Feron, Jean-Guillaume; Rampanou, Aurore; Tijeras-Raballand, Annemilaï; Ropert, Stanislas; Leconte, Laurence; Levy, Bernard I; Pocard, Marc

    2011-01-01

    A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vas...

  14. Roles of Integrins in Tumor Angiogenesis and Lymphangiogenesis

    OpenAIRE

    Garmy-susini, Barbara; Varner, Judith A.

    2008-01-01

    The lifelong dedication of Dr. Judah Folkman to understand how tumors co-opt vasculature to promote tumor growth and spread resulted in the development of an astounding body of knowledge and development of new clinical therapeutics for cancer. Angiogenesis is a critical point in the development and dissemination of most human tumors. Tumor-associated lymphangiogenesis also plays an important role in mediating tumor spread to lymph nodes. The molecular regulations of these processes are comple...

  15. Mouse Mammary Tumor Virus Suppresses Apoptosis of Mammary Epithelial Cells through ITAM-Mediated Signaling

    OpenAIRE

    Kim, Hyoung H.; Grande, Shannon M.; Monroe, John G.; Ross, Susan R.

    2012-01-01

    Many receptors in hematopoietic cells use a common signaling pathway that relies on a highly conserved immunoreceptor tyrosine-based activation motif (ITAM), which signals through Src family tyrosine kinases. ITAM-bearing proteins are also found in many oncogenic viruses, including the mouse mammary tumor virus (MMTV) envelope (Env). We previously showed that MMTV Env expression transformed normal mammary epithelial cells and that Src kinases were important mediators in this transformation. T...

  16. Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis

    Science.gov (United States)

    Arumugam, Arunkumar; Agullo, Pamela; Boopalan, Thiyagarajan; Nandy, Sushmita; Lopez, Rebecca; Gutierrez, Christina; Narayan, Mahesh; Rajkumar, Lakshmanaswamy

    2014-01-01

    Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in rat models. Seven-week-old female Sprague Dawley rats were given a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Upon the appearance of palpable mammary tumors, the rats were divided into vehicle-treated control groups and EFNL-treated groups. Treatment with EFNL inhibited MNU-induced mammary tumor progression. EFNL treatment was also highly effective in reducing mammary tumor burden and in suppressing mammary tumor progression even after the cessation of treatment. Further, we found that EFNL treatment effectively upregulated proapoptotic genes and proteins such as p53, B cell lymphoma-2 protein (Bcl-2)-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (PTEN), and c-Jun N-terminal kinase (JNK). In contrast, EFNL treatment caused downregulation of anti-apoptotic (Bcl-2), angiogenic proteins (angiopoietin and vascular endothelial growth factor A [VEGF-A]), cell cycle regulatory proteins (cyclin D1, cyclin-dependent kinase 2 [Cdk2], and Cdk4), and pro-survival signals such as NF?B, mitogen-activated protein kinase 1 (MAPK1). The data obtained in this study demonstrate that EFNL exert a potent anticancer effect against mammary tumorigenesis by altering key signaling pathways. PMID:24146019

  17. Malignant mammary tumor in female dogs: environmental contaminants.

    Science.gov (United States)

    Andrade, Fábio He; Figueiroa, Fernanda C; Bersano, Paulo Ro; Bissacot, Denise Z; Rocha, Noeme S

    2010-01-01

    Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adjacent adipose tissue of canine mammary tumor. High Precision Liquid Chromatography - HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in nine female dogs, without predilection for breed or age. After surgery, masses were carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected to detect of environmental contaminants. The identified pyrethroids were allethrin, cyhalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 33.3%. Histopathology demonstrated six female dogs (66.7%) as having complex carcinoma and three (33.3%) with simple carcinoma. From these tumors, seven (77.8%) presented aggressiveness degree III and two (22.2%) degree I. Five tumors were positive for estrogen receptors in immunohistochemical analysis. The contamination level was observed in more aggressive tumors. This was the first report in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis. Hence, the dog may be used as a sentinel animal for human breast cancer, since human beings share the same environment and basically have the same eating habits. PMID:20587072

  18. Malignant mammary tumor in female dogs: environmental contaminants

    Directory of Open Access Journals (Sweden)

    Bissacot Denise Z

    2010-06-01

    Full Text Available Abstract Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adjacent adipose tissue of canine mammary tumor. High Precision Liquid Chromatography - HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in nine female dogs, without predilection for breed or age. After surgery, masses were carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected to detect of environmental contaminants. The identified pyrethroids were allethrin, cyhalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 33.3%. Histopathology demonstrated six female dogs (66.7% as having complex carcinoma and three (33.3% with simple carcinoma. From these tumors, seven (77.8% presented aggressiveness degree III and two (22.2% degree I. Five tumors were positive for estrogen receptors in immunohistochemical analysis. The contamination level was observed in more aggressive tumors. This was the first report in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis. Hence, the dog may be used as a sentinel animal for human breast cancer, since human beings share the same environment and basically have the same eating habits.

  19. Mammary gland tumors in irradiated and untreated guinea pigs

    International Nuclear Information System (INIS)

    This is a report of mammary gland tumors from 62 guinea pigs. The tumors arose in the terminal ductal-lobular units as either lobular acinar carcinoma or cystadenocarcinoma or as papillary carcinomas within large ducts near the mammilla. About half the number of the males had terminal ductal-lobular carcinomas and all but 2 of the papillary duct carcinomas also arose in males. Large tumors frequently exhibited squamous, chondromatous, osseous, fatty and myoepitheliomatous types of tissues. In 2 irradiated males and 1 female the tumors metastasized. Whole-body irradiation did not produce significant changes in the number or sex distribution or in the morphology of mammary gland tumors in inbred or outbred guinea pigs. All females had cystic ovaries without increase in granulosa cells, 24 (66.6%) had uterine tumors and 13 (34.2%) had adrenal gland tumors; all males had atrophic testes, 5 (16.5%) had testicular and 6 (22.2%) had adrenal gland tumors

  20. Matrix metalloproteinases and their inhibitors in canine mammary tumors

    OpenAIRE

    Bradaschia Alice; Aricò Arianna; Garbisa Spiridione; Granato Anna; Zancanella Vanessa; Lopparelli Rosa; Castagnaro Massimo; Vascellari Marta; Morello Emanuela; Giantin Mery; Aresu Luca; Mutinelli Franco; Dacasto Mauro

    2011-01-01

    Abstract Background Malignant canine mammary tumors represent 50% of all neoplasms in female dogs. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression, and they are also associated with the reactive stroma, which provides structural and vascular support for tumor growth. Results MMP-2, MMP-9 and MT1-MMP were expressed at both the mRNA and protein levels in tumor samples. MMP-2 and MMP-9 immunohistochemical reacti...

  1. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ? CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ? The pro-angiogenic effects of CYP4Z1 have been studied in vitro and in vivo. ? CYP4Z1 regulates expression and production of VEGF-A and TIMP-2. ? CYP4Z1-induced angiogenesis is associated with PI3K and ERK1/2 activation. ? CYP4Z1 may be an attractive target for anti-cancer therapy.

  2. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    International Nuclear Information System (INIS)

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ? CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ? The pro-angiogenic effects of CYP4Z1 have been studied in vitro and in vivo. ? CYP4Z1 regulates expression and production of VEGF-A and TIMP-2. ? CYP4Z1-induced angiogenesis is associated with PI3K and ERK1/2 activation. ? CYP4Z1 may be an attractive target for anti-cancer therapy.

  3. Collagen density promotes mammary tumor initiation and progression

    Directory of Open Access Journals (Sweden)

    Knittel Justin G

    2008-04-01

    Full Text Available Abstract Background Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. Methods To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Results Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p p Conclusion This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

  4. Prognostic value of vascular endothelial growth factor and hypoxia-inducible factor 1? in canine malignant mammary tumors.

    Science.gov (United States)

    Moschetta, Marina Gobbe; Maschio, Larissa Bazela; Jardim-Perassi, Bruna Victorasso; Gelaleti, Gabriela Bottaro; Lopes, Juliana Ramos; Leonel, Camila; Gonçalves, Naiane Do Nascimento; Ferreira, Lívia Carvalho; Martins, Gustavo Rodrigues; Borin, Thaiz Ferraz; Zuccari, Debora Aparecida Pires De Campos

    2015-05-01

    Mammary tumors are the most common type of tumor in dogs, with approximately half of these tumors being malignant. Hypoxia, characterized by oxygen levels below normal, is a known adverse factor to cancer treatment. The hypoxia-inducible factor 1? (HIF-1?) is a central regulator of the pathophysiological response of mammalian cells to low oxygen levels. HIF-1? activates the transcription of vascular endothelial growth factor (VEGF), which in turn promotes angiogenesis through its ability to stimulate the growth, migration and invasion of endothelial cells to form new blood vessels, contributing to tumor progression. In this study, we evaluated the serum concentration and gene expression of VEGF and HIF-1? linking them with clinicopathological parameters and survival of dogs with mammary tumors in order to infer the possible prognostic value of these factors. We collected blood and tumor fragments of 24 female dogs with malignant mammary tumors (study group) and 26 non-affected female dogs (control group) to verify the gene expression of VEGF and HIF-1? by quantitative real-time PCR (qPCR) and the serum levels by ELISA (enzyme-linked immunosorbent). The results showed high serum levels of VEGF in the study group and its correlation between abundant vascularization, lymph node involvement, metastasis, death rate and low survival (pdogs with mammary neoplasia was lower than that in the control group and higher in female dogs with tumor metastasis and history of tumor recurrence (pdogs with poor outcome, in contrast to the gene underexpression of HIF-1A. Taken together, these results suggested that VEGF is important in tumor progression and can be used as a potential prognostic marker in the clinic and may be useful in predicting tumor progression in dogs with mammary neoplasia. PMID:25779537

  5. Occurrence of mammary tumors in beagls given radium-226

    International Nuclear Information System (INIS)

    A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with 226Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given 226Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P < 0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose, but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative sure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon ? polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. 27 refs., 5 figs., 4 tabs

  6. MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model

    International Nuclear Information System (INIS)

    The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (KPS) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (PPS) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (PPS values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (PPS), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy. (orig.)

  7. Carboxymethyl chitosan represses tumor angiogenesis in vitro and in vivo.

    Science.gov (United States)

    Jiang, Zhiwen; Han, Baoqin; Li, Hui; Yang, Yan; Liu, Wanshun

    2015-09-20

    Carboxymethyl chitosan (CMCS), with potent water solubility, biocompatibility, and non-toxicity, has emerged as a promising candidate for biomedical applications. In this study, the anti-tumor angiogenesis effects of CMCS were evaluated in vitro and in vivo. Our results showed that CMCS could inhibit the 2-dimensional and 3-dimensional migration of human umbilical vein endothelial cells (HUVECs) in vitro. CMCS significantly inhibited the growth of mouse hepatocarcinoma 22 tissues and could promote tumor cell necrosis as suggested by pathological observations. The CD34 expression in H22 tumor tissue, the levels of vascular endothelial growth factor and tissue inhibitor of metalloproteinase 1 in serum was regulated by CMCS treatment. CMCS could significantly improve thymus index, spleen index, tumor necrosis factor ? and interferon ? level. In a conclusion, CMCS possessed potent anti-tumor effects by inhibiting tumor angiogenesis, stimulating immune functions. Our date provide more foundation for application of CMCS in biomedicine or biomaterials for targeted anticancer drugs delivery. PMID:26050881

  8. Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

    OpenAIRE

    Andreas Pircher; Wolfgang Hilbe; Isabel Heidegger; Joachim Drevs; André Tichelli; Michael Medinger

    2011-01-01

    Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new dr...

  9. Establishing a link between oncogenes and tumor angiogenesis.

    OpenAIRE

    Kerbel, R. S.; Viloria-petit, A.; Okada, F.; Rak, J.

    1998-01-01

    We have tried to stress that mutant oncogenes or overexpressed, nonmutated proto-oncogenes, in addition to their direct affect on promoting aberrant tumor cell proliferation (and survival), may possess a crucial indirect means of stimulating tumor cell growth through regulation of angiogenesis. This effect would never be observed in tissue culture studies of oncogene function using pure cultures of tumor cells, which probably helps explain why the pro-angiogenic function of oncogenes has not ...

  10. Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    VijayaIragavarapu-Charyulu

    2014-02-01

    Full Text Available Semaphorins, a large family of molecules involved in the axonal guidance and development of the nervous system, have been recently shown to have both angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A has been reported to have a chemotactic activity in neurogenesis, and to be an immune modulator via it binding to ?1?1integrins. Additionally, SEMA7A has been shown to promote chemotaxis of monocytes, inducing them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in the tumoral context. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4, and that peritoneal macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to peritoneal macrophages derived from normal control mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecules, such as CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2 expression. Mice implanted with SEMA7A silenced tumor cells showed decreased angiogenesis in the tumors compared to the wild type tumors. Furthermore, peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly (p< 0.01 lower levels of angiogenic proteins, such as MIP-2, CXCL1 and MMP-9, compared to macrophages from control DA-3 mammary tumors. We postulate that SEMA7A derived from mammary carcinomas may serve as a monocyte chemoattractant and skew monocytes into a pro-tumorigenic phenotype. A putative relationship between tumor-derived SEMA7A and monocytes could prove valuable in establishing new research avenues towards unraveling important tumor-host immune interactions in breast cancer patients.

  11. Comparative expression pathway analysis of human and canine mammary tumors

    OpenAIRE

    Marconato Laura; Zappulli Valentina; Mesiti Giuseppe; Viti Valentina; Palombo Fabio; Castle John; Kulkarni Amit; Loboda Andrey; Watters James; Aurisicchio Luigi; Uva Paolo; Abramo Francesca; Ciliberto Gennaro; Lahm Armin; La Monica Nicola

    2009-01-01

    Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically sig...

  12. Intravital Fluorescence Videomicroscopy to Study Tumor Angiogenesis and Microcirculation

    Directory of Open Access Journals (Sweden)

    Peter Vajkoczy

    2000-01-01

    Full Text Available Angiogenesis and microcirculation play a central role in growth and metastasis of human neoplasms, and, thus, represent a major target for novel treatment strategies. Mechanistic analysis of processes involved in tumor vascularization, however, requires sophisticated in vivo experimental models and techniques. Intravital microscopy allows direct assessment of tumor angiogenesis, microcirculation and overall perfusion. Its application to the study of tumor-induced neovascularization further provides information on molecular transport and delivery, intra- and extravascular cell-to-cell and cell-tomatrix interaction, as well as tumor oxygenation and metabolism. With the recent advances in the field of bioluminescence and fluorescent reporter genes, appropriate for in vivo imaging, the intravital fluorescent microscopic approach has to be considered a powerful tool to study microvascular, cellular and molecular mechanisms of tumor growth.

  13. Angiogenesis and immune supression: yin and yang of tumor progression?

    Directory of Open Access Journals (Sweden)

    Stanis?aw Szala

    2009-12-01

    Full Text Available Specialized variants of neoplastic cells that appear in tumors during cancer disease progression possess the ability to recruit certain kinds of hematopoietic and mesenchymal cells from the bone marrow or bloodstream. These tumor-recruited hematopoietic cells include monocytes, macrophages, granulocytes, mast and dendritic cells, as well as myeloblastic suppressor cells. Fibroblasts derived from undifferentiated mesenchymal cells are also recruited. Some of these cells (especially macrophages and fibroblasts then undergo “education-like” phenotype reprogramming under the influence of the neoplastic cell population, resulting in the appearance of tumor-associated macrophages (TAM and fibroblasts (CAF. Together with the extracellular matrix (ECM as well with the remaining types of recruited cells, they contribute to the formation of a specific tumor microenvironment. Both the cells forming the tumor microenvironment and neoplastic cells engage in the two intimately linked processes of angiogenesis and immune suppression. The network of defective blood vessels formed during tumor angiogenesis and the resulting fluctuations in blood flow lead to under-oxygenation of the surrounding neoplastic cells and have substantial impact on their metabolic profile. A number of processes triggered in these under-oxygenated neoplastic cells appear to strongly favor further tumor progression. Such processes result in lower oxygen demand, enhanced angiogenesis, and epithelial-mesenchymal transition, owing to which the neoplastic cells acquire the ability to translocate. Under-oxygenation also leads to augmented genetic instability of the neoplastic cells. The tumor environment-forming cells also have their share in the establishment of an immunosuppressive environment which enables the neoplastic cells to escape immune surveillance. By providing a sophisticated milieu for the selection of increasingly malignant neoplastic cells (i.e. with proangiogenic and immunosuppressive phenotypes, the tumor microenvironment-forming cells substantially contribute to the progression of a neoplasm. Inhibited angiogenesis thus makes an immune response, both nonspecific and specific, possible. The remarks presented here may prove helpful in devising novel anticancer strategies involving antiangiogenic in combination with immunomodulatory drugs.

  14. Survivin and related proteins in canine mammary tumors: immunohistochemical expression.

    Science.gov (United States)

    Bongiovanni, L; Romanucci, M; Malatesta, D; D'Andrea, A; Ciccarelli, A; Della Salda, L

    2015-03-01

    Survivin is reexpressed in most human breast cancers, where its expression has been associated with tumor aggressiveness, poor prognosis, and poor response to therapy. Survivin expression was evaluated in 41 malignant canine mammary tumors (CMTs) by immunohistochemistry, in relation to histological grade and stage, and correlated with that of some related molecules (?-catenin, caspase 3, heat shock proteins) to understand their possible role in canine mammary tumorigenesis. An increase in nuclear survivin expression, compared with healthy mammary glands, was observed in CMTs, where nuclear immunolabeling was related to the presence of necrosis. No statistically significant relation was found between the expression of the investigated molecules and the histological grade or stage. The present study may suggest an important involvement of survivin in CMT tumorigenesis. Its overexpression in most of the cases evaluated might suggest that targeting survivin in CMTs may be a valid anticancer therapy. PMID:24686389

  15. Evaluation of Tumor Angiogenesis by MRI Study Using Iron Nanoparticles

    Directory of Open Access Journals (Sweden)

    Mansour Ashoor

    2010-05-01

    Full Text Available Angiogenesis is the growth of new blood vessels from existing ones and it is a perquisite for the growth, invasion and metastasis of solid tumors. This complex process involves multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature and the surrounding extracellular tissue matrix. Tumors lay dormant yet viable, unable to grow beyond 2-3 mm3 in size without angiogenesis."nWith the development of novel therapies for treat-ment of several diseases, directed noninvasive imaging strategies will be critical for defining the pathophysiology of angiogenesis. Imaging modalities used to detect angiogenesis include PET, SPECT, MRI, CT, US and near-infrared optical imaging. For these modalities, methods have been developed to measure blood volume, blood flow and several other semi quantitative and quantitative kinetic hemodynamic parameters such as vascular permeability. Characteristic molecular makers of angiogenesis may be visualized with the aid of molecular imaging agents such as VEGFs or the ? vß3 integrin. "nMRI is a practical modality for assessing angiogenesis over time because it is already widely used clinically to assess tumor growth and for response evaluation. Anatomical information can be co registered with functional and molecular information within a single imaging method. Moreover, MRI does not involve ionizing radiation and the commonly used contrast agent has low toxicity. "nSuper paramagnetic iron oxides (SPIO are FDA-approved contrast agents for use in magnetic reson-ance (MR imaging. Most of the administered SPIO end up in the reticuloendotelial system via endocytosis and the iron core released from the SPIO is utilized in normal iron metabolism pathways. We utilize the paramagnetic characteristics of SPIO to improve the contrast of the image in MRI."nFor the first time we will introduce a method for evaluating angiogenesis by iron nanoparticles in clinical research and we will also assess some mathematical models of angiogenesis and will define an applicable model for using iron nanoparticles in MRI. We demonstrate that the negative contrast of nanoparticles in MRI for detecting angiogenesis has beneficial results.

  16. Comparative expression pathway analysis of human and canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Marconato Laura

    2009-03-01

    Full Text Available Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

  17. Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy

    Scientific Electronic Library Online (English)

    Carlos, Rosas; Mariana, Sinning; Arturo, Ferreira; Marcela, Fuenzalida; David, Lemus.

    Full Text Available BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx), a non-steroidal anti-inflammatory agent (NSAID) normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant t [...] o chemotherapeutical drugs used in cancer have not been described. Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR). RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM), inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF) production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs) and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.

  18. Partial Expression of Endogenous Mouse Mammary Tumor Virus in Mammary Tumors Induced in BALB/c Mice by Chemical, Hormonal, and Physical Agents

    OpenAIRE

    Butel, Janet S.; Dusing-swartz, Sandra; Socher, Susan H.; Medina, Daniel

    1981-01-01

    The possible interaction of environmental factors with the endogenous mouse mammary tumor virus (MMTV) genome in the development of mammary tumors in the low-tumor-incidence BALB/c mouse strain was examined. Tumors were induced in virgin female animals by treatment with chemical carcinogen 7,12- dimethylbenz[?]anthracene or urethan, with or without prolonged hormonal stimulation, or by X-irradiation. Concomitant hormonal stimulation resulted in increased tumor incidences compared with those ...

  19. Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop.

    OpenAIRE

    Garderen, E.; Wit, M.; Voorhout, W. F.; Rutteman, G. R.; Mol, J. A.; Nederbragt, H.; Misdorp, W.

    1997-01-01

    The role of progestins in the pathogenesis of breast cancer in women remains controversial. To advance this discussion, we report the demonstration and localization of progestin-induced biosynthesis of growth hormone (GH) in canine mammary gland tissue. Nontumorous mammary tissues and tumors, both benign and malignant, were obtained from private household dogs. Immunoreactive GH was localized in mammary epithelial cells and correlated with the presence of GH mRNA. Local synthesis of GH was al...

  20. Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice.

    Science.gov (United States)

    Yang, XiaoHe; Edgerton, Susan M; Kosanke, Stanley D; Mason, Terza L; Alvarez, Kathy M; Liu, Naxin; Chatterton, Robert T; Liu, Bolin; Wang, Qi; Kim, Aeree; Murthy, Satya; Thor, Ann D

    2003-05-15

    Exogenous and dietary estrogens have been associated with modification of breast cancer risk. Mammary cancer model systems can be used to explore interactions between specific transgenes, and hormonal and dietary factors. Transgenic mice bearing the rat wild-type erbB-2 gene were used to study the effects of short-term hormonal exposure [17beta-estradiol (E2) or tamoxifen] or a soy meal diet on mammary carcinogenesis. In mice fed a casein diet, mammary tumors developed at an earlier age after short-term E2 exposure during the early reproductive period. The median mammary tumor latency was shortest (29 weeks) for the high-dose estrogen as compared with the lowest dose of E2 treated or placebo control mice (33 and 37 weeks, respectively). The timing of short-term E2 exposure was also important, with the most significant changes observed in mice exposed to E2 between 8 and 18 weeks of age. E2 exposure was associated with the subsequent development of more aggressive tumors as determined by histologic grade, multifocal tumor development, stromal invasion, and pulmonary metastasis. In contrast, short-term tamoxifen-exposed mice generally failed to develop mammary tumors by 60 weeks of age. Mice fed a soy meal diet developed mammary tumors at a later age than casein-fed animals treated with E2 or placebo, whereas no differences were observed by diet for the tamoxifen-treated mice. Mammary tumor prevention was >80% in tamoxifen-treated mice on either diet. Novel histologic tumor types were identified, suggesting greater phenotypic diversity than described previously. Benign mammary gland morphogenesis was also significantly altered by short-term hormonal exposure or dietary factors, consistent with the modification of mammary tumor risk in specific treatment groups. Estrogenic modulation of the mammary tumor phenotype in wild-type erbB-2 transgenic mice was observed. Histologic tumor types and clinical aggressivity not reported previously in this transgenic model were noted, suggesting greater biologic heterogeneity than reported previously. In addition, dietary phytoestrogens modified mammary development and tumor latency, suggesting a need for greater stringency in dietary assignment for transgenic mouse models of mammary neoplasia. PMID:12750262

  1. Activation of the Canonical Wnt/?-Catenin Pathway in ATF3-Induced Mammary Tumors

    OpenAIRE

    Yan, Leqin; Coletta, Luis Della; Powell, K. Leslie; Shen, Jianjun; Thames, Howard; Aldaz, C Marcelo; Macleod, Michael C.

    2011-01-01

    Female transgenic mice that constitutively overexpress the transcription factor ATF3 in the basal epithelium of the mammary gland develop mammary carcinomas with high frequency, but only if allowed to mate and raise pups early in life. This transgenic mouse model system reproduces some features of human breast cancer in that about 20% of human breast tumor specimens exhibit overexpression of ATF3 in the tumor cells. The ATF3-induced mouse tumors are phenotypically similar to mammary tumors in...

  2. Matrix metalloproteinases and their inhibitors in canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Bradaschia Alice

    2011-07-01

    Full Text Available Abstract Background Malignant canine mammary tumors represent 50% of all neoplasms in female dogs. Matrix metalloproteinases (MMPs and tissue inhibitors of metalloproteinases (TIMPs are thought to be involved in tumor progression, and they are also associated with the reactive stroma, which provides structural and vascular support for tumor growth. Results MMP-2, MMP-9 and MT1-MMP were expressed at both the mRNA and protein levels in tumor samples. MMP-2 and MMP-9 immunohistochemical reactions were evident both in the epithelial tumor cells and in the stromal compartment to varying degrees; in particular, the intensity of the MMP-2 staining was stronger in the stromal fibroblasts close to epithelial tumor cells in simple carcinomas than in adenomas. These data were supported by gelatin-zymography; bands for the active form of MMP-2 were found in 94% of carcinoma samples, compared with 17% of benign tumor samples. The gene expression and immunohistochemical results for MT1-MMP were comparable to those for MMP-2. The immunoreactivity for MMP-13 and TIMP-2 was lower in carcinomas than in adenomas, confirming the mRNA data for MMP-13 and the other MMP inhibitors that were evaluated. The active form of MMP-9, but not the active form of MMP-2, was identified in the plasma of all of the tested dogs. Conclusions Our findings suggest that MMP-9, MMP-2 and MT1-MMP, which are synthesized by epithelial cancer cells and cancer-associated fibroblasts, play an important role in malignant canine mammary tumors. The reduction of MMP-13 and TIMP-2 could also be a significant step in malignant transformation. MMP-2 and MT1-MMP could be further evaluated as future biomarkers for predicting the progression and prognosis of canine mammary tumors.

  3. The Dynamics of Developmental and Tumor Angiogenesis—A Comparison

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    Yi Jin

    2012-04-01

    Full Text Available The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of vessels in tumor biology is needed to fully take advantage of such strategies. The vasculature serves the surrounding tissue in a multitude of ways that all must be taken into consideration in therapeutic manipulation. Aspects of delivery of conventional cytostatic drugs, induction of hypoxia affecting treatment by radiotherapy, changes in tumor cell metabolism, vascular leak and trafficking of leukocytes are affected by interventions on vascular function. Many tumors constitute a highly interchangeable milieu undergoing proliferation, apoptosis, and necrosis with abundance of growth factors, enzymes and metabolites. These aspects are reflected by the abnormal tortuous, leaky vascular bed with detached mural cells (pericytes. The vascular bed of tumors is known to be unstable and undergoing remodeling, but it is not until recently that this has been dynamically demonstrated at high resolution, facilitated by technical advances in intravital microscopy. In this review we discuss developmental genetic loss-of-function experiments in the light of tumor angiogenesis. We find this a valid comparison since many studies phenocopy the vasculature in development and tumors.

  4. Longitudinal Studies of Angiogenesis in Hormone-Dependent Shionogi Tumors

    Directory of Open Access Journals (Sweden)

    Trevor P. Wade

    2007-07-01

    Full Text Available Vessel size imaging was used to assess changes in the average vessel size of Shionogi tumors throughout the tumor growth cycle. Changes in R2 and R2* relaxivities caused by the injection of a superparamagnetic contrast agent (ferumoxtran-10 were measured using a 2.35-T animal magnetic resonance imaging system, and average vessel size index (VSI was calculated for each stage of tumor progression: growth, regression, and relapse. Statistical analysis using Spearman rank correlation test showed no dependence between vessel size and tumor volume at any stage of the tumor growth cycle. Paired Student's t test was used to assess the statistical significance of the differences in average vessel size for the three stages of the tumor growth cycle. The average VSI for regressing tumors (15.1 ± 6.6 wm was significantly lower than that for growing tumors (35.2 ± 25.5 ?m; P < .01. Relapsing tumors also had an average VSI (45.4 ± 41.8 ?m higher than that of regressing tumors, although the difference was not statistically significant (P = .067. This study shows that VSI imaging is a viable method for the noninvasive monitoring of angiogenesis during the progression of a Shionogi tumor from androgen dependence to androgen independence.

  5. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

    Directory of Open Access Journals (Sweden)

    Kuhnert Frank

    2011-09-01

    Full Text Available Abstract Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways. The endothelial Notch ligand Dll4 (delta-like 4 has recently emerged as a critical regulator of tumor angiogenesis and thus as a promising new therapeutic anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies. As Dll4 inhibitors are entering clinical cancer trials, this review aims to provide current perspectives on the function of the Dll4-Notch signaling axis during tumor angiogenesis and as a target for anti-angiogenic cancer therapy.

  6. Unique male mammary tumors developing in the inbred soft-furred field rats Millardia meltada.

    OpenAIRE

    Lu, J.; Aoyama, A.; Hoshino, M.; Tsuchiya, K.; Taguchi, O.; Matsuyama, M.; Kojima, A.

    1989-01-01

    Inbred lines of the soft-furred rat, Millardia meltada, were studied with special reference to spontaneous male mammary tumors. Adult males had the hyperplastic, pigmented inguinal mammary tissues and frequently developed bilateral mammary tumors. The tumors, no longer pigmented, were histologically well-differentiated adenocarcinomas associated with the myoepithelial cells and showed a variety of growth patterns depending on the stage of progression. They were transplantable to male, but not...

  7. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1

    Energy Technology Data Exchange (ETDEWEB)

    Sympson, Carolyn J; Bissell, Mina J; Werb, Zena

    1995-06-01

    An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

  8. Expression of vimentin filaments in canine malignant mammary gland tumors: A simulation of clinicopathological features of human breast cancer.

    Science.gov (United States)

    Rismanchi, Sanaz; Yadegar, Orly; Muhammadnejad, Samad; Amanpour, Saeid; Taghizadeh-Jahed, Masoud; Muhammadnejad, Ahad

    2014-09-01

    Canine malignant mammary gland tumors (CMMGTs) are the most common malignancies observed in females. Several biological similarities have been reported between CMMGTs and human breast cancer (HBC). The present study aimed to assess the correlation of vimentin filaments overexpression, as part of the process of epithelial-mesenchymal transition (EMT) and the clinicopathological characteristics in CMMGTs. The clinicopathological characteristics of 42 CMMGTs were collected. Paraffin-embedded blocks underwent immunohistochemistry staining, which was performed using vimentin (to assess the evolution of the EMT process), Ki-67 (for evaluation of tumor proliferation) and cluster of differentiation 34 (CD34) (for evaluation of angiogenesis) antibodies. The tumor stage, grade, vascular invasion, margin status, rate of expression of the vimentin filaments, microvessel density-CD34 and proliferation rate data were obtained. Finally, the association between the expression of the vimentin filaments and those parameters was resolved statistically. A significant association was shown between the overexpression of the vimentin filaments and tumor size (r=0.71, P=0.03), tumor grade (r=0.80, P=0.021), angiogenesis (r=0.57, P=0.043), proliferation coefficient (r=0.06, P=0.001) and vascular invasion (r=0.76, P=0.043). Vimentin overexpression did not statistically correlate with the tumor stage or the margin status. Similar to the findings of the present study, certain recent studies have indicated that vimentin filament expression in HBC and CMMGTs is associated with the severity of cancer. Thus, spontaneous canine mammary tumor models appear to be an appropriate animal model for breast cancer research, and the results of the present study could aid to reinforce the association. PMID:25054018

  9. Wogonin inhibits tumor angiogenesis via degradation of HIF-1? protein

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na, E-mail: luna555@163.com; Guo, Qinglong, E-mail: anticancer_drug@yahoo.com.cn

    2013-09-01

    Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1? (HIF-1?) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1? by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1? by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1?. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1? and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1?. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1? in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1? directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1? and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1?. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. • Wogonin decreases HIF-1? nuclear import and binding to DNA. • Wogonin may be a potent HIF-1? inhibitor for cancer therapeutics in the future.

  10. Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models.

    Science.gov (United States)

    Gad, Ekram; Rastetter, Lauren; Slota, Meredith; Koehnlein, Marlese; Treuting, Piper M; Dang, Yushe; Stanton, Sasha; Disis, Mary L

    2014-12-01

    Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA-DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4(+) and CD8(+) T-cells, FOXP3(+) T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p DMBA-induced tumors contained a higher percentage of FOXP3(+) CD4(+) T-cells (p < 0.01) and MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer. PMID:25395320

  11. Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy

    International Nuclear Information System (INIS)

    Introduction: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of ?-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. Methods: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for 99mTc and 9Y chelation and was further conjugated to a ?V?3 integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. Results: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P9Y treat100- and 250-?Ci 9Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. Conclusion: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth

  12. Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression

    OpenAIRE

    Mammoto, Tadanori; Jiang, Amanda; Jiang, Elisabeth; Panigrahy, Dipak; Kieran, Mark W.; Mammoto, Akiko

    2013-01-01

    Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and gliobla...

  13. Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53.

    Science.gov (United States)

    Fishler, T; Li, Y-Y; Wang, R-H; Kim, H-S; Sengupta, K; Vassilopoulos, A; Lahusen, T; Xu, X; Lee, M-H; Liu, Q; Elledge, S-J; Ried, T; Deng, C-X

    2010-07-15

    Checkpoint kinase 1 (Chk1) is a key element in the DNA-damage response pathway that is required for maintaining genomic stability. To study the potential role of Chk1 in mammary tumorigenesis, we disrupted it using a Cre/loxP system. We showed that although Chk1 heterozygosity caused abnormal development of the mammary gland, it was not sufficient to induce tumorigenesis. Simultaneous deletion of one copy of p53 failed to rescue the developmental defects; however, it synergistically induced mammary tumor formation in Chk1(+/-);MMTV-Cre animals with a median time to tumor latency of about 10 months. Chk1 deficiency caused a preponderance of abnormalities, including prolongation, multipolarity, misalignment, mitotic catastrophe and loss of spindle checkpoint, that are accompanied by reduced expression of several cell cycle regulators, including Mad2. On the other hand, we also showed that Chk1 deficiency inhibited mammary tumor formation in mice carrying a homozygous deletion of p53, uncovering a complex relationship between Chk1 and p53. Furthermore, inhibition of Chk1 with a specific inhibitor, SB-218078, or acute deletion of Chk1 using small hairpin RNA killed mammary tumor cells effectively. These data show that Chk1 is critical for maintaining genome integrity and serves as a double-edged sword for cancer: although its inhibition kills cancer cells, it also triggers tumorigenesis when favorable mutations are accumulated for cell growth. PMID:20473325

  14. Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors

    International Nuclear Information System (INIS)

    The influence of quantitative differences in dietary linoleic acid (18:2) and of the cyclooxygenase inhibitor, indomethacin (IM), on the metastasis of line 4526 mammary tumors was investigated. All mice were fed high fat (20%, w/w), semipurified diets that were prepared using different mixtures of coconut (primarily saturated) and safflower (mostly 18:2) oil and thus contained either 1, 2, 4, 8, or 12% 18:2 (w/w). The spontaneous metastasis of 4526 tumor cells from primary sites, was increased 2-4 fold in mice that were fed diets containing higher levels of 18:2 (8 and 12%). Chronic treatment of mice with a relatively low dosage of IM reduced the growth rate of primary 4526 tumors, slightly reduced metastasis in mice fed 1 and 4% 18:2, and completely inhibited the increased metastasis observed in mice fed 12% 18:2. Treatment with a higher dosage of IM reduced metastasis even further compared to controls, but did not decrease growth rate compared to the low dosage of IM. The level of 18:2 in the diet did not appear to affect the incorporation of 3H-thymidine into tumor cells of metastatic lung nodules. The effect of 18:2 may be through a modulation of arachidonic acid metabolism. This modulation, in turn, may affect particular steps in the metastatic cascade such as lodgement and survival of tumor cells

  15. The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model

    Directory of Open Access Journals (Sweden)

    Linette Castillo-Pichardo

    2014-10-01

    Full Text Available Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 ?M. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK, lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p. administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms.

  16. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis1

    OpenAIRE

    Abounader, Roger; Laterra, John

    2005-01-01

    The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conv...

  17. Role of pesticides in the induction of tumor angiogenesis.

    Science.gov (United States)

    Bharathi, Salimath P; Raj, Harsh M; Jain, Smita; Banerjee, Basu Dev; Ahmed, Tanzeel; Arora, Vinod Kumar

    2013-01-01

    Due to their estrogen-mimicking ability, pesticides are considered as prime etiological suspects of increasing tumor incidence, although a direct link is still undefined. The present study aimed to identify the effect of xenoestrogens (lindane, propoxur and endosulfan) at 20 mg/l each on tumorigenesis, by evaluating endothelial cell proliferation, H(3) thymidine incorporation, wound healing, ascites formation and secretion, shell less Chorio Allantoic Membrane (CAM) formation using in vitro, as well as in vivo, models. The genotoxic effect of xenoestrogens in terms of DNA damage was also studied. The results showed that the endothelial cell proliferation, H(3) thymidine incorporation, wound healing, CAM formation were increased following xenoestrogen exposure, but the intensity of angiogenesis was dependent on the structural homology of these xenoestrogens to endogenous estrogen. Moreover, lindane was the most potent angiogenesis stimulator followed by propoxur and Endosulfan. Further studies were undertaken to examine lindane for its possible carcinogenicity. However, no effect was observed on the integrity of DNA after exposure to these xenoestrogens. PMID:23267150

  18. Loss of Caveolin-3 Induces a Lactogenic Microenvironment that Is Protective Against Mammary Tumor Formation

    OpenAIRE

    Sotgia, Federica; Casimiro, Mathew C.; Bonuccelli, Gloria; Liu, Manran; Whitaker-menezes, Diana; Er, Ozlem; Daumer, Kristin M.; Mercier, Isabelle; Witkiewicz, Agnieszka K.; Minetti, Carlo; Capozza, Franco; Gormley, Michael; Quong, Andrew A.; Rui, Hallgeir; Frank, Philippe G.

    2009-01-01

    Here, we show that functional loss of a single gene is sufficient to confer constitutive milk protein production and protection against mammary tumor formation. Caveolin-3 (Cav-3), a muscle-specific caveolin-related gene, is highly expressed in muscle cells. We demonstrate that Cav-3 is also expressed in myoepithelial cells within the mammary gland. To determine whether genetic ablation of Cav-3 expression affects adult mammary gland development, we studied the phenotype(s) of Cav-3?/?-nu...

  19. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin

    OpenAIRE

    Evers, B.; Drost, R.; Schut, F. T.; Bruin, M.; Burg, E. D.; Derksen, P. W. B.; Holstege, H.; Liu, X.; Drunen, E.; Beverloo, H. B.; Smith, G. C. M.; Martin, N. M. B.; Lau, A.; O Connor, M. J.; Jonkers, J.

    2008-01-01

    Purpose: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin. Experimental Design: We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventi...

  20. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Rohit B. [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States); Wang, Qingde [Department of Surgery, University of Pittsburgh, PA 15261 (United States); Khillan, Jaspal S., E-mail: khillan@pitt.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States)

    2013-07-12

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29{sup hi}/CD49f{sup hi}/CD24{sup hi} markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance.

  1. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    International Nuclear Information System (INIS)

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29hi/CD49fhi/CD24hi markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance

  2. Biomarkers in tumor angiogenesis and anti-angiogenic therapy.

    Science.gov (United States)

    Pircher, Andreas; Hilbe, Wolfgang; Heidegger, Isabel; Drevs, Joachim; Tichelli, André; Medinger, Michael

    2011-01-01

    Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies. PMID:22072937

  3. Tumor angiogenesis in rabbit VX2 brain tumor: model establishment, pathologic study and preliminary imaging observation

    International Nuclear Information System (INIS)

    Objective: To establish a stable implanted model of VX2 rabbit brain tumor, and to evaluate the pathological and imaging features and tumor angiogenesis. Methods: Thirty New Zealand white rabbits were implanted with 100 ?l viable VX2 tumor cells (107/ml) through a hole 5 mm to the right of the sagittal suture and 5 mm posterior to the coronal suture bored by a dental drill. MRI was performed every 2 days after 7 days of implantation to evaluate the growth of the tumor, and perfusion CT studies were performed in different days of tumor growth. After that the animals were sacrificed on days 14, 18, 22, 26, and 30 of tumor implantation. 2% Evans blue (2 ml/kg) was given intravenously in 16 of these animals 1 hour prior to sacrifice to detect the breakdown of the blood-brain barrier (BBB). The specimens of the rabbit brains were examined pathologically and histologically. VEGF and MVD were evaluated in immunohistochemical examination. Results: Of the 22 animals included into the study, the tumor grew in 20 animals, which could be seen clearly on MR imaging. Pathologic examination showed characteristics of squamous carcinoma. VEGF was expressed in all tumors with the mean rate of positive cells of (52.51 ± 19.15)% (19.5%-92.9%). Mean MVD was (51.30 ± 14.42) pice piece/microscope (25-81 pice piece/microscope). Using Pearson's linear correlation analysis, positive correlation was found between tumor growth time and volume (r=0.791, P=0.000), between MVD and tum(r=0.791, P=0.000), between MVD and tumor growth time (r=0.875, P=0.000), and between MVD and tumor volume (r=0.901, P=0.000), respectively. Spearman's rank correlation analysis showed positive correlation between VEGF grade and blue stain of the tumor (rs=0.594, P=0.015). Conclusion: A stable model of VX2 rabbit brain tumor has been established with the method of skull drilling. The method was simple and easy to use, with a high tumor growth rate and remarkable angiogenesis. The model is helpful for the pathological and radiological study of tumor angiogenesis. (authors)

  4. Estrogen Receptor and Signal Transducer and Activator of Transcription 3 Expression in Equine Mammary Tumors.

    Science.gov (United States)

    Hughes, K; Scase, T J; Foote, A K

    2014-11-24

    Equine mammary tumors are uncommon, and relatively sparse histopathologic and molecular data exist. The present study describes the histopathologic features of 7 such tumors, which exhibited infiltrative growth, intermediate to high mitotic rates, and focally extensive necrosis. The tumors exhibited variably strong staining for vimentin and cytokeratin 14, as well as frequently weak cytoplasmic staining for pan-cytokeratin. E-cadherin expression was strong. Interestingly, a subgroup of the tumors exhibited strong nuclear staining for estrogen receptor ?. Three of 7 tumors exhibited nuclear expression of the transcription factor STAT3, suggesting that STAT3 was transcriptionally active. Rare to absent nuclear STAT3 expression was observed in carcinomas exhibiting moderate to intense staining for cytokeratin 14. This investigation confirms previous investigators' assertions that equine mammary tumors have a malignant phenotype. A subset of the equine mammary tumors exhibited estrogen receptor ? expression, suggesting that these tumors may potentially have similar molecular characteristics to their feline and canine counterparts. PMID:25421423

  5. Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA-induced rat mammary tumors

    Directory of Open Access Journals (Sweden)

    Steen Vidar M

    2007-01-01

    Full Text Available Abstract Background This study investigated the effects of hyperoxic treatment on growth, angiogenesis, apoptosis, general morphology and gene expression in DMBA-induced rat mammary tumors. Methods One group of animals was exposed to normobaric hyperoxia (1 bar, pO2 = 1.0 bar and another group was exposed to hyperbaric hyperoxia (1.5 bar, pO2 = 1.5 bar. A third group was treated with the commonly used chemotherapeutic drug 5- Fluorouracil (5-FU, whereas animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar served as controls. All treatments were performed on day 1, 4, 7 and 10 for 90 min. Tumor growth was calculated from caliper measurements. Biological effects of the treatment, was determined by assessment of vascular morphology (immunostaining for von Willebrandt factor and apoptosis (TUNEL staining. Detailed gene expression profiles were obtained and verified by quantitative rtPCR. Results Tumor growth was significantly reduced (~57–66 % after hyperoxic treatment compared to control and even more than 5-FU (~36 %. Light microscopic observations of the tumor tissue showed large empty spaces within the tissue after hyperoxic treatment, probably due to loss of glands as indicated by a strong down-regulation of glandular secretory proteins. A significant reduction in mean vascular density (30–50% was found after hyperoxic treatment. Furthermore, increased apoptosis (18–21% was found after hyperoxic treatment. Conclusion Thus, by increasing the pO2 in mammary tumor tissue using normobaric and moderate hyperbaric oxygen therapy, a significant retardation in tumor growth is achieved, by loss of glands, reduction in vascular density and enhanced cell death. Hyperbaric oxygen should therefore be further evaluated as a tumor treatment.

  6. Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression

    OpenAIRE

    Gracanin, Ana; Timmermans-sprang, Elpetra P. M.; Wolferen, Monique E.; Rao, Nagesha A. S.; Grizelj, Juraj; Vince, Silvijo; Hellmen, Eva; Mol, Jan A.

    2014-01-01

    Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt li...

  7. Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination.

    Science.gov (United States)

    Jannasch, Katharina; Wegwitz, Florian; Lenfert, Eva; Maenz, Claudia; Deppert, Wolfgang; Alves, Frauke

    2015-07-01

    In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single-dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell-like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas. PMID:25449528

  8. ?-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia

    OpenAIRE

    Suryatheja Ananthula; Parash Parajuli; Behery, Fathy A.; Alayoubi, Alaadin Y.; Sami Nazzal; Khalid El Sayed; Sylvester, Paul W.

    2014-01-01

    In response to low oxygen supply, cancer cells elevate production of HIF-1?, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of ?-tocotrienol and a semisynthetic ?-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150?µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in H...

  9. Specific activation of the cellular Harvey-ras oncogene in dimethylbenzanthracene-induced mouse mammary tumors.

    OpenAIRE

    Dandekar, S.; Sukumar, S.; Zarbl, H.; Young, L. J.; Cardiff, R. D.

    1986-01-01

    Genomic DNAs from dimethylbenzanthracene-induced BALB/c mouse mammary tumors arising from the transplantable hyperplastic outgrowth (HPO) line designated DI/UCD transformed NIH 3T3 cells upon transfection. Transforming activity was attributed to the presence of activated Harvey ras-1 oncogenes containing an A----T transversion at the middle adenosine nucleotide in codon 61. DNAs from untreated DI/UCD HPO cells and radiation-induced and spontaneous mammary tumors from the DI/UCD HPO line faile...

  10. A study on mammary gland tumors in rats born of parents irradiated before mating

    International Nuclear Information System (INIS)

    The effect of exposure of male or female rats to radiation 5 days before conception on the frequency of development of mammary tumors in their progeny is described. It was shown that mammary tumor incidence and the rate of their development increase in a population of female rats-descendants of one of parents exposed. Irradiation of would-be mothers produced a stronger blastogenic reaction in their progeny than that of fathers

  11. Identification and characterization of cancer initiating cells from BRCA1 related mammary tumors using markers for normal mammary stem cells

    Directory of Open Access Journals (Sweden)

    Athanassios Vassilopoulos, Rui-Hong Wang, Constantinos Petrovas, David Ambrozak, Richard Koup, Chu-Xia Deng

    2008-01-01

    Full Text Available It is hypothesized that cancer stem cells arise either from normal stem cells or from progenitor cells that have gained the ability to self-renew. Here we determine whether mammary cancer stem cells can be isolated by using antibodies that have been used for the isolation of normal mammary stem cells. We show that BRCA1 mutant cancer cell lines contained a subpopulation of CD24+CD29+ or CD24+CD49f+ cells that exhibited increased proliferation and colony forming ability in vitro, and enhanced tumor-forming ability in vivo. The purified CD24+CD29+ cells could differentiate and reconstitute the heterogeneity found in parental cells when plated as a monolayer. Under low-attachment conditions, we detected “tumorspheres” only in the presence of double positive cells, which maintained their ability to self-renew. Furthermore, CD24+CD29+ cells could form tubular structures reminiscent of the mammary ductal tree when grown in three-dimensional cultures, implying that these cancer cells maintain some of the characteristics of the normal stem cells. Nevertheless, they could still drive tumor formation since as low as 500 double positive cells immediately after sorting from BRCA1 mutant primary tumors were able to form tumors with the same heterogeneity found in the original tumors. These data provide evidence that breast cancer stem cells originate from normal stem cells and advance our understanding of BRCA1-associated tumorigenesis with possible implications for future cancer treatment.

  12. PI3K/PTEN/AKT Signaling Regulates Prostate Tumor Angiogenesis

    OpenAIRE

    Fang, Jing; DING, MIN; Yang, Lily; Liu, Ling-Zhi; Jiang, Bing-Hua

    2007-01-01

    PI3K pathway exerts its function through its downstream molecule AKT in regulating various cell functions including cell proliferation, cell transformation, cell apoptosis, tumor growth and angiogenesis. PTEN is an inhibitor of PI3K, and its loss or mutation is common in human prostate cancer. But the direct role and mechanism of PI3K/PTEN signaling in regulating angiogenesis and tumor growth in vivo remain to be elucidated. In this study, by using chicken chorioallantoic membrane (CAM) and i...

  13. Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer

    OpenAIRE

    Ischenko, Ivan

    2007-01-01

    Tumor angiogenesis is a process that requires migration, proliferation, and differentiation of endothelial cells. We hypothesized that decrease in pancreatic tumor growth due to inhibition of src activity is associated with the inability of src kinase to trigger a network of such signaling processes, which finally leads to endothelial cell death and dormancy of angiogenesis. The therapeutic efficacy of Src kinase inhibitor AZM475271 was tested in nude mice orthotopically xenografted with L...

  14. Canine classical seminoma: a specific malignant type with human classifications is highly correlated with tumor angiogenesis

    OpenAIRE

    Kim Jong-Hyuk; Yu Chi-Ho; Yhee Ji-Young; Im Keum-Soon; Kim Na-Hyun; Sur Jung-Hyang

    2010-01-01

    Abstract Background Human seminoma is classified as classical seminoma (SE) and spermatocytic seminoma (SS). Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD) being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then co...

  15. Different Regulation of Physiological and Tumor Angiogenesis in Zebrafish by Protein Kinase D1 (PKD1)

    OpenAIRE

    Hollenbach, Marcus; Stoll, Sandra Jasmin; Jo?rgens, Kristina; Seufferlein, Thomas; Kroll, Jens

    2013-01-01

    Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angio...

  16. The role of the Delta-like 4 Notch ligand in tumor angiogenesis

    OpenAIRE

    Djokovic, Dusan

    2011-01-01

    Clinically significant tumors induce their own vascularization using molecular mechanisms involved in the regulation of physiological angiogenesis. One of these mechanisms is mediated by Delta-like 4 (Dll4)/Notch signaling, which is known to play a fundamental role in the regulation of embryonic angiogenesis and arterial specification. Up-regulated in animal and human tumors, Dll4 represents the focus of the work presented in this thesis, which aimed to characterize its function(s) in the reg...

  17. Evaluation of melatonin treatment in primary culture of canine mammary tumors.

    Science.gov (United States)

    Lopes, Juliana Ramos; Maschio, Larissa Bazela; Jardim-Perassi, Bruna Victorasso; Moschetta, Marina Gobbe; Ferreira, Lívia Carvalho; Martins, Gustavo Rodrigues; Gelaleti, Gabriela Bottaro; De Campos Zuccari, Debora Aparecida Pires

    2015-01-01

    Mammary neoplasias are the most common tumors observed in female dogs. Identification of these tumors is valuable in order to identify beneficial therapeutic agents as alternative treatments for this tumor type. Oral administration of melatonin appears to exert an oncostatic effect on mammary neoplasia and may have a possible mechanism of action through its interaction with estrogen receptors on epithelial cells. Hence, we analyzed the potential therapeutic value of melatonin in tumors that are estrogen-dependent or -independent, and established a relationship of its action with the expression of the melatonin receptors MT1 and MT2. Furthermore, we analyzed the rate of cell proliferation and apoptosis after treatment with melatonin. Cell cultures were performed using 10 canine mammary tumor fragments and were divided into estrogen receptor (ER)-positive and ER-negative tumors. The results showed that both ER-positive and ER-negative tumors had decreased cell viability and proliferation after treatment with melatonin (ptreatment was more effective in the ER-positive tumors. Analysis of the relative expression of the MT1 and MT2 genes by quantitative PCR was performed and the data were compared with the expression of ER in 24 canine mammary tumors and the cellular response to melatonin in 10 samples. MT1 was overexpressed in ER-positive tumors (ptreatment in ER-positive tumors showed an efficient oncostatic effect by inhibiting cell viability and proliferation and inducing apoptosis. These results suggest that melatonin decreased neoplastic mammary cell proliferation and viability and induced apoptosis, with greater efficacy in ER-positive tumors that have a high expression of melatonin receptor MT1. This is a strong evidence for the use of melatonin as a therapeutic agent for estrogen-dependent canine mammary tumors. PMID:25384569

  18. Mouse Mammary Tumor Virus c-rel Transgenic Mice Develop Mammary Tumors

    OpenAIRE

    Romieu-mourez, Raphae?lle; Kim, Dong W.; Min Shin, Sang; Demicco, Elizabeth G.; Landesman-bollag, Esther; Seldin, David C.; Cardiff, Robert D.; Sonenshein, Gail E.

    2003-01-01

    Amplification, overexpression, or rearrangement of the c-rel gene, encoding the c-Rel NF-?B subunit, has been reported in solid and hematopoietic malignancies. For example, many primary human breast cancer tissue samples express high levels of nuclear c-Rel. While the Rev-T oncogene v-rel causes tumors in birds, the ability of c-Rel to transform in vivo has not been demonstrated. To directly test the role of c-Rel in breast tumorigenesis, mice were generated in which overexpression of mouse ...

  19. Two regions of the mouse mammary tumor virus long terminal repeat regulate the activity of its promoter in mammary cell lines.

    OpenAIRE

    Lefebvre, P.; Berard, D S; Cordingley, M G; Hager, G L

    1991-01-01

    In vivo expression of the mouse mammary tumor virus (MMTV) is restricted to a few organs, with the highest rate of transcription found in the mammary gland. Using a series of mammary and nonmammary murine cell lines, we have identified two regulatory elements, located upstream of the hormone responsive element, that specifically regulate the MMTV promoter. The first element displays an enhancerlike activity and is coincident with the binding of a nuclear factor (designated MP4; position -1078...

  20. Transgenic Mice Expressing a Dominant-Negative Mutant Type II Transforming Growth Factor-? Receptor Exhibit Impaired Mammary Development and Enhanced Mammary Tumor Formation

    OpenAIRE

    Gorska, Agnieszka E.; Jensen, Roy A.; Shyr, Yu; Aakre, Mary E.; Bhowmick, Neil A.; Moses, Harold L.

    2003-01-01

    We have previously shown that expression of a dominant-negative type II transforming growth factor-? receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carc...

  1. Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype

    Directory of Open Access Journals (Sweden)

    Li Yi

    2004-06-01

    Full Text Available Abstract Background MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to Wnt1-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase. Methods cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53-/-, MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype. Results We found activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu mutations were found in these tumors, which were phenotypically similar to those arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene. Conclusions Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.

  2. MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF

    OpenAIRE

    Zou, Chao; Xu, Qing; Mao, Feng; Li, Dan; Bian, Chuanxiu; Liu, Ling-Zhi; Jiang, Yue; Chen, Xiaona; Qi, Yanting; Zhang, XiaoLong; Wang, Xuejing; SUN, QIANG; Kung, Hsiang-Fu; Lin, Marie C; Dress, Andreas

    2012-01-01

    MiR-145 is known as a tumor suppressor in numerous human cancers. However, its role in tumor angiogenesis remains poorly defined. In this study, we found that miR-145 was significantly downregulated in breast cancer tissues by using 106 cases of normal and cancer tissues as well as in breast cancer cells. MiR-145 exhibited inhibitory role in tumor angiogenesis, cell growth and invasion and tumor growth through the post-transcriptional regulation of the novel targets N-RAS and VEGF-A. In addit...

  3. Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.

    Science.gov (United States)

    Holopainen, Tanja; López-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari

    2012-07-15

    Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth. PMID:22593188

  4. Sonodynamic therapy inhibits angiogenesis and tumor growth in a xenograft mouse model.

    Science.gov (United States)

    Gao, Zhongxiuzi; Zheng, Jinhua; Yang, Bin; Wang, Zhu; Fan, Haixia; Lv, Yanhong; Li, Haixia; Jia, Limin; Cao, Wenwu

    2013-07-10

    Studies of sonodynamic therapy (SDT) have mainly focused on its direct cytotoxic effect on tumor cells. Its effects on the tumor microenvironment, especially angiogenesis, remain unknown. In this study, we found that SDT significantly inhibited endothelial cell proliferation, migration, invasion, and tube formation. Furthermore, in a tumor xenograft mouse model, SDT was found to remarkably suppress tumor growth, intratumoral vascularity, and expression of vascular endothelial growth factor in tumor cells. An ultrastructural study showed damage and disruption of tumor microvasculature after STD. Our results indicate that SDT inhibits neovascularization in tumor, which is partially responsible for the anti-tumor effect of SDT. PMID:23402818

  5. Modulation of prostaglandin biosynthesis in murine mammary adenocarcinoma tumor cells

    International Nuclear Information System (INIS)

    In efforts to exploit the differential oxygen levels within the subcompartments of solid neoplasms, this project has focused on modulating prostaglandin (PG) biosynthesis under aerobic and hypoxic conditions. Mammary adenocarcinoma tumor cells (Line 4526), either intact or sonicated, were incubated with either 2.0 uM 14C-arachidonic acid (AA) or 20.0 uM 14C-PGH2, respectively. Following metabolism, products were extracted, separated by thin layer chromatography and analyzed by radiochromatographic scan. PGE2 was predominantly formed with minimal amounts of PGF2a or PGD2. Indomethacin and ibuprofen inhibited the PGE2 formation from AA with an IC50 value of 6.3 x 10-8 and 9.6 x 10-5M, respectively. Suspended cells in glass vials were made hypoxic by flushing with N2 for varying time intervals to study AA metabolism. A time-dependent inhibition of PG biosynthesis was observed under hypoxia, and by 30 min, the PGE2 synthesis was reduced by 50% which was further inhibited by indomethacin. Misonidazole, a 2-nitroimidazole analogue, partially reversed the inhibition of PGE2 synthesis under hypoxia by 49% at 100 uM. However, misonidazole did not affect PG biosynthesis under aerobic conditions. The stimulation of PGE2 biosynthesis by misonidazole under hypoxia was blocked by indomethacin, suggesting that misonidazole can not cin, suggesting that misonidazole can not act independently of the cyclooxygenase

  6. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    Science.gov (United States)

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGF?1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGF?1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures. PMID:25747469

  7. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.

    Science.gov (United States)

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H; Blakely, Eleanor A; Bissell, Mina J; Barcellos-Hoff, Mary Helen; Snijders, Antoine M; Mao, Jian-Hua

    2015-01-01

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGF?1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGF?1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures. PMID:25747469

  8. Synthetic progestins differentially promote or prevent DMBA-induced mammary tumors in Sprague-Dawley rats

    OpenAIRE

    Benakanakere, Indira; Besch-williford, Cynthia; Carroll, Candace E.; Hyder, Salman M.

    2010-01-01

    Recent clinical trials demonstrate that combined oral dosing with estrogen and progestin increases the incidence of breast cancer in post-menopausal women. Similarly, in a rat model system of mammary carcinogenesis, the synthetic progestin medroxyprogesterone acetate (MPA) decreases latency and increases incidence of DMBA-induced mammary tumors [Clin Can Res (2006) 12:4062]. The goal of this study was to compare the effects of four clinically-relevant progestins, MPA, norgestrel (N-EL), noret...

  9. An approach to malignant mammary phyllodes tumors detection

    Directory of Open Access Journals (Sweden)

    Ili? Ivan

    2009-01-01

    Full Text Available Background/Aim. Mammary phyllodes tumors (MPT are uncommon fibroepithelial (biphasic neoplasms whose clinical behavior is difficult to predict on the basis of histological criteria only. They are divided into benign, borderline malignant and malignant groups. Sometimes it appears difficult to distinguish these tumors from other types of soft tissue sarcomas. Because of the relatively scant data on the role of biological markers in MPT histogenesis, we have decided to undertake the following study, trying to shed more light on the issue by investigating the following elements that make up MPT: their histological patterns, biological behavior, enzymohistochemical, histochemical and immunohistochemical characteristics (ICH together with the mast cell analysis. Methods. We examined the biopsy material of 35 MPT in our laboratory. Enzymohistochemistry was performed on frozen sections (method of Crowford, Nachlas and Seligman. The used methods were classical hematoxylin-eosin (H&E; histochemical Massontrichrome, Alcian-blue, Periodic acid Schiff and immunohistochemical LSAB2 method (DacoCytomation. Ki-67, ckit, vimentin, estrogen receptor (ER, progesterone receptor (PR and Her-2 oncoprotein immunohistochemistry was performed on all tumors. Results. The patients were ranged per age from 30-62 years (mean 43.3 years, median 39 years. A total of 35 cases of MPT were included: 20 benign (57%, 6 borderline malignant (17% and 9 malignant (26%. Twenty-two patients (62.8 % underwent segmental mastectomy, while 13 (37.2% had total mastectomies. Twenty-eight patients had negative surgical margins at original resection. The mean size of malignant MPT (7.8 cm was larger than that of benign MPT (4.5 cm. Significant features of the malignant MPT were: stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour and heterologous stromal elements. Benign MPT showed strong enzymohistochemical Leucine Amino Peptidase (LAP activity in both epithelial and stromal components while it was weak or absent in the epithelial parts of the malignant tumors. Acid mucopolysacharides were present in the stromal component of all types of these tumors. Benign MPT had a lower Ki-67 than did borderline malignant MPT (4 versus 28. Malignant MPT had a greater than 8-fold higher Ki-67 activity than did benign tumors (35 versus 4. Intracytoplasmatic c-kit expression was associated with a pathological diagnosis of malignant MPT, correlating with increasing grade (p < 0.05. In hypercellular stroma of borderline malignant and especially malignant forms of MPT, high activity of ER in mast cells was confirmed. Oncoprotein Her-2 activity, mostly in epithelial components, correlated with the degree of malignant progression of MPT (p < 0.05. Conclusion. Besides the well-known malignant features additional parameters have been found to be high Ki-67 and ckit stromal expressions, and weak LAP activity in the epithelial part of malignant MPT, as well as mast cells with a high expression of ER.

  10. Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis

    OpenAIRE

    Arumugam, Arunkumar; Agullo, Pamela; Boopalan, Thiyagarajan; Nandy, Sushmita; Lopez, Rebecca; Gutierrez, Christina; Narayan, Mahesh; Rajkumar, Lakshmanaswamy

    2013-01-01

    Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in ra...

  11. Prognostic factors in canine mammary tumors: a multivariate study of 202 consecutive cases.

    Science.gov (United States)

    Hellmén, E; Bergström, R; Holmberg, L; Spångberg, I B; Hansson, K; Lindgren, A

    1993-01-01

    The prognostic variables of 223 consecutively sampled spontaneous mammary tumors from female dogs were studied. These variables included flow cytometric DNA analysis and cell proliferation measured as cells in S-phase rate evaluated from DNA histograms. The dogs were surgically treated, in most cases with unilateral mastectomy (all mammary glands), and 202 of the 223 dogs were studied temporally following surgery. Univariate analysis with correction for age indicated that the variables of lymph node metastasis, elevated S-phase rate, presence of a sarcoma, DNA aneuploidy, and ulceration and infiltrative growth into underlying tissue had a statistically significant negative influence on the survival rates of dogs with a diagnosed malignant tumor. Similar results were obtained from tests on all dogs, but tumor size and its relative hazard increased with increasing size of the tumors, regardless of whether total or disease-specific mortality was considered. Using multivariate-analysis conducted Cox's proportional hazards model, elevated S-phase rate, increased age, and presence of a sarcoma remained statistically significant risk factors. The prognostic value of DNA ploidy and lymph node status varied depending on choice of end point. The study of tumor growth pattern and tumor size provided no prognostic information in the multivariate analysis. Flow cytometric cell analysis, including S-phase rate and DNA ploidy, is of value in predicting the prognosis of canine mammary tumors and can be used as a new prognostic tool to improve the preoperative diagnostics of canine mammary tumors. PMID:8442324

  12. Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue.

    Science.gov (United States)

    Qin, Wenyi; Zhang, Ke; Clarke, Kaitlin; Weiland, Timothy; Sauter, Edward R

    2014-01-01

    We reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. We investigated the effects of resveratrol on DNMT and miRNA expression in normal and tumor mammary tissue in a rodent model of estrogen dependent mammary carcinoma. Eighty-nine female ACI rats received estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 wk of treatment, animals were sacrificed and mammary glands harvested. Matched tumor/normal tissues were available from 36 rats. DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (P = .04) and hi (P = .007) resveratrol and Aza treatment. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204, and -489 >twofold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, -204, and -489 in normal and/or tumor tissue. Treatment with resveratrol differentially influences tumor vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation. PMID:24447120

  13. Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

    DEFF Research Database (Denmark)

    Gordon, Ryan R; Hunter, Kent W

    2008-01-01

    High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F2 mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F2 mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL × diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations Udgivelsesdato: March

  14. Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis

    OpenAIRE

    Streit, Michael; Riccardi, Lucia; Velasco, Paula; Brown, Lawrence F.; Hawighorst, Thomas; Bornstein, Paul; Detmar, Michael

    1999-01-01

    Recent evidence suggests a potential role for thrombospondin-2 (TSP-2), a matricellular glycoprotein, in the regulation of primary angiogenesis. To directly examine the biological effect of TSP-2 expression on tumor growth and angiogenesis, human A431 squamous cell carcinoma cells, which do not express TSP-2, were stably transfected with a murine TSP-2 expression vector or with vector alone. A431 cells expressing TSP-2 did not show an altered growth rate, colony-forming ability, or susceptibi...

  15. The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth

    OpenAIRE

    Thulin, A?sa

    2009-01-01

    Histidine-rich glycoprotein (HRG) is a heparin-binding plasma protein modulating immune, hemostatic and vascular functions. I have studied the antiangiogenic functions of HRG in vitro and in vivo in order to understand the molecular mechanisms of action of HRG as an angiogenesis inhibitor. Angiogenesis is the formation of new blood vessels from the pre-existing vasculature. It is a central rate-limiting step of tumor development and thus a possible target for cancer therapeutics. Previous stu...

  16. DNA flow cytometry of canine mammary tumors: comparative aspects with human breast tumors Citometria de fluxo de DNA em tumores mamários da cadela: aspectos comparativos com tumores mamários humano

    OpenAIRE

    Cassali, G. D.; Salvador, A.; Freitas, C.; Dutra, A. P.; Schmitt, F. C.

    2007-01-01

    Flow cytometric analysis of DNA content was performed on 28 samples of canine mammary tumors. Nine of them were benign and 19 were malignant. All benign tumors and 11 malignant tumors (57.9%) were diploid (P

  17. Stanniocalcin-1 promotes tumor angiogenesis through up-regulation of VEGF in gastric cancer cells

    Directory of Open Access Journals (Sweden)

    Yu Li-ke

    2011-06-01

    Full Text Available Abstract Background Stanniocalcin-1(STC-1 is up-regulated in several cancers including gastric cancer. Evidences suggest that STC-1 is associated with carcinogenesis and angiogenic process. However, it is unclear on the exact role for STC-1 in inducing angiogenesis and tumorigeneisis. Method BGC/STC cells (high-expression of STC-1 and BGC/shSTC cells (low- expression of STC-1 were constructed to investigate the effect of STC-1 on the xenograft tumor growth and angiogenesis in vitro and in vivo. ELISA assay was used to detect the expression of vascular endothelial growth factor (VEGF in the supernatants. Neutralizing antibody was used to inhibit VEGF expression in supernatants. The expression of phosphorylated -PKC?II, phosphorylated -ERK1/2 and phosphorylated -P38 in the BGC treated with STC-1protein was detected by western blot. Results STC-1 could promote angiogenesis in vitro and in vivo, and the angiogenesis was consistent with VEGF expression in vitro. Inhibition of VEGF expression in supernatants with neutralizing antibody markedly abolished angiogenesis induced by STC-1 in vitro. The process of STC-1-regulated VEGF expression was mediated via PKC?II and ERK1/2. Conclusions STC-1 promotes the expression of VEGF depended on the activation of PKC?II and ERK1/2 pathways. VEGF subsequently enhances tumor angiogenesis which in turn promotes the gastric tumor growth.

  18. Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1

    Directory of Open Access Journals (Sweden)

    Anver Miriam R

    2008-04-01

    Full Text Available Abstract Background Development of therapies for patients with BRCA1 mutations has been hampered by lack of readily available in vitro and in vivo models. We recently showed that transplantation of transgenic mammary tumors as cell suspensions into naïve recipients generates reproducible tumors with remarkable stability of gene expression profile. We examined the expression profiles of original and serially transplanted mammary tumors from Brca1 deficient mice, and tumor derived cell lines to validate their use for preclinical testing and studies of tumor biology. Methods Original tumors, serially transplanted and multiple cell lines derived from Brca1 mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers. Results Gene expression among Brca1 tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -Wnt1 models. Gene expression data segregated Brca1 tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT. Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44+/CD24-/low population that may correlate with human breast cancer stem cells. Conclusion Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among Brca1 tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCA1 deficiency.

  19. Immunotherapy of the rat 13762SC mammary adenocarcinoma by vaccinia virus augmentation of tumor immunity.

    Science.gov (United States)

    Archer, T P; Bretscher, P; Ziola, B

    1990-01-01

    We studied whether vaccinia virus (VV) functioned as an immunogenic carrier in augmenting anti-tumor immunity in rats bearing a syngeneic metastatic tumor. The primary tumor was induced by injecting 10(6) 13762SC mammary adenocarcinoma cells subcutaneously into the right hind footpad of Fischer 344 rats. A concomitant anti-tumor response is induced by the tumor as demonstrated by the inhibited growth of a second tumor challenge given in the contralateral footpad 3-15 days later. Attempts were made to increase the concomitant immunity by injecting tumor-bearing animals intramuscularly with irradiated, VV-infected or uninfected 13762SC cells without adjuvant. Provided the immunotherapy was done within 5 days of the tumor challenge, administration of 10(6)-10(7) irradiated, VV-infected 13762SC cells resulted in significantly slower tumor growth, or led to complete tumor regression, compared to control animals given no treatment. In contrast, tumor growth in animals given only VV or given irradiated, uninfected 13762SC cells, alone or mixed with VV, was the same as that in control animals. Kinetics of early primary tumor growth were predictive of a longer-term anti-tumor effect. Rechallenge of 13762SC tumor-cured animals with either the homologous or with a heterologous syngeneic mammary adenocarcinoma showed the animals to be specifically 13762SC tumor-resistant, since only rats challenged with the heterologous mammary adenocarcinoma developed progressive tumors. We interpret these results to mean that early immunotherapy with irradiated, VV-infected 13762SC cells enhances an on-going anti-tumor immune response sufficiently to cause rejection of the primary tumor and any metastases that have occurred. We also believe that later immunotherapy with irradiated, VV-infected cells has no effect due to tumor-induced immunosuppression becoming paramount. PMID:2225567

  20. Manipulation of cell-cell and cell-substratum interactions in mouse mammary tumor epithelial cells using broad spectrum antisera

    OpenAIRE

    1981-01-01

    Two antisera were raised in goats against material shed by two different mammary epithelial cell lines into serum-free culture medium. These antisera, when added to the medium of intact, growing mouse mammary tumor cells in the absence of complement, cause distinct and dramatic alterations in cell morphology and adhesiveness. One antiserum (anti-SFM I) causes mouse mammary tumor epithelial cells to round and detach from the substratum. Treatment with the other antiserum (anti- SFM II) does no...

  1. Modulation of prostaglandin biosynthesis in murine mammary adenocarcinoma tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Shalinsky, D.R.

    1988-01-01

    In efforts to exploit the differential oxygen levels within the subcompartments of solid neoplasms, this project has focused on modulating prostaglandin (PG) biosynthesis under aerobic and hypoxic conditions. Mammary adenocarcinoma tumor cells (Line 4526), either intact or sonicated, were incubated with either 2.0 uM {sup 14}C-arachidonic acid (AA) or 20.0 uM {sup 14}C-PGH{sub 2}, respectively. Following metabolism, products were extracted, separated by thin layer chromatography and analyzed by radiochromatographic scan. PGE{sub 2} was predominantly formed with minimal amounts of PGF{sub 2a} or PGD{sub 2}. Indomethacin and ibuprofen inhibited the PGE{sub 2} formation from AA with an IC{sub 50} value of 6.3 {times} 10{sup {minus}8} and 9.6 {times} 10{sup {minus}5}M, respectively. Suspended cells in glass vials were made hypoxic by flushing with N{sub 2} for varying time intervals to study AA metabolism. A time-dependent inhibition of PG biosynthesis was observed under hypoxia, and by 30 min, the PGE{sub 2} synthesis was reduced by 50% which was further inhibited by indomethacin. Misonidazole, a 2-nitroimidazole analogue, partially reversed the inhibition of PGE{sub 2} synthesis under hypoxia by 49% at 100 uM. However, misonidazole did not affect PG biosynthesis under aerobic conditions. The stimulation of PGE{sub 2} biosynthesis by misonidazole under hypoxia was blocked by indomethacin, suggesting that misonidazole can not act independently of the cyclooxygenase.

  2. Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer.

    Science.gov (United States)

    Mao, Guangmei; Liu, Yan; Fang, Xi; Liu, Yahan; Fang, Li; Lin, Lianjun; Liu, Xinmin; Wang, Nanping

    2015-07-01

    Angiogenesis, a crucial step in tumor growth and metastasis, is regulated by various pro- or anti-angiogenic factors. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, roles of tumor-derived microRNAs in regulating tumor vascularization remain to be elucidated. In this study, we found that delivery of miR-494 into human vascular endothelial cells (ECs) enhanced the EC migration and promoted angiogenesis. The angiogenic effect of miR-494 was mediated by the targeting of PTEN and the subsequent activation of Akt/eNOS pathway. Importantly, co-culture experiments demonstrated that a lung cancer cell line, A549, secreted and delivered miR-494 into ECs via a microvesicle-mediated route. In addition, we found that the expression of miR-494 was induced in the tumor cells in response to hypoxia, likely via a HIF-1?-mediated mechanism. Furthermore, a specific miR-494 antagomiR effectively inhibited angiogenesis and attenuated the growth of tumor xenografts in nude mice. Taken together, these results demonstrated that miR-494 is a novel tumor-derived paracrine signal to promote angiogenesis and tumor growth under hypoxic condition. PMID:26040900

  3. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells.

    Science.gov (United States)

    Kim, Jae-Won; Jung, Seok-Yun; Kwon, Yi-Hong; Lee, Jun-Hee; Lee, You Mie; Lee, Boo-Yong; Kwon, Sang-Mo

    2012-05-01

    Accumulating evidence suggests that Ginsenoside Rg3 appears to inhibit tumor growth including Lewis lung carcinoma, intestinal adenocarcinomas or B16 melanoma by inhibiting cell proliferation, tumor cell invasion and metastasis. Endothelial progenitor cells (EPCs) appear to play a key role in the growth of early tumors by intervening with the angiogenic switch promoting tumor neovessel formation by producing angiogenic cytokines during tumor progression. This paper reports a novel mechanism of Ginsenoside Rg3, a candidate anticancer bio-molecule, on tumor angiogenesis by inhibiting the multiple bioactivities of EPCs. When Ginsenoside Rg3 was applied to the ex vivo cultured outgrowth ECs, a type of EPCs, it inhibited the cell proliferation, cell migration and tubular formation of EPCs. Importantly, Ginsenoside Rg3 attenuated the phosphorylation cascade of the VEGF dependent p38/ERK signaling in vitro. The xenograft tumor model clearly showed that Ginsenoside Rg3 suppresses tumor growth and tumor angiogenesis by inhibiting the mobilization of EPCs from the bone marrow microenvironment to the peripheral circulation and modulates VEGF-dependent tumor angiogenesis. In conclusion, this study provides a potential therapeutic molecule, Ginsenoside Rg3, as an anticancer drug by inhibiting the EPC bioactivities. PMID:22406998

  4. Effects of reproduction on spontaneous development of endometrial adenocarcinomas and mammary tumors in Donryu rats.

    Science.gov (United States)

    Nagaoka, T; Takegawa, K; Takeuchi, M; Maekawa, A

    2000-04-01

    Effects of reproduction on spontaneous development of uterine endometrial adenocarcinomas and mammary tumors in Donryu rats were investigated. While the incidence of endometrial adenocarcinomas in Donryu rats was not influenced by a single reproductive experience (SRE), it showed a tendency to decrease in animals having three reproductive experiences (TRE), compared to the nulliparous case (NRE). In addition, both SRE and TRE animals showed delayed occurrence and decreased incidences and mean numbers of mammary tumors, along with reduced incidences of proliferative lesions in the pituitary gland and mucinous epithelium in the vagina. The appearance-time and incidences of persistent estrus in TRE rats were delayed and low, respectively, compared to the SRE and NRE values. The hormonal environment was altered in both groups, the prolactin level in TRE especially being decreased. These results suggest that suppression of the occurrence of endometrial adenocarcinomas and mammary tumors in rats experiencing reproduction is associated with change in the hormonal milieu. PMID:10804284

  5. Mo polyoxometalate nanoparticles inhibit tumor growth and vascular endothelial growth factor induced angiogenesis

    Science.gov (United States)

    Zheng, Wenjing; Yang, Licong; Liu, Ying; Qin, Xiuying; Zhou, Yanhui; Zhou, Yunshan; Liu, Jie

    2014-06-01

    Tumor growth depends on angiogenesis, which can furnish the oxygen and nutrients that proliferate tumor cells. Thus, blocking angiogenesis can be an effective strategy to inhibit tumor growth. In this work, three typical nanoparticles based on polyoxometalates (POMs) have been prepared; we investigated their capability as antitumor and anti-angiogenesis agents. We found that Mo POM nanoparticles, especially complex 3, inhibited the growth of human hepatocellular liver carcinoma cells (HepG2) through cellular reactive oxygen species levels’ elevation and mitochondrial membrane potential damage. Complex 3 also suppressed the proliferation, migration, and tube formation of endothelial cells in vitro and chicken chorioallantoic membrane development ex vivo. Furthermore, western blot analysis of cell signaling molecules indicated that Mo POMs blocked the vascular endothelial growth factor receptor 2-mediated ERK1/2 and AKT signaling pathways in endothelial cells. Using transmission electron microscopy, we demonstrated their cellular uptake and localization within the cytoplasm of HepG2 cells. These results indicate that, owing to the extraordinary physical and chemical properties, Mo POM nanoparticles can significantly inhibit tumor growth and angiogenesis, which makes them potential drug candidates in anticancer and anti-angiogenesis therapies.

  6. Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis

    OpenAIRE

    Tsui Paulus; Rubenstein Marvin; Guinan Patrick

    2005-01-01

    Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growt...

  7. Involvement of Matrix Metalloproteinase Activity in Hormone-Induced Mammary Tumor Regression

    OpenAIRE

    Simian, Marina; Molinolo, Alfredo; Lanari, Claudia

    2006-01-01

    Proteolytic activity and remodeling of the extracellular matrix are important players in tumor progression. However, to date the role of the extracellular matrix in tumor regression remains unresolved. To address this, we used a progesterone-dependent in vivo mouse mammary tumor line, C4-HD, which regresses in response to hormone therapy. Within the first 72 hours of treatment, massive apoptosis was accompanied by changes in the staining patterns of laminin and collagens I, III, and IV. We th...

  8. Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice

    OpenAIRE

    Shan, Dandan; Chen, Lin; Njardarson, Jon T.; Gaul, Christoph; Ma, Xiaojing; Danishefsky, Samuel J.; Huang, Xin-yun

    2005-01-01

    Tumor metastasis is the most common cause of death in cancer patients. Here, we show that two, fully synthetic migrastatin analogues, core macroketone and core macrolactam, are potent inhibitors of metastasis in a murine breast tumor model. Administration of these readily accessible compounds nearly completely inhibits lung metastasis of highly metastatic mammary carcinoma cells. Treatment of tumor cells with core macroketone and core macrolactam blocks Rac activation, lamellipodia formation,...

  9. Alterations of a mouse mammary tumor virus glycoprotein with interferon treatment.

    OpenAIRE

    Yagi, M. J.; King, N. W.; Bekesi, J. G.

    1980-01-01

    The effects of exogenous mouse interferon on the MJY-alpha mammary tumor cell line chronically infected with mouse mammary tumor virus (MMTV) were examined. Interferon at concentrations of 25 to 2,000 IU/ml in culture medium did not alter the growth rate or morphology of the cell layers. Electron microscopic examination of interferon-treated cells indicated a decrease in the numbers of A-type and budding B-type particles of MMTV. However, the levels of extracellular MMTV virions in the cultur...

  10. Radiolabeled RGD peptides as tumor angiogenesis markers: from molecular imaging to targeted therapy

    International Nuclear Information System (INIS)

    Integrin ???3 plays a significant role in tumor angiogenesis which is one of the key requirements for cancer growth. During the past two decades, a number of radiolabeled linear and cyclic RGD peptide derivatives have been evaluated as integrin ???3-targeting radiotracers for detection and prognosis of cancer by SPECT and PET imaging. However, there is a continuing need for more efficient integrin ???3 -targeted radiotracers that could be readily prepared from a kit formulation without further post-labeling purification. The present article gives a brief overview of the fundamental aspects in the design and development of ideal radiotracers for targeting tumor angiogenesis based on RGD peptides. (author)

  11. Neovascularization and tumor growth in the rabbit brain. A model for experimental studies of angiogenesis and the blood-brain barrier.

    OpenAIRE

    Zagzag, D.; Brem, S.; Robert, F.

    1988-01-01

    A model for the study of tumor angiogenesis within the rabbit brain is presented. Implantation of the VX2 carcinoma provides a reproducible tumor accompanied by angiogenesis. The authors report the sequential growth, histology, tumor neovascularization, and vascular permeability of this tumor following its intracerebral implantation. Tumor angiogenesis correlates with the rapid and logarithmic intracerebral tumor growth. The proliferation of blood vessels in the tumor and the organization of ...

  12. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K

    2004-01-28

    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  13. Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer

    Science.gov (United States)

    Miwa, Hazuki E; Koba, Wade R; Fine, Eugene J; Giricz, Orsi; Kenny, Paraic A; Stanley, Pamela

    2013-01-01

    Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the mouse mammary tumor virus (MMTV) promoter. However, the penetrance of the tumor phenotype became variable in mixed FVB/N and C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3?/?/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3?/?/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors and lung metastasis. Nevertheless, activation of extracellular signal-regulated kinase (ERK)1/2 or protein kinase B (AKT) was reduced in ?20-week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of focal adhesion kinase (FAK), protein tyrosine kinase Src, and p38 mitogen-activated protein kinase were similar to that of controls. All the eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least 10 galectin and 7 N-glycan N-acetylglucosaminyl (GlcNAc)-transferase (MGAT) genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identification of key galectins that promote mammary tumor progression in mice is not straightforward because all the eight galectin genes are expressed; and high levels of MGAT3, galectin-4, -8, -10, -13 and -14 transcripts correlate with better relapse-free survival in human breast cancer. PMID:24037315

  14. Cell proliferation and tumor formation induced by eserine, an acetylcholinesterase inhibitor, in rat mammary gland.

    Science.gov (United States)

    Calaf, G M; Parra, E; Garrido, F

    2007-01-01

    Environmental chemicals may be involved in the etiology of breast cancer. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones. Among these hormonal influences a leading role is attributed to the ovarian hormone estradiol, since breast cancer does not develop in the absence of ovaries. The rat mammary gland has special characteristics that make it an ideal organ for studying development, cell proliferation and transformation. In vivo and in vitro model systems for cell proliferation and mammary carcinogenesis have allowed morphological and biochemical analysis under different experimental conditions. The aim of this study was to examine the effect of eserine, an acetylcholinesterase inhibitor, as are the organophosphorous compounds malathion and parathion, and 17beta estradiol on cell proliferation and tumor formation that takes place in the rat mammary gland after in vivo and in vitro treatment. These studies showed that eserine and 17beta estradiol were capable of inducing carcinogenesis in the epithelium of rat mammary glands. It was found that there was a significant increase in the number of cells per duct of the 44-day-old rat mammary gland after the 10-day eserine treatment, compared to the control. A higher increase was observed in the animals treated for 10 days with eserine followed by 30-daily injections of estrogen in comparison to control animals. In 12 animals, two mammary tumors were directly developed in response to 17beta estradiol injected at 39 days of age with a latency period of 180 and 245 days, respectively. Such tumors were metastatic to the lung. These results suggest that terminal end buds are major targets related to rat mammary carcinogenesis and 17beta estradiol can be an initiator and promoter in this process. PMID:17143474

  15. Sustained Endothelial Expression of HoxA5 In Vivo Impairs Pathological Angiogenesis And Tumor Progression

    Science.gov (United States)

    Cuevas, Ileana; Layman, Hans; Coussens, Lisa; Boudreau, Nancy

    2015-01-01

    HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis. PMID:25821967

  16. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

    Directory of Open Access Journals (Sweden)

    Li Zhong-Lian

    2010-10-01

    Full Text Available Abstract Background The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ER?. Methods Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. Results In vitro study demonstrated that the ER? in BJMC3879luc2 cells was smaller (between 50 and 64 kDa than the normal-sized ER? (66 kDa and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ER? mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ER? mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. Conclusion These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ER? may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.

  17. Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice

    Directory of Open Access Journals (Sweden)

    Marshall Aaron M

    2012-01-01

    Full Text Available Abstract Background The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions. The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition. The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy. Results Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ER?-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice, exhibit appreciable ER expression. Moreover, genetic-ablation of ER?, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis. Conclusions Ron receptor overexpression is associated with ER?-positive human and murine breast tumors. In addition, loss of ER? on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ER?, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic.

  18. Immunohistochemical Study Effects of Spirulina Algae on the Induced Mammary Tumor in Rats

    International Nuclear Information System (INIS)

    This work aimed at investigating the protective effects of Spirulina platensis on the induced mammary tumor in rats by dimethylbenz(a)anthracene (DMBA) and the proliferation of the tumor cells by using immunohistochemical staining for proliferating cell nuclear antigen (PCNA). At 50 days of age, group 1 remained untreated, group 2 treated with 2% Spirulina platenesis in food, group 3 received 50 mg/kg DMBA i.p. groupe 4 received 50 mg/kg DMBA i.p and fed on 2% spirulina. Rats were killed when the largest mammary tumor reached 1-2 cm in diameter or after 6 months of animal>s age. All the tumors produced by DMBA were ductal carcinoma in 100% of group 3, but in group 4 two rats had mammary tumor. The groups 1 and 2 had no tumor and have the same histological and immunostaining features, but in group 4, 13/15 rats had no tumor except formation of some cysts and hyperplasia in epithelial cells. The conclusion of this work suggests that Spirulina platnesis could be considered as a chemotherapeutic agent that causes apoptosis to tumor cells by reducing the number of malignant cells and resists cancer formation. (author)

  19. The combination of tamoxifen and the rexinoid LG100268 prevents ER-positive and ER-negative mammary tumors in p53-null mammary gland mice.

    Science.gov (United States)

    Mazumdar, Abhijit; Medina, Daniel; Kittrell, Francis S; Zhang, Yun; Hill, Jamal L; Edwards, David E; Bissonnette, Reid P; Brown, Powel H

    2012-10-01

    In pursuit of effective therapeutic agents for the estrogen receptor (ER)-negative breast cancer, we previously showed that bexarotene reduced mammary tumor development by 75% in ErbB2 mice. To further improve the effectiveness of breast cancer prevention, we have now investigated the effects of a combinatorial therapy consisting of two cancer preventive drugs. On the basis of the hypothesis, rexinoid LG100268 plus tamoxifen would more effectively prevent the development of both ER-positive and ER-negative breast cancer. We treated p53-null mammary gland mice with tamoxifen and LG100268, individually and in combination. By 60 weeks of age, vehicle-treated mice developed tumors in 52% of transplanted mammary glands, whereas mice treated with tamoxifen and LG100268 developed tumors in only 13% of transplanted mammary glands. To further define the mechanistic effects of this combinatorial treatment, we investigated the effects of tamoxifen and LG100268 on mammary tissue biomarkers. In mammary tissue harvested before tumor development, the proliferation markers Ki67 and cyclin D1 were significantly reduced in mice treated with the combination therapy. In addition, the rexinoid target genes ABCA1 and ABCG1 were induced in both the rexinoid and combination treatment groups, whereas expression remained constant in tamoxifen group. These results show that tamoxifen-LG100268 combinatorial treatment is more effective in preventing mammary tumors than either agent alone. In addition, these studies have identified relevant tissue biomarkers that can be used to show the effect of these agents on mammary tissue. These results support the development of clinical trials of antiestrogen and rexinoid combinatorial therapy for the prevention of patients with high-risk breast cancer. PMID:22926341

  20. Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

    OpenAIRE

    Gupta, V.; Carey, J. L.; Kawakubo, H.; Muzikansky, A.; Green, J. E.; Donahoe, P. K.; Maclaughlin, D. T.; Maheswaran, S.

    2005-01-01

    Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated...

  1. Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study

    Directory of Open Access Journals (Sweden)

    Rinat Abramovitch

    2004-09-01

    Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type ?1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

  2. Mammary and other tumors as a response to radiation and multiple stresses

    International Nuclear Information System (INIS)

    Parabiosis of paired NEDH rats and subsequent irradiation of one produced multiple stresses, particularly altered hormonal milieu. Benign mammary tumors developed in 8.6% of the control pairs, 12.7% of the shielded partners, and 19.7% of the irradiated rats. Mammary cancers developed in 5% of control pairs, 14.2% of the shielded partners, and 11.9% of the irradiated rats. With increased amounts of prolactin, the rate was 50% in shielded partner, 10% in the irradiated rats. Mesenchymal sarcomas develop at the anastomosis in parabiont rats. Their incidence rate in single controls is 3.1%, in parabiont control pairs 12.5%, in pairs with one partner irradiated 16.6%, and with both irradiated 23.1%. The incidence rate in other parts was increased threefold over controls in the irradiated partners. Radiation appears to be the dominant factor in both mammary and anastomotic tumors

  3. Mammary and other tumors as a response to radiation and multiple stresses

    International Nuclear Information System (INIS)

    Parabiosis of paired NEDH rats and subsequent irradiation of one produced multiple stresses, particularly altered hormonal milieu. Benign mammary tumors developed in 8.6% of the control pairs, 12.7% of the shielded partners, and 19.7% of the irradiated rats. Mammary cancers developed in 5% of control pairs, 14.2% of the shielded partners, and 11.9% of the irradiated rats. With increased amounts of prolactin, the rate was 50% in shielded partners, 10% in the irradiated rats. Mesenchymal sarcomas develop at the anastomosis in parabiont rats. Their incidence rate in single controls is 3.1%, in parabiont control pairs 12.5%, in pairs with one partner irradiated 16.6%, and with both irradiated 23.1%. The incidence rate in other parts was increased threefold over controls in the irradiated partners. Radiation appears to be the dominant factor in both mammary and anastomotic tumors

  4. Lysyl Oxidase Plays a Critical Role in Endothelial Cell Stimulation to Drive Tumor Angiogenesis

    DEFF Research Database (Denmark)

    Baker, Ann-Marie; Bird, Demelza

    2013-01-01

    Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor ß (PDGFRß) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRß, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. Cancer Res; 73(2); 1-12. ©2012 AACR.

  5. SK-216, an inhibitor of plasminogen activator inhibitor-1, limits tumor progression and angiogenesis.

    Science.gov (United States)

    Masuda, Takeshi; Hattori, Noboru; Senoo, Tadashi; Akita, Shin; Ishikawa, Nobuhisa; Fujitaka, Kazunori; Haruta, Yoshinori; Murai, Hiroshi; Kohno, Nobuoki

    2013-11-01

    Plasminogen activator inhibitor-1 (PAI-1), which can be produced by host and tumor cells in the tumor microenvironment, is intimately involved in tumor progression. In the present study, to pursue the possibility that PAI-1 could be a therapeutic target in the management of malignancy, SK-216, a specific PAI-1 inhibitor, was orally administered to wild-type mice that were subcutaneously implanted or intravenously injected with either PAI-1-secreting Lewis lung carcinoma (LLC) or PAI-1-nonsecreting B16 melanoma cells. The systemic administration of SK-216 was found to reduce the size of subcutaneous tumors and the extent of metastases, regardless of PAI-1 secretion levels from the tumor cells. SK-216 also reduced the extent of angiogenesis in the tumors and inhibited VEGF-induced migration and tube formation by human umbilical vein endothelial cells in vitro. Then, to determine whether host or tumor PAI-1 was more crucial in tumor progression and angiogenesis, PAI-1-deficient or wild-type mice were subcutaneously implanted or intravenously injected with LLC or PAI-1 knockdown LLC cells. Tumor progression was shown to be controlled by the presence of host PAI-1 and not affected by the PAI-1 levels in the tumors. Similarly, host PAI-1 played a more crucial role in tumor angiogenesis than did tumor PAI-1. These observations suggest that regardless of the PAI-1 levels in the tumor, the systemic administration of SK-216 exerts an antitumor effect through its interaction with host PAI-1. This antitumor effect might be mediated by the antiangiogenic properties of SK-216. PMID:23990114

  6. Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis.

    Science.gov (United States)

    Strijkers, Gustav J; Kluza, Ewelina; Van Tilborg, Geralda A F; van der Schaft, Daisy W J; Griffioen, Arjan W; Mulder, Willem J M; Nicolay, Klaas

    2010-06-01

    Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy. PMID:20390447

  7. Obesity decreases serum selenium levels in DMBA-induced mammary tumor using Obese Zucker Rat Model

    Science.gov (United States)

    Recently, we reported that obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. Several studies suggest that lower serum selenium may play an important role in increasing the risk of several types of cancers (e.g, colon, breast and prostate canc...

  8. Celecoxib exerts antitumor effects in canine mammary tumor cells via COX?2?independent mechanisms.

    Science.gov (United States)

    Tamura, Dai; Saito, Teruyoshi; Murata, Kanae; Kawashima, Masafumi; Asano, Ryuji

    2015-03-01

    Celecoxib plays antitumor roles via multiple mechanisms in a variety of human cancers. The aim of this study was to clarify the mechanism of action of celecoxib in canine mammary tumors. We examined the antitumor effects of celecoxib in AZACB canine mammary tumor cells expressing low levels of cyclooxygenase?2 (COX?2) to minimize the effect of COX?2 on its activity. Our data revealed that celecoxib inhibited cell proliferation mainly via COX?2?independent mechanisms. Specifically, celecoxib decreased the proportion of cells in S phase and increased G2/M arrest, which was associated with increased expression of the cyclin?dependent kinase inhibitors (CDKIs) p21 and p27. In addition, treatment with celecoxib downregulated COX?2 expression, and induced apoptosis via both the intrinsic and extrinsic pathways. These findings suggest that celecoxib might be a useful agent for the treatment of canine mammary tumors, regardless of COX?2 expression. In the future, it might be possible to use a combination of celecoxib and other antitumor agents to treat canine mammary tumors. PMID:25571853

  9. Surgical removal of a mammary adenocarcinoma and a granulosa cell tumor in an African pygmy hedgehog

    OpenAIRE

    Wellehan, James F. X.; Southorn, Erin; Smith, Dale A.; Taylor, Michael

    2003-01-01

    A 3-year-old, female African pygmy hedgehog (Atelerix albiventris) was referred with a history of hematuria. Hyperglycemia and glucosuria were found at presentation. Mammary adenocarcinoma and a granulosa cell tumor were found and removed surgically. Glucosuria and hematuria resolved, and the hedgehog has done well for 10 mo postoperatively.

  10. Erythropoietin Promotes the Growth of Tumors Lacking Its Receptor and Decreases Survival of Tumor-Bearing Mice by Enhancing Angiogenesis

    Directory of Open Access Journals (Sweden)

    Tatsuma Okazaki

    2008-09-01

    Full Text Available Erythropoietin (Epo, a known hematopoietic growth factor, has been reported to promote tumor growth and angiogenesis in Epo receptor (EpoR–positive tumors, but its effects on EpoR-negative tumors have not been clearly shown. Here, we show that Epo accelerates the growth of EpoR-negative tumors by promoting tumor angiogenesis. Mice were inoculated with Lewis lung carcinoma cells and treated with Epo. Erythropoietin accelerated tumor growth and increased intratumoral microvessel density, although it did not accelerate Lewis lung carcinoma cell tumor proliferation in vitro. To observe the direct effect of Epo on endothelial cells, we examined human dermal microvascular endothelial cells (HMVECs that expressed EpoR. Erythropoietin induced the proliferation of HMVECs and protected them from H2O2-induced cell death. Erythropoietin activated the extracellular signal–regulated kinase signaling pathway and up-regulated the expression of the downstream antiapoptotic protein Bcl-xL in HMVECs. Moreover, in both the absence and presence of tumors, in vivo treatment of mice with Epo increased circulating endothelial progenitor cells. To investigate the role of Epo in a primary tumor model, we inoculated the chemical carcinogen methylcholanthrene (MCA subcutaneously into mice at two doses, a high or a low dose, which induced fibrosarcoma, and treated them with Epo. Erythropoietin promoted tumor growth after MCA inoculation at both doses and decreased the overall survival of the mice inoculated with the high-dose MCA. However, Epo did not increase the incidence of fibrosarcoma at either dose. Lewis lung carcinoma cells and MCA-induced fibrosarcomas did not express EpoR. These results suggest that Epo accelerates the growth of tumors that lack EpoR expression by promoting tumor angiogenesis.

  11. Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene

    OpenAIRE

    Witt-Enderby, Paula A.; Davis, Vicki L.; Foster, Warren G; King, Tracy L.; Kotlarczyk, Mary P.; J. Mark Cline; William P. Clafshenkel

    2012-01-01

    Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it wo...

  12. Exacerbated metastatic disease in a mouse mammary tumor model following latent gammaherpesvirus infection

    Directory of Open Access Journals (Sweden)

    Chauhan Vinita S

    2012-05-01

    Full Text Available Abstract Background Controversy exists as to the ability of human gammaherpesviruses to cause or exacerbate breast cancer disease in patients. The difficulty in conducting definitive human studies can be overcome by investigating developing breast cancer in a mouse model. In this study, we utilized mice latently infected with murine gammaherpesvirus 68 (HV-68 to question whether such a viral burden could exacerbate metastatic breast cancer disease using a mouse mammary tumor model. Results Mice latently infected with HV-68 had a similar primary tumor burden, but much greater metastatic disease, when compared to mock treated mice given the transplantable tumor, 4?T1. This was true for lung lesions, as well as secondary tumor masses. Increased expression of pan-cytokeratin and VEGF-A in tumors from HV-68 infected mice was consistent with increased metastatic disease in these animals. Surprisingly, no viral particles could be cultured from tumor tissues, and the presence of viral DNA or RNA transcripts could not be detected in primary or secondary tumor tissues. Conclusions Latent HV-68 infection had no significant effect on the size of primary 4?T1 mammary tumors, but exacerbated the number of metastatic lung lesions and secondary tumors when compared to mock treated mice. Increased expression of the tumor marker, pan-cytokeratin, and VEGF-A in tumors of mice harboring latent virus was consistent with an exacerbated metastatic disease. Mechanisms responsible for this exacerbation are indirect, since no virus could be detected in cancerous tissues.

  13. A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer

    OpenAIRE

    Zheng, Lixiang; Zhou, Bugao; Meng, Xianming; Zhu, Weifeng; Zuo, Airen; Wang, Xiaomin; Jiang, Runde; Yu, Shiping

    2014-01-01

    Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular str...

  14. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

    Science.gov (United States)

    Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

    2014-07-01

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3? activation, while p38? phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID:24789042

  15. Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer : Correlation with Tumor Angiogenesis

    OpenAIRE

    Cianchi, Fabio; Cortesini, Camillo; Fantappiè, Ornella; Messerini, Luca; Schiavone, Nicola; Vannacci, Alfredo; Nistri, Silvia; SARDI, IACOPO; Baroni, Gianna; Marzocca, Cosimo; Perna, Federico; Mazzanti, Roberto; Bechi, Paolo; Masini, Emanuela

    2003-01-01

    To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity...

  16. Hyperspectral imaging system to discern malignant and benign canine mammary tumors

    Science.gov (United States)

    Sahu, Amrita; McGoverin, Cushla; Pleshko, Nancy; Sorenmo, Karin; Won, Chang-Hee

    2013-05-01

    Hyperspectral imaging is an emerging technology in the field of biomedical engineering which may be used as a noninvasive modality to characterize tumors. In this paper, a hyperspectral imaging system was used to characterize canine mammary tumors of unknown histopathology (pre-surgery) and correlate these results with the post-surgical histopathology results. The system consisted of a charge coupled device (CCD) camera, a liquid crystal tunable filter in the near infrared range (650-1100 nm) and a controller. Spectral signatures of malignant and benign canine mammary tumors were extracted and analyzed. The reflectance intensities of malignant tumor spectra were generally lower than benign tumor spectra over the entire wavelength range. Previous studies have shown that cancerous tissues have a higher hemoglobin and water content, and lower lipid concentration with respect to benign tissues. The decreased reflectance intensity observed for malignant tumors is likely due to the increased microvasculature and therefore higher blood content of malignant tissue relative to benign tissue. Peaks at 700, 840, 900 and 970 nm were observed in the second derivative absorption spectra, these peaks were attributed to deoxy-hemoglobin, oxy-hemoglobin, lipid and water respectively. A `Tissue Optical Index' was developed that enhances contrast between malignant and benign canine tumors. This index is based on the ratio of the reflectance intensity values corresponding to the wavelengths associated with the four chromophores. Preliminary results from 22 canine mammary tumors showed that the sensitivity and specificity of the proposed method is 85.7% and 94.6% respectively. These results show promise in the non-invasive optical diagnosis of canine mammary cancer.

  17. Relationship between Major Histocompatibility Complex Class I Expression and Prognosis in Canine Mammary Gland Tumors

    OpenAIRE

    Tanaka, Toshiyuki; Shimada, Terumasa; Akiyoshi, Hideo; Shimizu, Junichiro; Zheng, Cao; Yijyun, Li; Mie, Keiichiro; Hayashi, Akiyoshi; Kuwamura, Mitsuru; Hoshi, Fumio; Ohashi, Fumihito

    2013-01-01

    The aim of this study was to evaluate MHC class I expression and prognosis using tumor tissues surgically removed from 9 dogs with mammary gland carcinomas and from 13 dogs with complex carcinomas. We assessed MHC class I expression and its correlation with tumor size, B2M expression, infiltration of lymphocytes, histological grade and prognosis. Hematoxylin and eosin-stained sections were histologically graded using the Elston and Ellis grading method. MHC class I expression o...

  18. Immunotherapy of radioresistant mammary tumors with early metastasis using molecular chaperone vaccines combined with ionizing radiation

    OpenAIRE

    Weng, Desheng; Song, Baizheng; Koido, Shigeo; Calderwood, Stuart K.; Gong, Jianlin

    2013-01-01

    In the present study, exposure of mammary tumor cells derived from mice transgenic for the polyomavirus middle T (PyMT) oncogene to ionizing radiation resulted in the generation of a tumor cell population that preferentially expressed cancer stem cell markers. In addition, these cells were more resistant to further radiation treatments and appeared to acquire enhanced capacity for dissemination to the lungs of mice. We therefore tested an immunotherapy approach to treatment of local and disse...

  19. Computational analysis of tumor angiogenesis patterns using a two-dimensional model.

    Science.gov (United States)

    Shim, Eun Bo; Kwon, Young-Guen; Ko, Hyung Jong

    2005-04-30

    Tumor angiogenesis was simulated using a two-dimensional computational model. The equation that governed angiogenesis comprised a tumor angiogenesis factor (TAF) conservation equation in time and space, which was solved numerically using the Galerkin finite element method. The time derivative in the equation was approximated by a forward Euler scheme. A stochastic process model was used to simulate vessel formation and vessel elongation towards a paracrine site, i.e., tumor-secreted basic fibroblast growth factor (bFGF). In this study, we assumed a two-dimensional model that represented a thin (1.0 mm) slice of the tumor. The growth of the tumor over time was modeled according to the dynamic value of bFGF secreted within the tumor. The data used for the model were based on a previously reported model of a brain tumor in which four distinct stages (multicellular spherical, first detectable lesion, diagnosis, and death of the virtual patient) were modeled. In our study, computation was not continued beyond the 'diagnosis' time point to avoid the computational complexity of analyzing numerous vascular branches. The numerical solutions revealed that no bFGF remained within the region in which vessels developed, owing to the uptake of bFGF by endothelial cells. Consequently, a sharp declining gradient of bFGF existed near the surface of the tumor. The vascular architecture developed numerous branches close to the tumor surface (the brush-border effect). Asymmetrical tumor growth was associated with a greater degree of branching at the tumor surface. PMID:15861502

  20. PET imaging of tumor angiogenesis in mice with VEGF-A targeted 86Y-CHX-A?-DTPA-bevacizumab

    OpenAIRE

    Nayak, Tapan K.; Garmestani, Kayhan; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.

    2011-01-01

    Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted VEGF-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the United States FDA for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, 86Y-CHX-A?-DTPA-bevacizumab, for potential use in PET imaging of VEGF-A tumor angiogenesis and as a surrogate marker for 90Y based radioimmunotherapy. Bevac...

  1. Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines

    OpenAIRE

    1992-01-01

    Subtractive hybridization, selecting for mRNAs expressed in normal human mammary epithelial cells (NMECs) but not in mammary tumor cell lines (TMECs), led to the cloning of the human gap junction gene connexin 26 (Cx26), identified by its sequence similarity to the rat gene. Two Cx26 transcripts derived from a single gene are expressed in NMECs but neither is expressed in a series of TMECs. Northern analysis using rat Cx probes showed that Cx43 mRNA is also expressed in the normal cells, but ...

  2. Tumor delivery of chemotherapy combined with inhibitors of angiogenesis and vascular targeting agents

    Directory of Open Access Journals (Sweden)

    MartaCesca

    2013-10-01

    Full Text Available Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most of them are used in polytherapy regimens. This review will address recent progress together with our preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways and vascular targeting agents with conventional chemotherapy and discuss the critical factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated to drug distribution and activity will be reviewed. Finally modalities to improve drug delivery and strategies for the optimization of combination therapy will be addressed.

  3. Rapid spread of mouse mammary tumor virus in cultured human breast cells

    Directory of Open Access Journals (Sweden)

    Günzburg Walter H

    2007-10-01

    Full Text Available Abstract Background The role of mouse mammary tumor virus (MMTV as a causative agent in human breast carcinogenesis has recently been the subject of renewed interest. The proposed model is based on the detection of MMTV sequences in human breast cancer but not in healthy breast tissue. One of the main drawbacks to this model, however, was that until now human cells had not been demonstrated to sustain productive MMTV infection. Results Here, we show for the first time the rapid spread of mouse mammary tumor virus, MMTV(GR, in cultured human mammary cells (Hs578T, ultimately leading to the infection of every cell in culture. The replication of the virus was monitored by quantitative PCR, quantitative RT-PCR and immunofluorescence imaging. The infected human cells expressed, upon cultivation with dexamethasone, MMTV structural proteins and released spiked B-type virions, the infectivity of which could be neutralized by anti-MMTV antibody. Replication of the virus was efficiently blocked by an inhibitor of reverse transcription, 3'-azido-3'-deoxythymidine. The human origin of the infected cells was confirmed by determining a number of integration sites hosting the provirus, which were unequivocally identified as human sequences. Conclusion Taken together, our results show that human cells can support replication of mouse mammary tumor virus.

  4. c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Dutra A.P.

    2004-01-01

    Full Text Available The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil and the Veterinary Faculty of Porto University (Portugal. c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4% of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P < 0.0001, histological grade (P = 0.0017 and mitotic count (P < 0.05. Nuclear pleomorphism also showed a positive association with MIB-1 index (P < 0.0001. These results suggest that some of the biological and morphological characteristics of the tumor are associated in canine mammary gland tumors, as also reported for human breast cancer. It was also possible to show that the immunoexpression of c-erbB-2 can be a factor in mammary carcinogenesis. This fact opens the possibility of using anti-c-erbB-2 antibodies in the treatment of canine mammary tumors.

  5. 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis

    International Nuclear Information System (INIS)

    Brain tumors are highly angiogenesis dependent. The cell adhesion receptor integrin ?v?3 is overexpressed in glioma and activated endothelial cells and plays an important role in brain tumor growth, spread and angiogenesis. Suitably labeled ?v?3-integrin antagonists may therefore be useful for imaging brain tumor associated angiogenesis. Cyclic RGD peptide c(RGDyK) was labeled with 18F via N-succinimidyl-4-[18F]fluorobenzoate through the side-chain ?-amino group of the lysine residue. The radiotracer was evaluated in vivo for its tumor targeting efficacy and pharmacokinetics in subcutaneously implanted U87MG and orthotopically implanted U251T glioblastoma nude mouse models by means of microPET, quantitative autoradiography and direct tissue sampling. The N-4-[18F]fluorobenzoyl-RGD ([18F]FB-RGD) was produced in less than 2 h with 20-25% decay-corrected yields and specific activity of 230 GBq/?mol at end of synthesis. The tracer showed very rapid blood clearance and both hepatobiliary and renal excretion. Tumor-to-muscle uptake ratio at 30 min was approximately 5 in the subcutaneous U87MG tumor model. MicroPET imaging with the orthotopic U251T brain tumor model revealed very high tumor-to-brain ratio, with virtually no uptake in the normal brain. Successful blocking of tumor uptake of [18F]FB-RGD in the presence of excess amount of c(RGDyK) revealed receptor specific c(RGDyK) revealed receptor specific activity accumulation. Hence, N-4-[18F]fluorobenzoyl labeled cyclic RGD peptide [18F]FB-RGD is a potential tracer for imaging ?v?3-integrin positive tumors in brain and other anatomic locations

  6. Cloning and expression analysis of prohibitin mRNA in canine mammary tumors.

    Science.gov (United States)

    Matsuyama, Satoshi; Nakano, Yuko; Nakamura, Mieko; Yamamoto, Ryohei; Shimada, Terumasa; Ohashi, Fumihito; Kubo, Kihei

    2015-01-01

    Prohibitin is an antiproliferative protein that is a product of a putative tumor suppressor gene. However, there is little information on prohibitins in companion animals. In this study, we cloned canine prohibitin mRNA using RT-PCR and 3'-RACE (Rapid Amplification of cDNA Ends). The sequence was well conserved compared with those of other mammals, including human. The deduced amino acid sequence translated from the open reading frame completely corresponded to the human sequence. Canine prohibitin mRNA was expressed in all normal mammary and tumor samples examined. These results suggest that this protein plays a vital role in cell growth mechanisms and may be related to the occurrence of canine mammary tumors. PMID:25312047

  7. Development of dog mammary tumor xenograft in immunosuppressed Swiss albino mice.

    Science.gov (United States)

    Rajmani, R S; Singh, Prafull Kumar; Kumar, Sanjay; Kumar, G Ravi; Sahoo, Aditya P; Santra, Lakshman; Saxena, Shikha; Singh, Lakshya Veer; Chaturvedi, Uttara; Saxena, Lovleen; Desai, G S; Gupta, Shishir Kumar; Kumar, Amit; Jadon, N S; Tiwari, Ashok K

    2014-10-01

    Development and study of dog mammary tumour xenograft in immunosuppressed Swiss Albino Mice adds a new dimension in cancer research as dog tumors have many similarities with human tumors regarding progression, histopathology, molecular mechanism, immune response and therapy. Failure of the immune system to recognize and eliminate cancer cells leads to cancer progression and the fight between immune cells and cancer cells has a great role in understanding the mechanism of cancer progression and elimination. Rejection and acceptance of tumour xenograft depends on efficiency of CD4+, CD8+ and NK cell populations. In the present investigation, dog mammary tumor xenograft in cyclosporine-A and gamma-irradiated, immunosuppressed Swiss Albino mice was developed and the immune cell status of graft accepted and rejected mice was assessed. It was observed that all the major immune cells (CD4+, CD8+ and NK cells) play an equal role in tumour rejection. PMID:25345242

  8. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo.

    Science.gov (United States)

    Bai, Xianhe; Cerimele, Francesca; Ushio-Fukai, Masuko; Waqas, Muhammad; Campbell, Paul M; Govindarajan, Baskaran; Der, Channing J; Battle, Traci; Frank, David A; Ye, Keqiang; Murad, Emma; Dubiel, Wolfgang; Soff, Gerald; Arbiser, Jack L

    2003-09-12

    Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent. PMID:12816951

  9. Wilms' tumor protein (WT1) in mammary myofibroblastoma: an immunohistochemical study.

    Science.gov (United States)

    Magro, Gaetano; Longo, Francesca; Salvatorelli, Lucia; Vecchio, Giada Maria; Parenti, Rosalba

    2014-06-01

    Wilms' tumor protein (WT1) has been immunohistochemically detected in the cytoplasm of some developing, adult normal and neoplastic human tissues, suggesting its complex regulator activity in transcriptional/translational processes. Among neoplastic tissues, WT1 has been documented in the cytoplasm of benign and malignant vascular tumors and in rhabdomyosarcoma, while there are no available studies about its expression in myofibroblastic tumors. Accordingly, we studied immunohistochemically the potential expression of WT1 in mammary myofibroblastoma (MFB), a prototypical myofibroblastic tumor. A series of 18 cases of mammary MFB, including several morphological variants (classic, fibrotic, myxoid, lipomatous, Schwannian-like, and epithelioid variants), were tested with antibodies against the N-terminal of WT1. The most striking finding was a diffuse and strong WT1 cytoplasmic immunostaining restricted to the "epithelioid cell MFB", a rare and diagnostically challenging variant. Conversely the other variants of MFB, including the classic-type, were negative or only focally positive. The present study shows that mammary epithelioid cell MFB should be added to the list of mesenchymal tumors which express WT1 in the cytoplasm of neoplastic cells. Accordingly, we suggest that the detection of WT1 cytoplasmic immunoreactivity is of complementary diagnostic value to conventional myofibroblastic markers in identifying epithelioid cell myofibroblastoma. PMID:24709316

  10. RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini? †

    OpenAIRE

    Gonzalez-suarez, Eva; Branstetter, Daniel; Armstrong, Allison; Dinh, Huyen; Blumberg, Hal; Dougall, William C.

    2006-01-01

    RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cel...

  11. Intraductally administered pegylated liposomal doxorubicin reduces mammary stem cell function in the mammary gland but in the long term, induces malignant tumors

    OpenAIRE

    Chun, Yong Soon; Yoshida, Takahiro; Mori, Tsuyoshi; Huso, David L.; Zhang, Zhe; Stearns, Vered; Perkins, Brandy; Jones, Richard J.; Sukumar, Saraswati

    2012-01-01

    Previously, we have shown that the intraductal (i.duc) administration of pegylated liposomal doxorubicin (PLD) to Her2/neu transgenic mice is associated with mammary tumor regression and prevention. Exploring the mechanism underlying the protection afforded by PLD, we studied: the effects of i.duc PLD-treatment with a subsequent pregnancy on outgrowth of tumors in Her2/neu mice; whether the i.duc PLD antitumor effect was mediated partially through changes in normal mammary stem cells (MaSCs);...

  12. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis

    International Nuclear Information System (INIS)

    Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining. Results: Celecoxib (4 and 30 ?M; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 ± 8.6% of tumor region, compared with irradiation alone (2.7 ± 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradreduced in combined celecoxib and irradiated tumors (52.5 ± 2.9 microvessels per mm2 tumor region), compared with irradiated tumors alone (65.4 ± 4.0 microvessels per mm2). Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necrosis

  13. Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis

    Directory of Open Access Journals (Sweden)

    Toshiyuki Ishiwata, Yoko Matsuda, Zenya Naito

    2011-01-01

    Full Text Available Nestin is a class VI intermediate filament protein that was originally described as a neuronal stem cell marker during central nervous system (CNS development, and is currently widely used in that capacity. Nestin is also expressed in non-neuronal immature or progenitor cells in normal tissues. Under pathological conditions, nestin is expressed in repair processes in the CNS, muscle, liver, and infarcted myocardium. Furthermore, increased nestin expression has been reported in various tumor cells, including CNS tumors, gastrointestinal stromal tumors, pancreatic cancer, prostate cancer, breast cancer, malignant melanoma, dermatofibrosarcoma protuberances, and thyroid tumors. Nestin is reported to correlate with aggressive growth, metastasis, and poor prognosis in some tumors; however, the roles of nestin in cancer cells have not been well characterized. Furthermore, nestin is more specifically expressed in proliferating small-sized tumor vessels in glioblastoma and gastric, colorectal, and prostate cancers than are other tumor vessel markers. These findings indicate that nestin may be a marker for newly synthesized tumor vessels and a therapeutic target for tumor angiogenesis. It has received a lot of attention recently as a cancer stem cell marker in various cancer cells including brain tumors, malignant rhabdoid tumors, and uterine, cervical, prostate, bladder, head and neck, ovarian, testicular, and pancreatic cancers. The purpose of this review is to clarify the roles of nestin in cancer cells and in tumor angiogenesis, and to examine the association between nestin and cancer stem cells. Nestin has the potential to serve as a molecular target for cancers with nestin-positive cancer cells and nestin-positive tumor vasculature.

  14. ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO

    Science.gov (United States)

    ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO. SE Fenton and CC Davis Reproductive Toxicology Division, NHEERL, ORD, USEPA, Durham, NC, USA Recently, we found that ATR exposure during ma...

  15. Prostaglandin I2 analog suppresses lung metastasis by recruiting pericytes in tumor angiogenesis.

    Science.gov (United States)

    Minami, Yoshinori; Sasaki, Takaaki; Bochimoto, Hiroki; Kawabe, Jun-Ichi; Endo, Satoshi; Hira, Yoshiki; Watanabe, Tsuyoshi; Okumura, Shunsuke; Hasebe, Naoyuki; Ohsaki, Yoshinobu

    2015-02-01

    Prostaglandin I2 (PGI2) agonist has been reported to reduce tumor metastasis by modifying tumor angiogenesis; however, the mechanisms of how PGI2 affects the endothelial cells or pericytes in tumor vessel maturation are still unclear. The purpose of this study was to clarify the effects of PGI2 on tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma (LLC) cells. The mice were treated continuously with beraprost sodium (BPS), a PGI2 analog, for 3 weeks and then examined for lung metastases. The number and size of lung metastases were decreased significantly by BPS treatment. In addition, scanning electron microscopy and immunohistochemistry revealed that BPS increased the number of tumor?associated pericytes and improved intratumor hypoxia. Collectively, this study suggests that BPS attenuated vascular functional maturation in metastatic tumors. PMID:25434699

  16. TROP2 expression and its correlation with tumor proliferation and angiogenesis in human gliomas.

    Science.gov (United States)

    Ning, Shanglei; Liang, Nan; Liu, Bin; Chen, Xin; Pang, Qi; Xin, Tao

    2013-10-01

    Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is associated with tumor development and progression in a variety of epithelial carcinomas, while its expression and role in gliomas have not been considered. The aim of the study was to investigate TROP2 expression in malignant gliomas with different World Health Organization (WHO) classification and its correlation with tumor proliferation and angiogenesis. Immuohistochemistry was used to determine TROP2 and Ki-67 expression and microvessel density (MVD) in tumor specimens and normal brain tissues from 69 glioma patients and the relationship between TROP2 and Ki-67 and MVD was investigated. Immunohistochemistry results showed that the TROP2 expression was found in 59 (85.5 %) of the 69 tumor specimens, but no expression in normal brain tissues. Furthermore, TROP2 expression is significantly higher in WHO grade III (P = 0.025) and WHO grade IV (P = 0.011) gliomas than in WHO grade II gliomas. TROP2 expression correlates with Ki-67 (r = 0.676, P = 0.012) and MVD (r = 0.365, P = 0.035), but not with gender or age in human gliomas. These results suggested that the TROP2 correlated with malignancy, proliferation and angiogenesis in human gliomas. This is the first study describing TROP2 expression in gliomas and its proliferation and angiogenesis-related characteristic may serve as a potential therapeutic target for glioma treatment. PMID:23397225

  17. Tumor angiogenesis: evidence of new blood channels from plasma infiltrations.

    Science.gov (United States)

    Freitas, I; Baronzio, G F; Barni, S; Bertone, V; Griffini, P; Accossato, P; Pontiggia, P

    1992-01-01

    Stroma formation in Ehrlich carcinoma, studied with histochemical and TEM techniques, is similar to wound healing. In this tumour mast cells, macrophages, adipocytes, platelets and fibrin seem to co-operate locally with malignant cells in regulating stroma formation. The gaps opened in the tumor parenchyma by plasma outpouring from local blood vessels seem to offer easy routes for endothelial cell migration towards ill-nourished areas, and may explain the irregular aspect of tumor microvascularity. PMID:1377579

  18. Obesity, expression of adipocytokines, and macrophage infiltration in canine mammary tumors.

    Science.gov (United States)

    Lim, H Y; Im, K S; Kim, N H; Kim, H W; Shin, J I; Sur, J H

    2015-03-01

    Obesity influences the development, progression and prognosis of human breast cancer and canine mammary cancer (MC) but the precise underlying mechanism is not well-documented in the fields of either human or veterinary oncology. In the present study, the expression of major adipocytokines, including leptin, adiponectin, and leptin receptor (ObR) in benign (n?=?28) and malignant (n?=?70) canine mammary tumors was investigated by immunohistochemistry and on the basis of the subject's body condition score (BCS). To evaluate the relationship between obesity and chronic inflammation of the mammary gland, macrophages infiltrating within and around tumoral areas were counted. The mean age of MC development was lower in overweight or obese dogs (9.0?±?1.8 years) than in lean dogs or optimal bodyweight (10.2?±?2.9 years), and the evidence of lymphatic invasion of carcinoma cells was found more frequently in overweight or obese group than in lean or optimal groups. Decreased adiponectin expression and increased macrophage numbers in overweight or obese subjects were significantly correlated with factors related to a poor prognosis, such as high histological grade and lymphatic invasion. Leptin expression was correlated with progesterone receptor status, and ObR expression was correlated with estrogen receptor status of MCs, regardless of BCS. Macrophage infiltration within and around the tumor may play an important role in tumor progression and metastasis in obese female dogs and may represent a prognostic factor for canine MCs. PMID:25641553

  19. Paradox between angiogenesis and oxygen effect in the treatment of tumor

    International Nuclear Information System (INIS)

    The paradox in the title is described on recent findings concerning the effects of anti-angiogenetic drugs on possible radiation resistance and sensitivity of tumor tissue. Suppression of angiogenesis leads to inhibition of tumor growth, based on which anti-tumor drugs like anti- vascular endotherial growth factor (VEGF) antibody bevacizumab to suppress the genesis have been developed and clinically used, but they conceivably increase the population of hypoxic tumor cells. Those drugs are essentially used in combination with other chemotherapeutic agents and/or radiation. Hypoxic tumor cells present in the tissue are generally radioresistant. There are reported findings, however, that the drugs sometimes elevate the efficacy of radiotherapy, which hypothesizes that the drugs induces a proangiogenetic state, where increased level of growth factors in the tissue is reduced to normalize the vasculature and thereby reoxygenation occurs, the oxygen effect. Because copper is a cofactor of growth factors like VEGF and basic fibroblast growth factor (bFGF) and essential for angiogenesis, authors have studied the effect of a Cu-chelator, trientine, on transplanted mouse tumors which has been shown to induce apoptosis of the target cells. Combination of the chelator with X-ray irradiation is found effective in tumor growth inhibition and in survival increase. For more effective combination therapy, the interaction occurring in combinations of regimen should be elucidated. (R.T.ons of regimen should be elucidated. (R.T.)

  20. Tumores de glándula mamaria en caninos Tumors of mammary gland in canine

    Directory of Open Access Journals (Sweden)

    Osmar Fajardo

    2005-10-01

    Full Text Available De los animales de compañía, los caninos son los que sufren con mayor frecuencia tumores de glándula mamaria y dentro de ellos las hembras son las que contribuyen con el mayor número de casos. Cuando estos tumores se presentan en machos por lo general tienen características histológicas malignas. Para el diagnóstico histopatológico la clasificación que ha tenido mayor aceptación es la propuesta por Hampe and Misdorp. A través de muchos años de investigación en este campo se han descrito varios factores considerados como predisponentes, entre los cuales están: raza, sexo, edad, dentro de estos la que presenta mayor disparidad de conceptos es la raza ya que, según algunos autores, se puede ver influenciada por factores externos como la localización geográfica y el gusto de los propietarios por ciertas razas como animales de compañía. Otro hecho importante es la descripción de agentes causales: el invalance hormonal (estrógenos, progesterona, mutaciones genéticas, (gen supresor del tumor, protooncogenes y consumo de dietas ricas en grasas. Finalmente, es importante hacer énfasis en el hecho que del diagnóstico adecuado y pautas de tratamiento llevados a cabo por el médico veterinario clínico, depende el pronóstico y las expectativas de vida del paciente canino.Among domestic animals, canines are those that most frequently suffertumors of mammary gland and among them females are those that present the biggest number of cases. When these tumors are present in males, they have malign hystologic characteristics. For the hysto-pathologic diagnosis the best accepted classification is Hampe and Misford ' s proposal. Through many years of research in this field several predisposition factors, as race, sex andage have been described. Among these, race accounts for the highest disparity of concepts since, as some authors argue, this can be influenced by some external factors as geographic location and the owners ' likes for certain races as company animals. Another important fact is the description of causal agents such as hormonal imbalance (estrogens, progesterone, genetic mutations (suppressive gene of the tumor and proto- oncogenesis, consumption of fat-rich diets. Finally, it is important to emphasize the fact that the prognosis and life expectations of the canine patient depend on the basis of a good diagnosis and clues for treatment carried out by the Clinic Veterinarian.

  1. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice

    DEFF Research Database (Denmark)

    Willmann, Jürgen K; Cheng, Zhen

    2008-01-01

    To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice.

  2. Targeted Microbubbles for Imaging Tumor Angiogenesis: Assessment of Whole-Body Biodistribution with Dynamic Micro-PET in Mice

    OpenAIRE

    Willmann, Ju?rgen K.; Cheng, Zhen; Davis, Corrine; Lutz, Amelie M.; Schipper, Meike L.; Nielsen, Carsten H.; Gambhir, Sanjiv S.

    2008-01-01

    Purpose: To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis–related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro–positron emission tomography (PET) in living mice.

  3. Optimization of methods to assess mitochondrial DNA in archival paraffin-embedded tissues from mammary canine tumors Otimização dos métodos para avaliar o DNA mitocondrial obtido a partir de tumores mamários caninos incluídos em parafina

    OpenAIRE

    Bertagnolli, Ange?lica C.; Valdemar Máximo; Bárbara van Asch; António Amorim; Luis Cirnes; Paula Soares; Cassali, Geovanni D.

    2008-01-01

    In this study we describe the alterations used to extract and amplify mitochondrial desoxyribonucleic acid (DNA) from formalin-fixed paraffin-embedded samples of canine mammary tumors. The epithelial and mesenchymal components (chondromyxoid and chondroid) of each tumor, as well as the normal mammary gland tissues, were manually microdissected from 19 mixed canine mammary tumors (10 benign mixed tumors and nine carcinomas arising in mixed tumors). DNA was extracted by Invisorb® Spin Tissue M...

  4. Detection and characterization of a glycoprotein encoded by the mouse mammary tumor virus long terminal repeat gene.

    OpenAIRE

    Brandt-carlson, C.; Butel, J. S.

    1991-01-01

    Mouse mammary tumor virus (MMTV) is a retrovirus that causes mammary tumors in susceptible mice. MMTV contains a unique open reading frame (ORF) in the unique 3' region of the proviral long terminal repeat (LTR) with the potential to encode a 36-kDa protein. However, the ORF gene product has not been detected in murine mammary tissues or cell lines. We utilized the baculovirus expression vector system to generate large amounts of the ORF protein. Putative ORF gene products of 36 and 45 kDa we...

  5. Regulation of endogenous murine mammary tumor virus expression in C57BL mouse lactating mammary glands: transcription of functional mRNA with a block at the translational level.

    OpenAIRE

    Vaidya, A. B.; Taraschi, N. E.; Tancin, S. L.; Long, C. A.

    1983-01-01

    Expression of endogenous murine mammary tumor viruses (MuMTVs) in various mouse strains is regulated in different ways, and in the absence of exogenous MuMTV, this regulation influences the incidence of spontaneous mammary tumors. Two mouse strains with low mammary tumor incidence, BALB/c and C57BL, control endogenous MuMTV expression at different stages. Neither of the strains had any detectable MuMTV polypeptides in its lactating mammary glands (LMG). However, in C57BL LMG, substantial amou...

  6. Control of metastatic mammary tumors by laser immunotherapy through local treatment

    Science.gov (United States)

    Chen, Wei R.; Nordquist, Robert E.

    1998-08-01

    Malignant tumors kill hosts almost entirely by tumor invasion to multiple sites including vital organs. These metastases are often difficult to detect and when detected it is usually too late for effective treatment. Therefore, control of metastatic tumors is by far the biggest challenge in cancer treatment. Can the metastases be prevented or eradicated by a treatment of local tumor that can be easily detected and treated? It apparently requires a systemic reaction, usually a tumor- specific immune response. Laser immunotherapy, a novel approach using laser, photosensitizer and immunoadjuvant, has shown the potential to achieve such an immune reaction. This new method was applied in treatment of rat metastatic mammary tumors. The tumor model is DMBA-4, an aggressive tumor that invades different sites through blood vessels and lymphatics. Without treatment, all the tumor-bearing rats died with an average survival time of less than 35 days. Remote metastases were observed in all late-stage tumor-bearing rats. Laser immunotherapy was capable of eradicating treated primary tumors, and more importantly, the metastases at remote sites were also eradicated without direct treatment. The probable mechanism is an induced tumor-specific immune response, and this hypothesis has been supported by several immunoassays. This new therapy may prove to be an effective treatment modality for metastatic tumors by a non-invasive local laser application.

  7. Myeloid cell receptor LRP1/CD91 regulates monocyte recruitment and angiogenesis in tumors.

    Science.gov (United States)

    Staudt, Nicole D; Jo, Minji; Hu, Jingjing; Bristow, Jeanne M; Pizzo, Donald P; Gaultier, Alban; VandenBerg, Scott R; Gonias, Steven L

    2013-07-01

    Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 was deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly increased in these mice, compared with control mice. LRP1-deficient bone marrow-derived macrophages (BMDM) expressed higher levels of multiple chemokines, including, most prominently, macrophage inflammatory protein-1?/CCL3, which is known to amplify inflammation. Increased levels of CCL3 were detected in LRP1-deficient tumor-associated macrophages (TAM), isolated from PanO2 tumors, and in RAW 264.7 macrophage-like cells in which LRP1 was silenced. LRP1-deficient BMDMs migrated more rapidly than LRP1-expressing cells in vitro. The difference in migration was reversed by CCL3-neutralizing antibody, by CCR5-neutralizing antibody, and by inhibiting NF-?B with JSH-23. Inhibiting NF-?B reversed the increase in CCL3 expression associated with LRP1 gene silencing in RAW 264.7 cells. Tumors formed in mice with LRP1-deficient myeloid cells showed increased angiogenesis. Although VEGF mRNA expression was not increased in LRP1-deficient TAMs, at the single-cell level, the increase in TAM density in tumors with LRP1-deficient myeloid cells may have allowed these TAMs to contribute an increased amount of VEGF to the tumor microenvironment. Our results show that macrophage density in tumors is correlated with cancer angiogenesis in a novel model system. Myeloid cell LRP1 may be an important regulator of cancer progression. PMID:23633492

  8. Co-expression of vimentin and cytokeratin in bitch mammary gland tumors

    Directory of Open Access Journals (Sweden)

    Jovi? Slavoljub

    2007-01-01

    Full Text Available This work presents the results of immunohistochemical studies on the distribution of intermediary filamentous proteins vimentin and cytokeratin in bitch mammary gland tumors, which had been previously classified according to the latest WHO-classification (1999. The overall test specimen included 45 bitches of different breeds and age, which resulted in diagnosing 27 malignant neoplasms, 11 benign neoplasms, and 3 hyperplastic-dysplastic changes, while 4 test specimens were taken from healthy bitches. The commonest malignant neoplasms were: simple adenocarcinoma (13 cases and complex adenocarcinoma (7. Among the benign neoplasms the ones that dominated were benign mixed tumors (8 cases. Vimentin was expressed on neoplastic proliferative suprabasal myoepithelial cells of simple adenocarcinomas; on resting, spindleshaped and star-shaped myoepithelial cells of complex adenocarcinomas; on cartilage cells of carcinomas in the mixed tumor and benign mixed tumors; on osteoid cells of osteosarcoma; and on myofibroblasts of simple adenocarcinomas, complex adenocarcinomas, carcinomas in the mixed tumor and benign mixed tumors, and connective tissue fibres of fibrosarcoma. The expression of cytokeratin was noticed on canalicular and alveolar lumen epithelium of simple adenocarcinomas; on epithelial cells of complex adenocarcinomas, carcinomas in the mixed tumor, mutinous carcinomas, fibrosarcoma and of osteosarcoma; on resting and starshaped myoepithelial cells of complex adenocarcinomas and carcinomas in the mixed tumor; as well as on spindle-shaped myoepithelial cells of carcinomas in the mixed tumor. Proliferative suprabasal myoepithelial cells of simple adenocarcinomas showed the co-expression of vimentin and cytokeratin, and so did the resting and spindle-shaped myoepithelial cells of complex tubular adenocarcinomas, whereas in complex solid adenocarcinomas the coexpression was also shown on star-shaped myoepithelial cells. The coexpression of vimentin and cytokeratin was found on resting myoepithelial cells of benign mixed tumors, simple and complex adenomas, and mammary gland hyperplasia; on spindle-shaped myoepithelial cells of benign mixed tumors, complex adenomas and myoepithelial solid adenomas; and on star-shaped myoepithelial cells of benign mixed tumors.

  9. Galectin-3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGF?1-induced macrophages

    International Nuclear Information System (INIS)

    In order to study the role of galectin-3 in tumor angiogenesis associated with tumor-associated macrophages (TAM) and tumor parenchyma, the galectin-3 expression was reconstituted in Tm1 melanoma cell line that lacks this protein. Galectin-3-expressing cells (Tm1G3) and mock-vector transfected cells (Tm1N3) were injected into wild-type (WT) and galectin-3 knockout (KO) C57Bl/6 mice. Tumors originated from Tm1G3 were larger in tumor volume with enlarged functional vessels, decreased necrotic areas, and increased vascular endothelial growth factor (VEGF) protein levels. Galectin-3-nonexpressing-cells injected into WT and KO showed increased levels of transforming growth factor beta 1 (TGF?1) and, in WT animals this feature was also accompanied by increased VEGFR2 expression and its phosphorylation. In KO animals, tumors derived from galectin-3-expressing cells were infiltrated by CD68+-cells, whereas in tumors derived from galectin-3-nonexpressing-cells, CD68+ cells failed to infiltrate tumors and accumulated in the periphery of the tumor mass. In vitro studies showed that Tm1G3 secreted more VEGF than Tm1N3 cells. In the latter case, TGF?1 induced VEGF production. Basal secretion of VEGF was higher in WT-bone marrow-derived macrophages (BMDM) than in KO-BMDM. TGF?1 induced secretion of VEGF only in WT-BMDM. Tm1G3-induced tumors had the Arginase I mRNA increased, which upregulated alternative macrophage (M2)/TAM induction. M2 stimulrleukin-4 (IL4) and TGF?1, increased Arginase I protein levels and galectin-3 expression in WT- BMDM, but not in cells from KO mice. Hence, we report that galectin-3 disruption in tumor stroma and parenchyma decreases angiogenesis through interfering with the responses of macrophages to the interdependent VEGF and TGF?1 signaling pathways

  10. Acacetin inhibits VEGF expression, tumor angiogenesis and growth through AKT/HIF-1? pathway

    OpenAIRE

    Liu, Ling-Zhi; Jing, Yi; Jiang, Lisa L.; Jiang, Xiu-E; Jiang, Yue; Rojanasakul, Yongyut; Jiang, Bing-Hua

    2011-01-01

    Acacetin (5,7-dihydroxy-4?-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of acacetin in inhibiting VEGF expression, we showed that acacetin inhibited HIF-1? expression and AKT activa...

  11. Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis

    OpenAIRE

    Pratheeshkumar, Poyil; Son, Young-ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

    2012-01-01

    Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube for...

  12. Pharmacoproteomic Analysis of a Novel Cell-permeable Peptide Inhibitor of Tumor-induced Angiogenesis*

    OpenAIRE

    Bang, Ji-Young; Kim, Eung-Yoon; Kang, Dong-Ku; Chang, Soo-Ik; Han, Moon-Hi; Baek, Kwang-Hyun; Kang, In-Cheol

    2011-01-01

    P11, a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integrin ?v?3 was identified from a hexapeptide library (PS-SPCL) using a protein microarray chip-based screening system. Here, we investigated the inhibitory mechanism of P11 (HSDVHK) on tumor-induced angiogenesis via a pharmacoproteomic approach. P11 was rapidly internalized by, human umbilical vein endothelial cells (HUVECs) via an integrin ?v?3-mediated event. Caveolin and clathrin appeared ...

  13. Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum sanctum

    OpenAIRE

    Nangia-Makker, Pratima; Tait, Larry; Hogan, Victor; Shekhar, Malathy P. V.; Funasaka, Tatsuyoshi; Raz, Avraham

    2007-01-01

    Ocimum sanctum (OS) is a traditionally used medicinal herb, which shows anti-oxidant, anti-carcinogenic, radio-protective and free radical scavenging properties. So far no detailed studies have been reported on its effects on human cancers. Thus, we analyzed its effects on human breast cancer utilizing in vitro and in vivo methodologies. Aqueous extracts were prepared from the mature leaves of Ocimum sanctum cultivated devoid of pesticides. Tumor progression and angiogenesis related processes...

  14. Myeloid Cell Receptor LRP1/CD91 Regulates Monocyte Recruitment and Angiogenesis in Tumors

    OpenAIRE

    Staudt, Nicole D.; Jo, Minji; Hu, Jingjing; Bristow, Jeanne M.; Pizzo, Donald P.; Gaultier, Alban; Vandenberg, Scott R.; Gonias, Steven L.

    2013-01-01

    Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 is deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly inc...

  15. Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice

    OpenAIRE

    Jian-Li Gao; Xing Ji; Tong-Chuan He; Qi Zhang; Kai He; Yan Zhao; Su-Hong Chen; Gui-Yuan Lv

    2013-01-01

    Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET) exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET's anticancer activity. We compare TET with che...

  16. Mammary Tumors Initiated by Constitutive Cdk2 Activation Contain an Invasive Basal-like Component

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    Patrick E. Corsino

    2008-11-01

    Full Text Available The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2 transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, ? smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and ?-catenin and p120ctn localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, ?-catenin, and p120ctn to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.

  17. 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.

    Science.gov (United States)

    DelNero, Peter; Lane, Maureen; Verbridge, Scott S; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia

    2015-07-01

    Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation. PMID:25934456

  18. Transcription factor access is mediated by accurately positioned nucleosomes on the mouse mammary tumor virus promoter.

    OpenAIRE

    Archer, T K; Cordingley, M G; Wolford, R G; Hager, G L

    1991-01-01

    A fragment of the mouse mammary tumor virus (MMTV) promoter was reconstituted from pure histones into a dinucleosome with uniquely positioned octamer cores. Core boundaries for the in vitro-assembled dinucleosome corresponded to the observed in vivo phasing pattern for long terminal repeat nucleosomes A and B. Nuclear factor 1 (NF1), a constituent of the MMTV transcription initiation complex, was excluded from the assembled dinucleosome, whereas the glucocorticoid receptor was able to bind. D...

  19. Morphological Aspects and Immunophenotypic Profiles of Mammary Carcinomas in Benign-Mixed Tumors of Female Dogs

    OpenAIRE

    Gustavo Meirelles Ribeiro; Angélica Cavalheiro Bertagnolli; Rafael Malagoli Rocha; Geovanni Dantas Cassali

    2012-01-01

    Carcinoma in benign-mixed tumor (CBMT) is common in the female canine mammary gland and comprises malignant epithelial between benign mesenchymal elements. This study investigated the morphological aspects of 29 CBMT and their immunophenotypical profiles, by using an immunohistochemistry panel based on five molecular markers—estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5 (CK5), and human epidermal growth factor receptor 1 (...

  20. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells

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    Li Fan

    2010-04-01

    Full Text Available Abstract Background In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells. Methods We constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7. Results CXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo. Conclusions Increased CXCR7 expression was found in hepatocellular carcinoma tissues. Knockdown of CXCR7 expression by transfected with CXCR7shRNA significantly inhibits SMMC-7721 cells invasion, adhesion and angiogenesis. Finally, down-regulation of CXCR7 expression lead to a reduction of tumor growth in a xenograft model of HCC. This study provides new insights into the significance of CXCR7 in invasion and angiogenesis of HCC.

  1. Connexin 43 Suppresses Tumor Angiogenesis by Down-Regulation of Vascular Endothelial Growth Factor via Hypoxic-Induced Factor-1?

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    Wei-Kuang Wang

    2014-12-01

    Full Text Available Previous work showed that connexin 43 (Cx43 reduced the expression of hypoxic-induced factor-1? (HIF-1? in astrocytes. HIF-1? is a master transcription factor for angiogenesis in tumor. Angiogenesis is essential for tumor progression. Here, we investigated the role of Cx43 in vascular endothelial growth factor (VEGF production and angiogenesis in murine tumor. In the study, mouse B16F10 and 4T1 cells were overexpressed or knockdown with Cx43. The expression profiles as well as activity of the treated cells were examined. Furthermore, reduced Cx43 expression in B16F10 and 4T1 cells causes increased expression of VEGF and enhanced the proliferation of endothelial cells. On the contrary, the expression of VEGF and the proliferation of endothelial were increased in the conditioned medium of Cx43-knockdown tumor cells. We subcutaneously transplanted Cx43-overexpressing B16F10 cells into mice to evaluate the roles of Cx43 in the tumor angiogenesis. Both tumor size and the number of vessels growing in the tumor were markedly decreased compare with control group. Our findings suggest that Cx43 inhibited tumor growth by reducing angiogenesis.

  2. Integrin-Associated CD151 Drives ErbB2-Evoked Mammary Tumor Onset and Metastasis

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    Xinyu Deng

    2012-08-01

    Full Text Available ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70–100 days in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through ?6?4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent ?6?4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly ?6?4 and ErbB2 (and EGFR receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.

  3. Optimizing the time of doxil injection to increase the drug retention in transplanted murine mammary tumors

    Directory of Open Access Journals (Sweden)

    Shaojin You

    2010-03-01

    Full Text Available Shaojin You, Lian Zuo, Wei LiExperimental Cancer Therapeutic Laboratory and Histopathology Core, Atlanta Research and Educational Foundation (151F, Atlanta VA Medical Center, Decatur, GA, USAAbstract: Sex hormonal milieus during the female fertility cycle modulate the tumor vascular permeability of breast cancer. It has been proposed that the liposomal formulated doxorubicin (ie, Doxil, given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor. In the current study, syngeneic murine 4T1 mammary tumors were established on the backs of female BALB/c mice and Doxil was administered at particular mouse estrous cycle stages. The results indicated that Doxil administration during certain times in the mouse estrous cycle was crucial for drug retention in 4T1 tumor tissues. Significantly higher drug concentrations were detected in the tumor tissues when Doxil was administered during the diestrus stage, as compared to when the drug injection was given at all other estrous stages. Our study also showed that the tumor-bearing mice exhibited nearly normal rhythmicity of the estrous cycle post drug injection, indicating the feasibility of continual injection of Doxil at the same estrous cycle stage. By using 4T1 cells cultured in vitro, we showed that progesterone (P4 significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1?, MIP-1?, and Flt3-L. Some of these factors have been shown to be vascular modulators in diverse tissues. In this report, we demonstrated that the concentration of P4 in the plasma and/or estrous cycle stage of 4T1 tumor-bearing mice can be used to select the best time for administrating the liposomal anticancer drugs.Keywords: progesterone, menstrual cycle, mouse mammary tumor, Doxil, breast cancer therapy

  4. Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss

    OpenAIRE

    Ou, Lihui; Ip, Clement; Lisafeld, Barbara; Ip, Margot M.

    2007-01-01

    Conjugated linoleic acid (CLA) is a powerful anticancer agent in a number of tumor model systems; however, its precise mechanism of action remains elusive. Here, we report that t10,c12 CLA, a component of synthetic CLA supplements, induced apoptosis and G1 arrest of p53 mutant TM4t murine mammary tumor cells. Furthermore, t10,c12-CLA induced a time- and concentration-dependent cleavage of caspases-3 and -9, and release of cytochrome c from mitochondria to cytosol. Levels of Bcl-2 protein were...

  5. Enhanced Doppler ultrasound imaging of interstitial laser therapy in rat mammary tumors

    Science.gov (United States)

    Zasuly, James M.; Fan, Ming; Dowlatshahi, Kambiz

    1997-05-01

    In order to better develop ultrasonography for use in monitoring interstitial laser therapy (ILT), we imaged rat mammary tumors using power Doppler ultrasound in conduction with intravenous contrast agent (Albunex) before and after laser therapy. Small vessel perfusion throughout a variable portion of the tumor could be detected by power Doppler ultrasound. Lesions created with diode laser by delivery of 500 to 3000 J appeared as perfusion defects on post-treatment images. Image topography and lesion size correlated with gross histologic findings. We conclude that ultrasonographic monitoring of local changes in blood flow using contrast enhancing agent can be useful in characterizing lesions created with ILT.

  6. c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors

    OpenAIRE

    Dutra, A. P.; Granja, N. V. M.; Schmitt, F. C.; Cassali, G. D.

    2004-01-01

    The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil) and the Veterinary Faculty of Porto University (Portugal). c-erbB-2 expression was determined according to the guidelines ...

  7. Usefulness of selective COX-2 inhibitors as therapeutic agents against canine mammary tumors.

    Science.gov (United States)

    Saito, Teruyoshi; Tamura, Dai; Asano, Ryuji

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme for converting arachidonic acids to prostanoids, which are known to be induced during inflammation and cancer initiation. Previously, it has been reported that COX inhibitors, such as aspirin, reduce the incidence of human colorectal cancer; therefore, it is widely believed that COX-2 is a potential therapeutic and chemoprevention target for several types of human cancer. However, whether selective COX-2 inhibitors have antitumor effects against canine mammary tumor cells remains unclear. In the present study, to elucidate the antitumor effect of selective COX-2 inhibitors against canine mammary tumors, we investigated the antitumor effects of meloxicam, etodolac and celecoxib using COX-2-expressing canine mammary tumor (CF33) cells. We analyzed the effects of selective COX-2 inhibitors on COX-2 protein expression levels in CF33 cells. Celecoxib (100 µM) was found to induce downregulation of COX-2 protein expression. We examined the effect of selective COX-2 inhibitors on CF33 cell proliferation. All the selective COX-2 inhibitors suppressed CF33 cell growth. Specifically, etodolac and celecoxib inhibited cell proliferation via a decrease in S-phase cells and an increase in G0/G1 arrest. We examined the apoptotic effect of selective COX-2 inhibitors on CF33 cells. Our data suggested that etodolac and celecoxib induced apoptosis in CF33 cells. In particular, celecoxib led to apoptosis mediated by the activation of the mitochondrial apoptosis pathway, including the upregulation of BAX expression, downregulation of Bcl-2 expression and activation of caspase-3/7. Furthermore, celecoxib increased the percentages of cells in both early apoptosis and late apoptosis. Our results revealed that celecoxib induced apoptosis and cell cycle arrest in CF33 cells. The data suggested that celecoxib is the most viable candidate as a therapeutic agent for the treatment of canine mammary tumors. Furthermore, our findings provide the first indication that COX-2 inhibition can provide a new therapeutic strategy for treating canine mammary tumors. PMID:24503782

  8. Tumor and non-tumor liver angiogenesis is traced and evaluated by hepatic arterial ultrasound in murine models.

    Science.gov (United States)

    Eveno, Clarisse; Le Henaff, Carole; Audollent, Raphaëlle; Soyer, Philippe; Rampanou, Aurore; Nemeth, Judith; Brouland, Jean-Philippe; Dupuy, Evelyne; Pocard, Marc; Bonnin, Philippe

    2012-07-01

    We studied the relationships between hepatic and mesenteric mean blood-flow velocities (mBFVs) measured by ultrasound imaging and (1) downstream tumor angiogenesis during liver metastasis induced by spleen injection of LS174 human colon cells overexpressing the antiangiogenic Netrin4 (LS174-NT4) or not (LS174-WT) and (2) downstream normal angiogenesis during hepatic regeneration after 50% hepatectomy. Liver volume and mBFVs were measured before and after surgery, at day 30 in the first model and at days 2, 7 and 16 in the second model. LS174-NT-4 vs. LS174-WT mice presented fewer metastases (25% vs. 90%, p < 0.001) and decreased hepatic mBFVs (16.5 ± 0.8 vs. 21.8 ± 1.4 cm s(-1), p < 0.01), without difference in mesenteric mBFVs. After partial hepatectomy, hepatic and mesenteric mBFVs increased at day 7, from 12.4 ± 1.7 and 11.8 ± 2.6 to 19.1 ± 1.8 and 17.5 ± 2.4 cm s(-1), respectively, (p < 0.01) then returned to baseline as liver volume. Duplex Doppler ultrasonography reliably assesses normal or tumor angiogenesis and may provide follow-up functional evaluation. PMID:22542260

  9. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis.

    Science.gov (United States)

    Zhang, Guodong; Panigrahy, Dipak; Mahakian, Lisa M; Yang, Jun; Liu, Jun-Yan; Stephen Lee, Kin Sing; Wettersten, Hiromi I; Ulu, Arzu; Hu, Xiaowen; Tam, Sarah; Hwang, Sung Hee; Ingham, Elizabeth S; Kieran, Mark W; Weiss, Robert H; Ferrara, Katherine W; Hammock, Bruce D

    2013-04-16

    Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg · kg(-1) · d(-1)) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ~70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers. PMID:23553837

  10. The Protective Effect Of SPIRULINA PLATENSIS Against MAMMARY Tumors Induction By Dimethylbenz(A)Anthracene In Sprague- Dawley Female Rats

    International Nuclear Information System (INIS)

    Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Despite extensive studies, the precise mechanisms of breast carcinogenesis remain unclear. One of the reasons for this is due, at least in part, to a lack of a suitable animal model, which can closely mimic the breast carcinogenesis in normal situations without using chemical carcinogens. Dimethylbenz(a)anthracene (DMBA) was used to developed mammary gland carcinogenesis in an animal model and succeeded in inducing mammary cancer in a relatively short time (?6 months) in Sprague-Dawely female rats. The possible therapeutic and protective effects of Spirulina platensis in Sprague-Dawely female rats were investigated. The results showed significant increased androgen testosterone level and significant decreased estrogen level in mammary gland carcinogenesis. Histopathological examination revealed hyperplasia and dysplasia and fully developed carcinoma of various forms including cribriform, papillary and camedo types which were observed after 6 months. They ranged from well differentiated to poorly differentiated forms with predominantly infiltrating ductal carcinoma. In addition to the high incidence of carcinoma, there was also a peculiar unexplained allocation of mammary gland tumors in virgin female rats between the site of implantation and the location of tumors through the whole body, and the highest incidence of carcinogenesis was found to be in thoracic mammary sis was found to be in thoracic mammary gland. Both estrogen and testosterone have a role in mammary cancers. The study showed that both estrogen and testosterone were important in mammary cancer diagnosis. It is suggested that sex hormones have a role in late stages in breast carcinogenesis. Estradiol, which is the main form of estrogen, affects the different stage of mammary gland carcinogenesis. Furthermore, the results indicated that Spirulina platensis may have therapeutic and protective effects (30%) on mammary cancers of Sprague-Dawely female rats chemically induced by DMBA.

  11. Lentivirus-Mediated Oncogene Introduction into Mammary Cells In Vivo Induces Tumors

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    Stefan K. Siwko

    2008-07-01

    Full Text Available We recently reported the introduction of oncogene-expressing avian retroviruses into somatic mammary cells in mice susceptible to infection by transgenic expression of tva, encoding the receptor for subgroup A avian leukosis-sarcoma virus (ALSV. Because ALSV-based vectors poorly infect nondividing cells, they are inadequate for studying carcinogenesis initiated from nonproliferative cells (e.g., stem cells. Lentivirus pseudotyped with the envelope protein of ALSV infects nondividing TVA-producing cells in culture but has not previously been tested for introducing genes in vivo. Here, we demonstrate that these vectors infected mammary cells in vivo when injected into the mammary ductal lumen of mice expressing tva under the control of the keratin 19 promoter. Furthermore, intraductal injection of this lentiviral vector carrying the polyoma middle T antigen gene induced atypical ductal hyperplasia and ductal carcinoma in situ-like premalignant lesions in 30 days and palpable invasive tumors at a median latency of 3.3 months. Induced tumors were a mixed epithelial/myoepithelial histologic diagnosis, occasionally displayed squamous metaplasia, and were estrogen receptor-negative. This work demonstrates the first use of a lentiviral vector to introduce oncogenes for modeling cancer in mice, and this vector system may be especially suitable for introducing genetic alterations into quiescent cells in vivo.

  12. Role of thrombin in the proliferative response of T-47D mammary tumor cells

    International Nuclear Information System (INIS)

    The growth of the human metastatic cell line (T-47D) in a chemically defined medium (DM) is shown to be dependent on the presence of three traditional growth factors: epidermal growth factor, insulin, and transferrin. The addition of thrombin further stimulates its growth. The mitogenic action on a human mammary tumor cell lines from epithelial origin is a novel action of thrombin. Cells in the DM show striking morphological changes which are dramatically enhanced by the addition of thrombin. These observations are part of a pleiotropic response to the growth factors: the protein content of the cells increases in the defined medium; the 2DG gels of the 35S- and 35P-labeled proteins show important changes in spots, several of which are probably of cytoskeletal origin. It is also shown that cells in a semisolid growth factor-supplemented medium have growth advantages over their counterparts grown with serum. All the phenotypic changes mentioned above reveal the important role of growth factors in the growth and behavior of this mammary cell line. The results obtained with thrombin indicate a new site of action of this enzyme which may be important in the metastatic spread of human mammary tumor cells

  13. Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene.

    Science.gov (United States)

    Clafshenkel, William P; King, Tracy L; Kotlarczyk, Mary P; Cline, J Mark; Foster, Warren G; Davis, Vicki L; Witt-Enderby, Paula A

    2012-01-01

    Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (cancer. PMID:22619689

  14. Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis

    Science.gov (United States)

    2005-01-01

    Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant (P = .005). Of particular interest was identifying a significant correlation (P < .000801) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases. PMID:16192687

  15. Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis

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    Tsui Paulus

    2005-01-01

    Full Text Available Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF, prostate-specific membrane antigen (PSMA, prostate-specific antigen (PSA, androgen receptor (AR, and epidermal growth factor receptor (EGFR. The effect of paclitaxel treatment on AR expression was the most significant ( P = .005 . Of particular interest was identifying a significant correlation ( P < .000801 between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.

  16. Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model

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    Nasim Akhtar

    2004-03-01

    Full Text Available We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF receptors 1 and 2, CD31, CD146, and ?v?3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy.

  17. Anti-angiogenesis and anti-tumor activity of recombinant anginex

    International Nuclear Information System (INIS)

    Anginex, a synthetic 33-mer angiostatic peptide, specifically inhibits vascular endothelial cell proliferation and migration along with induction of apoptosis in endothelial cells. Here we report on the in vivo characterization of recombinant anginex and use of the artificial anginex gene for gene therapy approaches. Tumor growth of human MA148 ovarian carcinoma in athymic mice was inhibited by 80% when treated with recombinant anginex. Histological analysis of the tumors showed an approximate 2.5-fold reduction of microvessel density, suggesting that angiogenesis inhibition is the cause of the anti-tumor effect. Furthermore, there was a significant correlation between the gene expression patterns of 16 angiogenesis-related factors after treatment with both recombinant and synthetic anginex. To validate the applicability of the anginex gene for gene therapy, stable transfectants of murine B16F10 melanoma cells expressing recombinant anginex were made. Supernatants of these cells inhibited endothelial cell proliferation in vitro. Furthermore, after subcutaneous injection of these cells in C57BL/6 mice, an extensive delay in tumor growth was observed. These data show that the artificial anginex gene can be used to produce a recombinant protein with similar activity as its synthetic counterpart and that the gene can be applied in gene therapy approaches for cancer treatment

  18. Correlation between spiral CT features and tumor angiogenesis in renal cell carcinoma

    International Nuclear Information System (INIS)

    Objective: To investigate the correlation of certain features of spiral CT (S-CT) with tumor microvascular density (MVD) and vascular endothelial growth factor (VEGF) in renal cell carcinoma (RCC). Methods: For each of the 18 pathological proved RCC cases, single slice dynamic scans were performed by spiral CT. Enhancement indexes were as follows: the slope of the contrast media uptake curve (S), area under the curve (AR), ?HU, and TBR. The indexes were calculated for all lesions. Time-density curve types were ranked from the lowest to the highest of the slope of the contrast media uptake curve (S) as type A, B and C. CD34 monoclonal antibody and VEGF polyclonal antibody immunohistochemical staining were performed in each cases, then the 'hot spots' of MVD and VEGF protein expression were counted with image analyzed. The distributions of microvessels on the slides were also observed. Results: (1) Tumor MVD had significant correlation with S, ?HU, TBR, AR, and T-DC types (r=0.51, 0.56, 0.5, and 0.57, P0.05). (2) Differences of CT features in RCC were shown, as well as that of tumor angiogenesis. Conclusion: Dynamic spiral CT scan is helpful to assess the tumor vascularity and angiogenesis, thus is useful for clinical evaluation and prediction of its prognosis

  19. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells.

    Science.gov (United States)

    Hoffmann, Sebastian; Rockenstein, Andreas; Ramaswamy, Anette; Celik, Ilhan; Wunderlich, Anette; Lingelbach, Susanne; Hofbauer, Lorenz C; Zielke, Andreas

    2007-01-29

    The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer. Moreover, a direct anti-proliferative effect of RA on human endothelial cells is suggested. PMID:17101211

  20. Differences in the Angiogenesis of Benign and Malignant Surface Epithelial Ovarian Tumors Demonstrated by Microvessel Density and Immunohistochemistry

    OpenAIRE

    Shelly Sehgal; Prashant Goyal; Reena Agarwal; Sompal Singh; Awanindra Kumar; Ruchika Gupta; Vinita Kumar; Dipti Agrawal

    2013-01-01

    OBJECTIVES: Angiogenesis plays a key role in tumor growth and metastasis. The analysis of tumor vascularization by microvessel density (MVD) and its prognostic significance has been evaluated in many tumors including ovary. However, very few studies have tried to evaluate the characteristics of these vessels. This study aims to quantitatively assess the characteristics of tumor vessels with the aid of immunohistochemistry and thus, establish its role in difference in biological behavior of be...

  1. Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.

    Science.gov (United States)

    Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S; Schaffner, Carl P; Zurakowski, David; Solomon, Keith R; Moses, Marsha A

    2014-07-01

    Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. PMID:24952430

  2. Experimental study of affinity of radioiodine labeling APRPGY peptide for tumor angiogenesis

    International Nuclear Information System (INIS)

    The purpose is to investigate the characteristics of APRPGY peptide labeled with radioiodine homing to tumor angiogenesis. The preparation of radioiodinated APRPGY was carried out by Ch-T method. Radiochemical purity was determined by the paper chromatographic system. Biodistribution studies were accomplished using wound healing model and tumor bearing model ICR mice. At 5, 10, 30, 60, 120 and 240 min after radiopharmaceutical administration (174 kBq/200 ?L of 131I-APRPGY), the animals were sacrificed. Blood samples and other interested tissues were collected, weighted and counted (n=6 animals each time). The percent injected dose per gram of organ (%ID/g) and the ratio of tumor/muscle for each animal were calculated. The radiochemical purity of the 131I-APRPGY was above 95%. The biodistribution of the radiolabeled peptide showed higher levels in both blood and kidneys than in other tissues. In all other organs, the radioactivity was rapidly excreted mainly by kidneys. The accumulation of radioactivity in the tumor was 6.7%ID/g at 10 min and decreased within 240 min to 2.1 %ID/g. The ratios of tumor/muscle of 131I-APRPGY were 2.1, 6.2, 3.3, 3.5 and 3.2 at 5, 10, 60, 120 and 240 min, respectively. In would healing model, the radios of would-healing tissue/muscle were 0.8, 1.3, 1.8, 1.9 and 1.4 at 10, 30, 60, 120 and 240 min, respectively. The high specific tumor uptake and predominantly renal excretion make 131I-APRPGY a potcretion make 131I-APRPGY a potential candidate for tumor angiogenesis imaging. This peptide is therefore worthy of further investigation. (authors)

  3. Combined Allogeneic Tumor Cell Vaccination and Systemic Interleukin 12 Prevents Mammary Carcinogenesis in HER-2/neu Transgenic Mice

    OpenAIRE

    Nanni, Patrizia; Nicoletti, Giordano; Giovanni, Carla; Landuzzi, Lorena; Di Carlo, Emma; Cavallo, Federica; Pupa, Serenella M.; Rossi, Ilaria; Colombo, Mario P.; Ricci, Cinzia; Astolfi, Annalisa; Musiani, Piero; Forni, Guido; Lollini, Pier-luigi

    2001-01-01

    Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tu...

  4. 4-methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells.

    Science.gov (United States)

    Saito, Teruyoshi; Tamura, Dai; Nakamura, Tatsuro; Makita, Yukihisa; Ariyama, Hitomi; Komiyama, Keiji; Yoshihara, Tomoko; Asano, Ryuji

    2013-01-01

    Hyaluronan (HA), a major component of the extracellular matrix (ECM), is synthesized by HA synthase (HAS) 1, HAS2 and HAS3 and is intricately involved in cell growth and metastasis. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has been reported to exhibit anticancer properties in various types of malignant tumors. However, the underlying mechanisms at the molecular and cellular levels remain unclear. In this study, to establish an animal model for studying the function of HA in human breast cancer, we investigated the antitumor effects of 4-MU using canine mammary tumor (CF33) cells. First, we investigated the effects of 4-MU on HA production in CF33 cells. Quantitative analysis of HA in culture media showed that 4-MU inhibited HA synthesis, accompanied by downregulation of HAS2 mRNA levels, in a dose-dependent manner at 24-72 h. Additionally, we observed a 4-MU-mediated decrease in the extent of the cell-associated HA matrix. We examined the effect of 4-MU on cell growth and apoptosis in CF33 cells. 4-MU markedly inhibited cell proliferation and induced apoptosis in CF33 cells. In particular, our experiments showed that the mechanism of 4-MU-induced apoptosis in CF33 cells involved increased levels of expression of pro-apoptotic BAX mRNA and protein molecules. These data suggest that 4-MU may be a candidate therapeutic agent for the treatment of canine mammary tumors. Furthermore, this study provides the first indication that the canine mammary tumor may be a suitable model for comparative study of the function of HA in human breast cancer. PMID:23124556

  5. Canine classical seminoma: a specific malignant type with human classifications is highly correlated with tumor angiogenesis

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    Kim Jong-Hyuk

    2010-05-01

    Full Text Available Abstract Background Human seminoma is classified as classical seminoma (SE and spermatocytic seminoma (SS. Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then compared them to tumor associated vessels. Methods Twenty-three cases of canine seminomas (2 intratubular, 9 diffuse, and 12 intratubular/diffuse seminomas showing both intratubular and diffuse patterns were classified as SE or SS by immunohistochemistry (IHC using monoclonal antibody against PLAP and by PAS stain. The histopathological data were then compared to see if there was a correlation with SE or SS. Angiogenesis of seminomas were evaluated by immunohistochemical assay using polyclonal antibody against Von Willebrand factor (vWF and by calculating the means of MVD, vessels area and perimeters using computerized image analysis. Statistical Package for Social Sciences (SPSS program was used for various statistical analyses. Results The numbers of PLAP+/PAS+ canine SEs were 8/23 (34.8% and PLAP-/PAS- SSs were 15/23 (61.2%. All SE cases (8/8, 100% were intratubular/diffuse types. SS types included 2 intratubular (2/15, 13.3%, 9 diffuse (9/15, 60%, and 4 intratubular/diffuse (4/15, 26.7% types. MVD and vascular parameters in SEs were significantly higher than in SSs, showing the highest value in the intratubular/diffuse type. Seminomas observed with neoplastic cells invasion of vessels presented higher perimeter and area values than seminomas without conformed neoplastic cells invasion. Conclusion In this study, we demonstrated a positive relationship between canine SE and tumor angiogenesis. Furthermore, we also showed that a tumor cells invasion of vessels were a correlated vascular parameter. Although metastasis of canine seminomas has rarely been reported, our results support that canine SE could have high metastatic potential similar to the human counterpart. Further studies are required to clarify the relationship between canine SE and clinical data with metastatic factors.

  6. An experimental study on angiogenesis in rabbit VX2 brain tumor using perfusion CT

    International Nuclear Information System (INIS)

    Objective: To validate the perfusion CT method for the reflection of angiogenesis in VX2 rabbit brain tumors, and to correlate CT findings with MVD and VEGF. Methods: VX2 rabbit brain tumor model was established by injection of viable tumor cells (107/ml) through a 5 mm-hole to the right of the sagittal suture and 5 mm posterior to the coronal suture bored by dental drill. MRI was performed every 2 days after seven days of implantation to evaluate the growth of the tumor. 20 New Zealand white rabbits with tumor size over 3 mm in diameter were randomly divided into 2 groups according to the tumor growth time with those less than 3 weeks as group 1 and those more than 3 weeks as group 2, and perfusion CT were performed accordingly. CT measurements of BV, BF and PS from tumor, peritumor and contralateral normal tissue regions were obtained. After that the animals were sacrificed and 2% Evans blue (2 ml/kg) was given intravenously in 16 of these animals 1 hour prior to sacrifice to detect breakdown of the blood brain barrier. VEGF and MVD were evaluated in immunohistochemical examination of the specimens. Results: Tumor had significantly higher BV [(13.25±4.58) ml·100 g-1], BF[(166.14±69.62) ml·100 g-1·min-1], and PS(8.01 ml·min-1·100 g-1) than peritumor[(2.38±0.80)ml·100 g-1, (62.49±25.83)ml· 100 g-1·min-1 and 0.03 ml·min-1·100 g-1-1·100 g-1] and normal tissue region [(2.24±0.75)ml·100 g-1, (55.72±21.24)ml·100 g-1·min-1, and 0.04 ml·min-1·100 g-l] (P=0.000). Tumor BV [(16.41±4.12)ml·100 g-1], BF[(208.77±63.00)ml·100 g-1·min-1], and MVD (61.20± 12.93)/high power field in group 2 were significantly higher than those [(10.09±2.27) ml·100 g-l, (123.51±47.18)ml·100 g-1·min-l, and (41.40±7.34)/high power field] in group 1 (Ps=0.861, P=0.000). Conclusion: Perfusion CT can distinguish tumor from peritumor and normal tissue clearly, reflect tumor angiogenesis accurately, and provide useful information for the evaluation of brain tumor. (authors)

  7. Induction of mammary tumors in virgin female BALB/c mice by single low doses of 7,12-dimethylbenz(a)anthracene

    Energy Technology Data Exchange (ETDEWEB)

    Ethier, S.P. (Univ. of Tennessee, Oak Ridge); Ullrich, R.L.

    1982-11-01

    The induction of mammary tumors in virgin female inbred BALB/c mice after administration of 7,12-dimethylbenz(a)anthracene (DMBA) over a wide range of doses was studied. Mice were exposed at 12 weeks of age to single or multiple doses of DMBA ranging from 0.0025 to 12.0 mg by gastric intubation and were checked regularly for mammary tumors. The experiment was terminated when the mice were 800 days of age. In the dose range of 0.0025-0.125 mg DMBA, the incidence of mammary tumors was dose-dependent. At higher doses, the mammary tumor incidence became less dose-dependent and was nearly independent of doses above the 0.25-mg level. Analysis of the data for the rate of appearance of mammary tumor with age of the animals and for the age at death of non-mammary tumor-bearing animals indicated that in the low dose range induction of mammary tumors was the predominant effect of DMBA exposure, whereas at moderate to high doses the toxic and carcinogenic effects of DMBA on other tissues significantly influenced the final incidence of mammary tumors. Greater than 90% of the tumors that resulted from administration of low doses of DMBA were adenocarcinomas. In contrast, adenocarcinomas and adenoacanthomas were found in approximately equal proportions following administration of high doses of DMBA.

  8. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.

    Science.gov (United States)

    Jaspers, Janneke E; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

    2015-02-15

    Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. PMID:25511378

  9. Proteasome levels and activities increase in canine mammary tumors

    OpenAIRE

    Buracco, Paolo; Bruno, Renato; Martano, Marina; Cerruti, Fulvia; Cascio, Paolo; Morello, Emanuela Maria

    2007-01-01

    In human tumors of distinct histology, changes in the surface expression and/or function of the MHC class I antigens are frequently found and may provide malignant cells with a mechanism to escape the control of immune system. This altered HLA class I phenotype can be caused by either structural alterations or dysregulation of genes encoding the subunits of HLA class I antigens and/or components of the MHC class I antigen-processing machinery (APM). So far abnormalities in the expression and/...

  10. Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis

    Science.gov (United States)

    Tan, Mingjia; Li, Hua; Sun, Yi

    2014-01-01

    SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING protein required for the activity of Cullin-RING ligase (CRL). Our recent study showed that Sag total knockout caused embryonic lethality at E11.5–12.5 days with associated defects in vasculogenesis. Whether Sag is required for de novo vasculogenesis in embryos and angiogenesis in tumors is totally unknown. Here, we report that Sag endothelial deletion also causes embryonic lethality at E15.5 with poor vasculogenesis. Sag deletion in primary endothelial cells or knockdown in MS-1 endothelial cells inhibits migration, proliferation and tube formation with p27 accumulation being responsible for the suppression of migration and proliferation. Furthermore, Sag deletion significantly inhibits angiogenesis in an in vivo Matrigel plug assay, and tumor angiogenesis and tumorigenesis in a B16F10 melanoma model. Finally, MLN4924, an investigational small molecule inhibitor of NEDD8-activating enzyme (NAE) that inhibits CRL, suppresses in vitro migration, proliferation, and tube formation, as well as in vivo angiogenesis and tumorigenesis. Taken together, our study, using both genetic and pharmaceutical approaches, demonstrates that Sag is essential for embryonic vasculogenesis and tumor angiogenesis, and provides the proof-of-concept evidence that targeting Sag E3 ubiquitin ligase may have clinical value for anti-angiogenesis therapy of human cancer. PMID:24213570

  11. Tumor angiogenesis imaging: radioiodinated NGR peptide containing t-butyloxycarbonyl as a pharmacokinetic modifier

    International Nuclear Information System (INIS)

    Tumor growth and metastasis largely depend on persistent new blood vessel growth, which is even the rate-limiting step in solid tumor growth. Identified as a cell adhesion motif, NGR has been proven an effective tumor-homing agent, binding specifically on CD13/APN that is expressed in tumor vasculature undergoing angiogenesis and not detected in blood vessels of various other normal tissues. Whether NGR also possesses the potential of tumor imaging in vivo is still in suspension. Internalization of small peptides is an important phenomenon. Internalization brings on deiodination of directly radioiodinated small peptides, and the low weight radiolabeled catabolites are quickly removed from tumor, resulting in poor tumor imaging. It is of good value to study whether Boc could be an effective tyrosine-protecting group, increasing peptide's resistance to deiodination, meanwhile preserving peptide's original specialty. The cyclic peptide YGGGGGCNGRC (G5) and the t-butyloxycarbonyl (Boc)-modified analog (Boc-G5) were synthesized and radiolabeled with iodine-131. Biodistribution results in normal mice indicated that in the case of G5, deiodination in vivo was found, whereas for Boc-G5, the phenomenon was scarce (Figs.1 and 2). Although the radiotracer clearance in tumor became faster for Boc-G5, tumor-to-tissue ratios still improved, arid at 1 h post injection, the uptake ratios of tumor to muscle, blood, heart, and lung reached 4.73, 1.70, 4.09 and 1.70, respectively. It is, 1.70, 4.09 and 1.70, respectively. It is demonstrated that Boc-group is an effective prosthetic one to prevent deiodination in vivo and meliorate tumor imaging for small peptide.

  12. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

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    Samuelson Emma

    2012-08-01

    Full Text Available Abstract Background Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Methods Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding and Comparative Genome Hybridization (CGH analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome CGH-array platform. Results Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Conclusions Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s. Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis.

  13. Rat differences in mammary tumor induction with estrogen and neutron radiation

    International Nuclear Information System (INIS)

    Young adult female rats of either the Sprague--Dawley stock or the ACI strain were each given an implant of a compressed pellet of 5 mg diethylstilbestrol (DES) and 15 mg cholesterol 2 days before irradiation with 0.4, 1.3, or 4.0 rads of 0.43-MeV neutrons. These rats were studied, along with appropriate irradiated and nonirradiated controls, until death or for a maximum of 48 weeks. Response differences between the strain and stock included the following: DES produced both pituitary tumors and mammary adenocarcinomas (MAC) only. Neutron radiation increased mammary fibroadenoma (MFA) formation in Sprague--Dawley rats only. No interactions between DES and radiation on MAC formation in Sprague--Dawley rats. However, when DES and neutron radiation were combined, DES appeared to inhibit the MFA response to radiation in Sprague--Dawley rats. In contrast, DES appeared to act synergistically with neutron radiation on MAC formation in ACI rats. These results clearly demonstrate rat differences in mammary gland carcinogenesis in response to estrogen, to radiation, or to a combination of both agents

  14. ?-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation

    Directory of Open Access Journals (Sweden)

    Okuno Yasushi

    2011-06-01

    Full Text Available Abstract Background The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound ?-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of ?-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. Methods Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with ?-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by ?-mangostin, in vitro studies were also conducted. Results Not only were in vivo survival rates significantly higher in the 20 mg/kg/day ?-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, ?-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by ?-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that ?-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308, but not serine 473 (Ser473, in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo. Conclusions Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of ?-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, ?-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.

  15. Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice

    Directory of Open Access Journals (Sweden)

    Castillo-Pichardo Linette

    2013-01-01

    Full Text Available Abstract Background Resveratrol, a polyphenol from grapes and red wine has many health beneficial effects, including protection against cardiovascular and neurodegenerative diseases and cancer. However, our group and others have provided evidence for a dual cancer promoting or inhibitory role for resveratrol in breast cancer, dependent on estrogenic or antiestrogenic activities. Moreover, much of the inhibitory effects of resveratrol have been reported from studies with high non-physiological concentrations. Methods We investigated the effects of a range of concentrations (0.5, 5, 50 mg/kg body weight of resveratrol on mammary tumor development post-initiation, using immunocompromised mice. Results Our findings suggest promotion of mammary tumor growth and metastasis by resveratrol at all concentrations tested in tumors derived from the low metastatic estrogen receptor (ER?(-, ER?(+ MDA-MB-231 and the highly metastatic ER(- MDA-MB-435 cancer cell lines. Additionally, the activity of the migration/invasion regulator Rac, which we have previously shown to be regulated by resveratrol in vitro, was measured in tumors from resveratrol treated mice. Our results show a significant induction of tumoral Rac activity and a trend in increased expression of the Rac downstream effector PAK1 and other tumor promoting molecules following resveratrol treatment. Conclusion Taken together, our findings implicate low concentrations of resveratrol in potential promotion of breast cancer. Therefore, this study illuminates the importance of further delineating resveratrol’s concentration dependent effects, particularly in breast cancer, before it can be tested in the clinic or used as a dietary supplement for breast cancer patients.

  16. The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway.

    Science.gov (United States)

    Chen, Jianchu; Chen, Allen Y; Huang, Haizhi; Ye, Xingqian; Rollyson, William D; Perry, Haley E; Brown, Kathleen C; Rojanasakul, Yon; Rankin, Gary O; Dasgupta, Piyali; Chen, Yi Charlie

    2015-06-01

    Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at <40 µM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1?, NF-?B and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1? by downregulation of Akt. Such decreased levels of HIF-1? were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers. PMID:25845666

  17. Modulation of enhancer activity by the hormone responsive regulatory element from mouse mammary tumor virus.

    OpenAIRE

    Ostrowski, M C; Huang, A L; Kessel, M.; Wolford, R G; Hager, G L

    1984-01-01

    Addition of the transcriptional enhancers present in the U3 region of the Harvey murine sarcoma virus (HaMuSV) long terminal repeat (LTR) to recombinant chimeras in which the HaMuSV transforming gene (Ha-v-ras) is expressed from the mouse mammary tumor virus (MMTV) promoter increases the ability of the MMTV v-ras chimeras to transform mouse fibroblasts in culture 50- to 100-fold. Significant stimulation of transfection efficiency occurs only when glucocorticoids are present in the culture med...

  18. Effect of dietary ascorbic acid on the incidence of spontaneous mammary tumors in RIII mice.

    OpenAIRE

    Pauling, L; Nixon, J. C.; Stitt, F; Marcuson, R; Dunham, W B; R. Barth; Bensch, K; Herman, Z S; Blaisdell, B E; Tsao, C

    1985-01-01

    A study of the effect of different amounts of L-ascorbic acid (vitamin C), between 0.076% and 8.3%, contained in the food has been carried out with ten groups of RIII mice (seven ascorbic acid and three control groups), with 50 mice in each group. With an increase in the amount of ascorbic acid there is a highly significant decrease in the first-order rate constant for appearance of the first spontaneous mammary tumor after the lag time to detection by palpation. There is also an increase in ...

  19. The Effect of Antineoplastic Drugs in a Male Spontaneous Mammary Tumor Model

    OpenAIRE

    Shishido, Stephanie N.; Faulkner, Emma B.; Beck, Amanda; Nguyen, Thu A.

    2013-01-01

    Male breast cancer is a rare disease. The limited number of clinical cases has led to the primary treatments for men being derived from female breast cancer studies. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden and drug sensitivity of the antineoplastic drugs tamoxifen, cisplatin, and paclitaxel on tumorigenesis at an early stage of mammary carcinoma development in a male mouse model. Cisplatin treatment sign...

  20. MR imaging of tumor angiogenesis using sterically stabilized Gd-DTPA liposomes targeted to CD105

    International Nuclear Information System (INIS)

    Aim: To depict tumor angiogenesis via the expression of CD105 in tumor-bearing rats using Gd-DTPA liposomes targeted to CD105 (CD105-Gd-SLs) on MR imaging. Materials and methods: Three Gd-DTPA liposomal nanoparticles were prepared in our trial: liposomes entrapping Gd-DTPA (Gd-SLs), Gd-SLs conjugated to immunoglobulins (IgG-Gd-SLs) and CD105-Gd-SLs. Forty glioma-bearing rats were randomized into four groups: (a) Gd-DTPA; (b) Gd-SLs; (c) IgG-Gd-SLs; (d) CD105-Gd-SLs. Axial T1WI MRI images were collected at baseline and repeated at 5, 30, 60 and 120 min post-intravenous injection of Gd-DTPA or liposome. Enhancement features and contrast-to-noise ratio of each group were analyzed. After imaging, tumors were resected for immunohistochemistry and immunofluorescence staining to assess vascularity and angiogenesis. Results: The four groups showed different enhancement features. The enhancement area was restricted for group CD105-Gd-SLs, while diffused for the other three. The degree of enhancement over time varied: group Gd-DTPA showed an early contrast enhancement at instant after injection with a peak at 30 min and a decline to baseline values at 60 min. In group CD105-Gd-SLs, the signal intensity (SI) continuously increased over 120 min. In groups IgG-Gd-SLs and Gd-SLs the SI peaked at 60 min, followed by a minor decrease for IgG-Gd-SLs and a rapid decrease for Gd-SLs almost to baseline. Immunohistochemistry and immunofluorescence showed that the enhancement in the CD105- showed that the enhancement in the CD105-Gd-SLs group resulted mainly from new microvessels. While in the other three groups, mature microvessels and new microvasculature resulted in the enhancement of the tumor. Conclusion: CD105-Gd-SLs can be used to detect early tumor angiogenesis on MR images. This might provide a means to non-invasively reveal a malignant phenotype of extracerebral F98 tumor and evaluate its progression.

  1. Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors

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    Avilés-Salas Alejandro

    2009-08-01

    Full Text Available Abstract Background Germ cell testicular tumors have survival rate that diminishes with high tumor marker levels, such as human chorionic gonadotropin (hCG. hCG may regulate vascular neoformation through vascular endothelial growth factor (VEGF. Our purpose was to determine the relationship between hCG serum levels, angiogenesis, and VEGF expression in germ cell testicular tumors. Methods We conducted a retrospective study of 101 patients. Serum levels of hCG, alpha-fetoprotein (AFP, and lactate dehydrogenase were measured prior to surgery. Vascular density (VD and VEGF tissue expression were determined by immunohistochemistry and underwent double-blind analysis. Results Histologically, 46% were seminomas and 54%, non-seminomas. Median follow-up was 43 ± 27 months. Relapse was present in 7.5% and mortality in 11.5%. Factors associated with high VD included non-seminoma type (p = 0.016, AFP ? 14.7 ng/mL (p = 0.0001, and hCG ? 25 mIU/mL (p = 0.0001. In multivariate analysis, the only significant VD-associated factor was hCG level (p = 0.04. When hCG levels were stratified, concentrations ? 25 mIU/mL were related with increased neovascularization (p Conclusion This is the first study that relates increased serum hCG levels with vascularization in testicular germ cell tumors. Hence, its expression might play a role in tumor angiogenesis, independent of VEGF expression, and may explain its association with poor prognosis. hCG might represent a molecular target for therapy.

  2. Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis.

    Science.gov (United States)

    Cianchi, Fabio; Cortesini, Camillo; Fantappiè, Ornella; Messerini, Luca; Schiavone, Nicola; Vannacci, Alfredo; Nistri, Silvia; Sardi, Iacopo; Baroni, Gianna; Marzocca, Cosimo; Perna, Federico; Mazzanti, Roberto; Bechi, Paolo; Masini, Emanuela

    2003-03-01

    To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis. PMID:12598314

  3. The Combination of Tamoxifen and the Rexinoid LG100268 Prevents ER-Positive and ER-Negative Mammary Tumors in P53-Null Mammary Gland Mice

    OpenAIRE

    Mazumdar, Abhijit; Medina, Daniel; Kittrell, Francis S.; Zhang, Yun; Hill, Jamal L.; Edwards, David E.; Bissonnette, Reid P.; Brown, Powel H.

    2012-01-01

    In pursuit of effective therapeutic agents for the ER-negative breast cancer, we previously demonstrated that bexarotene reduced mammary tumor development by 75% in ErbB2 mice. To further improve the effectiveness of breast cancer prevention, we have now investigated the effects of a combinatorial therapy consisting of two cancer preventive drugs. Based on the hypothesis, rexinoid LG100268 plus tamoxifen would more effectively prevent the development of both ER-positive and ER-negative breast...

  4. Visualization of a human mammary tumor in nude mice with In-111 labeled monoclonal antibody

    International Nuclear Information System (INIS)

    A monoclonal antibody designated 103D2, specific for a tumor associated 126 kilodalton phosphoglycoprotein antigen from human mammary carcinoma (HMC) was used to determine the feasibility of tumor detection and visualization in nude mice. 103D2 was precoupled to DTPA and labeled with In-111 by the transchelation method. The labeled 103D2 (200?Ci/20?g) was injected intravenously via the tail veins into nude mice hosting a HMC BT-20(n=8). The mice were imaged at 1 hr, and every 24 hr thereafter for up to 6 days with a pinhole collimator. Four animals were killed at 48 hr and 4 at 7 days, and biodistribution determined by gamma counting of various organs. To define the specificity of distribution of the antibody, 8 additional tumor bearing animals were studied: 4 with a different In-111 labeled IgG (MOPC-21-myeloma IgG/sub 1/) and 4 with injection of ionic In-111. Localization of the In-111 labeled 103D2 was 14.72 +- 2.25% injected dose per gram of the tumor (D/g) at 48 hr, whereas In-111 labeled MOPC-21 was 5.78 +- 1.08 D/g and ionic In-111 was 3.8 +- 0.81% D/g. Tumor localization at 7 days after iv administration of In-111 labeled 103D2 was observed to be 21.97 +- 4.44% D/g. Tumors were visualized with In-111 labeled 103D2 as early as 1-2 hr after iv injection but by 24 hr, unequivocal delineation of the tumors was observed in all animals, with the best tumor delineation at 2 to 4 days. Tumor visualization with In-111 labeled 103D2 was also possible even when the tumors were inplanted in the upper abdominal region over the liver and spleen. The authors conclude that monoclonal antibody specific to a HMC associated 126 kd phosphoglycoprotein antigen can be used to visualize human mammary tumors hosted in nude mice by gamma scintigraphy

  5. Effects of Acanthus ebracteatus Vahl on tumor angiogenesis and on tumor growth in nude mice implanted with cervical cancer

    Directory of Open Access Journals (Sweden)

    Mahasiripanth T

    2012-08-01

    Full Text Available Taksanee Mahasiripanth,1 Sanya Hokputsa,2 Somchai Niruthisard,3 Parvapan Bhattarakosol,4 Suthiluk Patumraj51Inter-Department of Physiology, Chulalongkorn University, Bangkok, Thailand; 2Research and Development Institute, Government Pharmaceutical Organization, Bangkok, Thailand; 3Obstetrics and Gynecology Department, 4Department of Microbiology, 5Center of Excellence for Microcirculation, Faculty of Medicine, Chulalongkorn University, Bangkok, ThailandPurpose: The aim of this study was to examine the effects of the crude extract of Acanthus ebracteatus Vahl (AE on tumor growth and angiogenesis by utilizing a tumor model in which nude mice were implanted with cervical cancer cells containing human papillomavirus 16 DNA (HPV-16 DNA.Materials and methods: The growth-inhibitory effect of AE was investigated in four different cell types: CaSki (HPV-16 positive, HeLa (HPV-18 positive, hepatocellular carcinoma cells (HepG2, and human dermal fibroblast cells (HDFs. The cell viabilities and IC50 values of AE were determined in cells incubated with AE for different lengths of time. To conduct studies in vivo, female BALB/c nude mice (aged 6–7 weeks, weighing 20–25 g were used. A cervical cancer-derived cell line (CaSki with integrated HPV-16 DNA was injected subcutaneously (1 × 107 cells/200 µL in the middle dorsum of each animal (HPV group. One week after injection, mice were fed orally with AE crude extract at either 300 or 3000 mg/kg body weight/day for 14 or 28 days (HPV-AE groups. Tumor microvasculature and capillary vascularity were determined using laser scanning confocal microscopy. Tumor tissue was collected from each mouse to evaluate tumor histology and vascular endothelial growth factor (VEGF immunostaining.Results: The time-response curves of AE and the dose-dependent effect of AE on growth inhibition were determined. After a 48-hour incubation period, the IC50 of AE in CaSki was discovered to be significantly different from that of HDFs (P < 0.05. A microvascular network was observed around the tumor area in the HPV group on days 21 and 35. Tumor capillary vascularity in the HPV group was significantly increased compared with the control group (P < 0.001. High-dose treatment of AE extract (HPV-3000AE group significantly attenuated the increase in VEGF expression and tumor angiogenesis in mice that received either the 14- or 28-day treatment period (P < 0.001.Conclusion: Our novel findings demonstrated that AE crude extract could inhibit cervical cancer growth, VEGF expression, and angiogenesis in a CaSki-cell transplant model in mice.Keywords: Acanthus ebracteatus Vahl, tumor angiogenesis, VEGF, CaSki cell-implanted nude mice, capillary vascularity, laser scanning confocal microscopy

  6. The hyaluronan synthesis inhibitor 4-methylumbelliferone exhibits antitumor effects against mesenchymal-like canine mammary tumor cells

    OpenAIRE

    Saito, Teruyoshi; Dai, Tamura; Asano, Ryuji

    2013-01-01

    Hyaluronan (HA), a principal constituent of the extracellular matrix (ECM), mediates growth and metastasis of tumor cells. The role of HA in the epithelial-mesenchymal transition (EMT) is well known, and increased ECM remodeling is observed in mesenchymal-like cells. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) is anti-tumorigenic for various malignant tumors. However, the antitumor effect of 4-MU against canine mammary tumor cells that possess a mesenchymal-like phenotype is uncle...

  7. Evaluation of angiogenesis of VX2 soft tissue tumor by arterial spin labeling perfusion imaging

    International Nuclear Information System (INIS)

    Objective: To evaluate the relationship between the blood flow values generated from MR arterial spin labeling (ASL) perfusion imaging and pathologic indicators of angiogenesis including microvascular density (MVD) counts and vascular endothelial growth factor (VEGF) expression levels of VX2 carcinoma in rabbit soft tissue. Methods: VX2 tumor was inoculated in the muscular tissue of right posterior limbs of 18 healthy New Zealand white rabbits, on which arterial spin labeling perfusion imaging was performed by using flow sensitive alternating inversion recovery pulse sequence 3 to 4 weeks later. Arterial spin labeling images were transferred to an independent computer for post-processing and blood flow (BF) maps were generated from them. BF values were measured in 2-4 regions of interest (ROIs) for each tumor. The rabbits were sacrificed after MR imaging. The gross specimens of tumors were obtained and tumor tissues were taken from the non-necrotic regions corresponding to ROIs on BF maps. Immunohistochemical staining of the specimens was performed by using CD31 monoclonal antibody to calculate MVD counts, using VEGF antibody to calculate VEGF expression levels. Correlation between BF values and MVD counts as well as between BF values and VEGF expression levels was evaluated using Spearman, correlative analysis. Results: On BF maps, viable tumor tissues showed high BF values compared with muscle, but there were areas without blood perfusion in some tumors. Under microscope, the microvessels positively stained by CD31 appeared as light brown areas, and the cells positively staied by VEGF showed reddish brown areas within their cytoplasm. Totally 39 pieces of VX2 tumor tissue were analyzed. There was a significant positive correlation between the BF values (M =6.4 ml · 100 g-1 · min-1) and MVD counts (M=6.8) (r=0.906, P<0.01), and no significant correlation between BF values and VEGF expression levels (M=8%) (r= 0.116, P=0.483). Conclusion: BF value can be used in evaluating angiogenesis of soft tissue tumor through its reflection of MVD counts, and thus may be helpful in evaluating the prognosis of soft tissue tumor and making plan for their treatment. (authors)

  8. Aspectos clínico e cirúrgicos do tumor mamário canino: clinical and surgical evolution Canine mammary neoplasia

    Directory of Open Access Journals (Sweden)

    Carlos Roberto Daleck

    1998-03-01

    Full Text Available As neoplasias mamárias em cadelas representam importante parcela das neoplasias em cães, merecendo atenção dos pesquisadores quanto ao diagnóstico, tratamento e prognóstico. No presente trabalho, 23 cadelas de várias raças ou cruzamentos, com idades entre 8 e 11 anos portadoras de neoplasia mamária foram estudadas. Doze eram multíparas, 6 primíparas e 5 nulíparas. Todas eram da região de Jaboticabal, SP, atendidas no Hospital Veterinário da FCAVJ-UNESP. Os animais foram avaliados clínica e radiolagicamente e submetidos à punção aspirativa da massa anormal de tecido, com agulha fina. Dessa mesma massa foi também retirado, cirurgicamente, um fragmento para exame histopatológico. A maior incidência foi de carcinoma (52,17%, seguidos por tumores mistos (17,39%. Os tratamentos cirúrgicos empregados nos 23 animais foram: mastectomia regional ou mastectomia em bloco, com remoção de linfonodos. Quinze cadelas foram tratadas com doxorubicina, na dose de 20mg/m² e ciclofosfamida, na dose de 100mg/m², aos 7, 9 e 11 dias após o ato cirúrgico. Todos os animais tiveram evolução favorável e, 12 meses após a cirurgia, 18 deles foram reavaliados, não constatando nenhuma recidiva ou surgimento de metástase.Mammary gland tumors in female dogs are among the most important neoplasia in dogs, deserving special attention regarding its diagnosis, treatment and prognosis. In this study, 23 biches of different breeds, from 8 to 11 years of age, with mammary tumors were evaluated. Of the se, 12 were multiparous, 6 primiparous and 5 were nuliparous. All dogs came from the region of Jaboticabal, SP and were referred to the Veterinary Teaching Hospital of the FCAVJ-UNESP. The animals were evaluated clinically and radiographically and the mammary mass submitted to an aspirative needle. A fragment of the tumor was also removed surgically for histopathological examination. Most tumors were classified as carcinomas (52.17°/o, followed in number by mixed tumors (17.39%. Treatment included mamectomy, partial mastectomy or "en bloc" mastectomy with removal of the lymphnodes. Most dogs also received Doxorubicin (20mg/m² and Cyclokphosphamide (100mg/m² at, 7, 9 and 11 days post-operative. All dogs recovered uneventfully and at one year post-operative. Twelve dogs were reevaluated an considered to be free of recurrence of metastasis.

  9. Aspectos clínico e cirúrgicos do tumor mamário canino: clinical and surgical evolution / Canine mammary neoplasia

    Scientific Electronic Library Online (English)

    Carlos Roberto, Daleck; Paulo Henrique, Franceschini; Antonio Carlos, Alessi; Áureo Evangelista, Santana; Maria Izabel Mello, Martins.

    1998-03-01

    Full Text Available As neoplasias mamárias em cadelas representam importante parcela das neoplasias em cães, merecendo atenção dos pesquisadores quanto ao diagnóstico, tratamento e prognóstico. No presente trabalho, 23 cadelas de várias raças ou cruzamentos, com idades entre 8 e 11 anos portadoras de neoplasia mamária [...] foram estudadas. Doze eram multíparas, 6 primíparas e 5 nulíparas. Todas eram da região de Jaboticabal, SP, atendidas no Hospital Veterinário da FCAVJ-UNESP. Os animais foram avaliados clínica e radiolagicamente e submetidos à punção aspirativa da massa anormal de tecido, com agulha fina. Dessa mesma massa foi também retirado, cirurgicamente, um fragmento para exame histopatológico. A maior incidência foi de carcinoma (52,17%), seguidos por tumores mistos (17,39%). Os tratamentos cirúrgicos empregados nos 23 animais foram: mastectomia regional ou mastectomia em bloco, com remoção de linfonodos. Quinze cadelas foram tratadas com doxorubicina, na dose de 20mg/m² e ciclofosfamida, na dose de 100mg/m², aos 7, 9 e 11 dias após o ato cirúrgico. Todos os animais tiveram evolução favorável e, 12 meses após a cirurgia, 18 deles foram reavaliados, não constatando nenhuma recidiva ou surgimento de metástase. Abstract in english Mammary gland tumors in female dogs are among the most important neoplasia in dogs, deserving special attention regarding its diagnosis, treatment and prognosis. In this study, 23 biches of different breeds, from 8 to 11 years of age, with mammary tumors were evaluated. Of the se, 12 were multiparou [...] s, 6 primiparous and 5 were nuliparous. All dogs came from the region of Jaboticabal, SP and were referred to the Veterinary Teaching Hospital of the FCAVJ-UNESP. The animals were evaluated clinically and radiographically and the mammary mass submitted to an aspirative needle. A fragment of the tumor was also removed surgically for histopathological examination. Most tumors were classified as carcinomas (52.17°/o), followed in number by mixed tumors (17.39%). Treatment included mamectomy, partial mastectomy or "en bloc" mastectomy with removal of the lymphnodes. Most dogs also received Doxorubicin (20mg/m²) and Cyclokphosphamide (100mg/m²) at, 7, 9 and 11 days post-operative. All dogs recovered uneventfully and at one year post-operative. Twelve dogs were reevaluated an considered to be free of recurrence of metastasis.

  10. Loss of STAT1 from Mouse Mammary Epithelium Results in an Increased Neu-Induced Tumor Burden

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    Peter J. Klover

    2010-11-01

    Full Text Available Type I and type II classes of interferons (IFNs signal through the JAK/STAT1 pathway and are known to be important in adaptive and innate immune responses and in protection against tumors. Although STAT1 is widely considered a tumor suppressor, it remains unclear, however, if this function occurs in tumor cells (cell autonomous or if STAT1 acts primarily through immune cells. Here, the question of whether STAT1 has a cell autonomous role in mammary tumor formation was addressed in a mouse model of ERBB2/neu-induced breast cancer in the absence and presence of STAT1. For this purpose, mice that carry floxed Stat1 alleles, which permit cell-specific removal of STAT1, were generated. To induce tumors only in mammary cells lacking STAT1, Stat1 floxed mice were crossed with transgenic mice that express cre recombinase and the neu oncogene under the mouse mammary tumor virus LTR (Stat1fl/fl NIC. Stat1 was effectively deleted in mammary epithelium of virgin Stat1fl/fl NIC females. Time-to-tumor onset was significantly shorter in Stat1fl/fl NIC females than in WT NIC (Wilcoxon rank sum test, P = .02. The median time-to-tumor onset in the Stat1fl/fl NIC mice was 49.4 weeks, whereas it was 62.4 weeks in the WT NIC mice. These results suggest that STAT1 in mammary epithelial cells may play a role in suppressing tumorigenesis. The Stat1 floxed allele described in this study is also a unique resource to determine the cellular targets of IFNs and STAT1 action, which should aid our understanding and appreciation of these pathways.

  11. Endogenous Angiogenesis Inhibitor Blocks Tumor Growth via Direct and Indirect Effects on Tumor Microenvironment

    OpenAIRE

    Bourboulia, Dimitra; Jensen-Taubman, Sandra; Rittler, Matthew R.; Han, Hui Ying; Chatterjee, Tania; Wei, Beiyang; William G. Stetler-Stevenson

    2011-01-01

    Tissue inhibitor of matrix metalloproteinase–2 (TIMP-2) belongs to a small family of endogenous proteins that inhibits a group of enzymes, the matrix metalloproteinases (MMPs). TIMP-2 inhibits endothelial cell proliferation and migration in vitro and angiogenesis in vivo, through MMP-dependent and -independent mechanisms. However, little is known regarding the contribution of these mechanisms to the antitumor effects of TIMP-2. Using a retroviral delivery system, we stably overexpressed TIMP-...

  12. Roles and Mechanism of miR-199a and miR-125b in Tumor Angiogenesis

    OpenAIRE

    He, Jun; Jing, Yi; Li, Wei; Qian, Xu; Xu, Qing; Li, Feng-Shan; Liu, Ling-Zhi; Jiang, Bing-Hua; Jiang, Yue

    2013-01-01

    MicroRNAs (miRNAs) have been shown to be involved in different aspects of cancer biology including tumor angiogenesis. In this study, we identified that two miRNAs, miR-199a and miR-125b were downregulated in ovarian cancer tissues and cell lines. Overexpression of miR-199a and miR-125b inhibited tumor-induced angiogenesis associated with the decrease of HIF-1? and VEGF expression in ovarian cancer cells. Moreover, the levels of miR-199a and miR-125b were negatively correlated with VEGF mRNA...

  13. Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble.

    Science.gov (United States)

    Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S; Mahakian, Lisa M; Lai, Chun-Yen; Tumbale, Spencer K; Teesalu, Tambet; Hubbard, Neil E; Borowsky, Alexander D; Ferrara, Katherine W

    2015-07-01

    Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ?6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7-21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis. PMID:25934284

  14. Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice.

    Science.gov (United States)

    Gao, Jian-Li; Ji, Xing; He, Tong-Chuan; Zhang, Qi; He, Kai; Zhao, Yan; Chen, Su-Hong; Lv, Gui-Yuan

    2013-01-01

    Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET) exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET's anticancer activity. We compare TET with chemotherapy drug doxorubicin in 4T1 tumor bearing BALB/c mice model and find that TET exhibits an anticancer metastatic and antiangiogenic activities better than those of doxorubicin. The lung metastatic sites were decreased by TET, which is confirmed by bioluminescence imaging in vivo. On the other hand, laser doppler perfusion imaging (LDI) was used for measuring the blood flow of tumor in 4T1-tumor bearing mice. As a result, the local blood perfusion of tumor was markedly decreased by TET after 3 weeks. Mechanistically, TET treatment leads to a decrease in p-ERK level and an increase in NF- ? B levels in HUVECs. TET also regulated metastatic and angiogenic related proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1 ? , integrin ? 5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo. PMID:23762115

  15. The maspin expression in canine mammary tumors: an immunohistochemical and molecular study A expressão do maspin nos tumores mamários caninos: um estudo imuno-histoquímico e molecular

    Directory of Open Access Journals (Sweden)

    Debora A.P.C. Zuccari

    2009-02-01

    Full Text Available The serpin maspin, a tumor suppressor in breast cancer was described as an inhibitor of cell migration and inducer of cell adhesion between the basement membrane and extracellular matrix resulting in inhibition of tumor metastasis. In contrast, overexpression of maspin is correlated with poor prognosis in other types of cancer. Little is known about expression, regulation and function of maspin in canine mammary tumors. It was demonstrated in this study, a loss of maspin expression in malignant canine mammary cells compared with a pool of normal canine mammary tissue, analyzed by quantitative real-time PCR; weak maspin expression in malignant canine mammary tumors were observed by immunohistochemistry. It was also demonstrated that a correlation with nuclear maspin expression and a good prognosis. It is suggested that maspin could be used as a prognostic marker in canine mammary neoplasia.O serpin maspin, um supressor tumoral no câncer de mama foi descrito como inibidor de migração celular e indutor de adesão celular entre a membrana basal e a matriz extracelular resultando na inibição da metástase tumoral. Por outro lado, a alta expressão do maspin está relacionada com um mau prognóstico em outros tipos de câncer. Pouco se sabe sobre a expressão, regulação e função do maspin nos tumores mamários caninos. Neste estudo, foi demonstrada uma perda da expressão de maspin nas células mamárias malignas de cães quando comparadas com um pool de tecido mamário normal de cães, analisado por PCR quantitativa em tempo real. Houve uma expressão fraca maspin em preparações de tumores mamários malignos observadas por imuno-histoquímica. Também foi verificado que a expressão nuclear do maspin em tumores mamários caninos está relacionada a um bom prognóstico. Assim, o maspin pode ser utilizado como um marcador prognóstico nas neoplasias mamárias em cães.

  16. The maspin expression in canine mammary tumors: an immunohistochemical and molecular study / A expressão do maspin nos tumores mamários caninos: um estudo imuno-histoquímico e molecular

    Scientific Electronic Library Online (English)

    Debora A.P.C., Zuccari; Rodrigo, Castro; Arieli F., Gavioli; Ulises M., Mancini; Eloisa H., Tajara; Cibelli S., Frade; Luana R., Pivaro; Juliana, Carmona-Raphe; Ana Carolina B., Terzian; Camila M., Ruiz; Eny M. Goloni, Bertollo; Érika C., Pavarino-Bertelli.

    2009-02-01

    Full Text Available O serpin maspin, um supressor tumoral no câncer de mama foi descrito como inibidor de migração celular e indutor de adesão celular entre a membrana basal e a matriz extracelular resultando na inibição da metástase tumoral. Por outro lado, a alta expressão do maspin está relacionada com um mau prognó [...] stico em outros tipos de câncer. Pouco se sabe sobre a expressão, regulação e função do maspin nos tumores mamários caninos. Neste estudo, foi demonstrada uma perda da expressão de maspin nas células mamárias malignas de cães quando comparadas com um pool de tecido mamário normal de cães, analisado por PCR quantitativa em tempo real. Houve uma expressão fraca maspin em preparações de tumores mamários malignos observadas por imuno-histoquímica. Também foi verificado que a expressão nuclear do maspin em tumores mamários caninos está relacionada a um bom prognóstico. Assim, o maspin pode ser utilizado como um marcador prognóstico nas neoplasias mamárias em cães. Abstract in english The serpin maspin, a tumor suppressor in breast cancer was described as an inhibitor of cell migration and inducer of cell adhesion between the basement membrane and extracellular matrix resulting in inhibition of tumor metastasis. In contrast, overexpression of maspin is correlated with poor progno [...] sis in other types of cancer. Little is known about expression, regulation and function of maspin in canine mammary tumors. It was demonstrated in this study, a loss of maspin expression in malignant canine mammary cells compared with a pool of normal canine mammary tissue, analyzed by quantitative real-time PCR; weak maspin expression in malignant canine mammary tumors were observed by immunohistochemistry. It was also demonstrated that a correlation with nuclear maspin expression and a good prognosis. It is suggested that maspin could be used as a prognostic marker in canine mammary neoplasia.

  17. In vivo monitoring of line 168 mammary tumors by topical nuclear magnetic resonance

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) shows considerable potential in the treatment of cancer. Recent advances in nuclear magnetic resonance spectroscopy have made in vivo imaging for clinical purposes a reality. Basic biochemical events can be monitored in vivo with /sup 31/p and /sup 13/C topical magnetic resonance (TMR). The authors have developed radiolabeled monoclonal antibodies/antibody fragments as specific RIT agents against several tumor lines. To determine the efficacy of various radiation dosages on tumor targets in a murine model, the authors chose /sup 31/p TMR to allow nondestructive monitoring of tumor metabolism in vivo. Major sources of free energy in cells contain phosphorus; NMR signal intensities are proportional to concentrations of nuclei in a given environment. Relative ratios of phosphorus metabolites describe the physiological status of tissue. TMR of 168 mammary tumors in BALB/C mice indicated that the peak intensity of inorganic phosphate and phosphocreatine (PCr) resonances correlated well with the presence and extent of necrosis. The spectrum of a tumor in which cells were rapidly dividing was significantly different from the necrotic tumor. Relative ratios of ATP and PCr provided information on metabolic function within the tumor. Striking spectral differences between rapidly dividing tumor tissue and necrotic tissue justify use of this method to predict therapeutic efficacy of RIT dosage regimens. This noninvasive determination of metabolic function appears useful in characterizing the extent of radiation-induced necrosis, spontaneous recurrence of tumor tissue, and sequential evaluation of various dose modalities. These data can be used for optimization of human RIT protocols and effective tracking of tumorigenesis in humans

  18. The maspin expression in canine mammary tumors: an immunohistochemical and molecular study A expressão do maspin nos tumores mamários caninos: um estudo imuno-histoquímico e molecular

    OpenAIRE

    Zuccari, Debora A. P. C.; Rodrigo de Castro; Gavioli, Arieli F.; Mancini, Ulises M.; Tajara, Eloisa H.; Frade, Cibelli S.; Pivaro, Luana R.; Juliana Carmona-Raphe; Terzian, Ana Carolina B.; Ruiz, Camila M.; Goloni Bertollo, Eny M.; Pavarino-bertelli, E?rika C.

    2009-01-01

    The serpin maspin, a tumor suppressor in breast cancer was described as an inhibitor of cell migration and inducer of cell adhesion between the basement membrane and extracellular matrix resulting in inhibition of tumor metastasis. In contrast, overexpression of maspin is correlated with poor prognosis in other types of cancer. Little is known about expression, regulation and function of maspin in canine mammary tumors. It was demonstrated in this study, a loss of maspin expression in maligna...

  19. Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands Identificação de mutações nos exons 4 a 8 do gene p53 supressor de tumor em glândulas mamárias caninas

    OpenAIRE

    Souza, D. M. B.; Barros, M. G. O.; Silva, J. S. C.; Silva, M. B.; Coleto, Z. F.; Jimenez, G. C.; Adria?o, M.; Wischral, A.

    2012-01-01

    Fifteen female canines with mammary tumors and 6 normal females were used to study mutations in exons 4 to 8 of the p53 gene. DNA samples from the tumors, respective adjacent normal mammary tissue and mammary glands from healthy animals were sequenced and analyzed for the presence of mutations. Mutations were found in 71.8% of the samples and the most frequent were missense mutations. The most attacked exons in the mammary tumor were 5, 7 and 8, with 23.4, 31.6 and 23.4% mutations, respective...

  20. Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

    Directory of Open Access Journals (Sweden)

    Salvesen Gerd S

    2009-12-01

    Full Text Available Abstract Background Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix. Methods One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO treatment (2 bar, pO2 = 2 bar, 4 exposures à 90 min, whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif, collagen content, oxygen stress (measured as malondialdehyd levels, lymphatics and transcapillary transport in the tumors. Results The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%, but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake. Conclusion We showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO2.

  1. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Science.gov (United States)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. PMID:25599228

  2. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue.

    Science.gov (United States)

    Santander, Ana M; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P; Gonzalez-Perez, Ruben R; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. PMID:25599228

  3. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Ana M. Santander

    2015-01-01

    Full Text Available The relationship between obesity and breast cancer (BC has focused on serum factors. However, the mammary gland contains adipose tissue (AT which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations. In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  4. Pilot study of p62 DNA vaccine in dogs with mammary tumors.

    Science.gov (United States)

    Gabai, Vladimir; Venanzi, Franco M; Bagashova, Elena; Rud, Oksana; Mariotti, Francesca; Vullo, Cecilia; Catone, Giuseppe; Sherman, Michael Y; Concetti, Antonio; Chursov, Andrey; Latanova, Anastasia; Shcherbinina, Vita; Shifrin, Victor; Shneider, Alexander

    2014-12-30

    Our previous data demonstrated profound anti-tumor and anti-metastatic effects of p62 (sqstm1) DNA vaccine in rodents with various types of transplantable tumors. Testing anti-cancer medicine in dogs as an intermediary step of translational research program provides two major benefits. First, clinical data collected in target animals is required for FDA/USDA approval as a veterinary anti-cancer drug or vaccine. It is noteworthy that the veterinary community is in need of novel medicine for the prevention and treatment of canine and feline cancers. The second more important benefit of testing anti-cancer vaccines in dogs is that spontaneous tumors in dogs may provide invaluable information for human trials. Here, we evaluated the effect(s) of p62 DNA vaccine on mammary tumors of dogs. We found that p62 DNA vaccine administered i.m. decreased or stabilized growth of locally advanced lesions in absence of its overall toxic effects. The observed antitumor activity was associated with lymphocyte infiltration and tumor encapsulation via fibrotic reaction. This data justifies both human clinical trials and veterinary application of p62 DNA vaccine. PMID:25296974

  5. Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine

    Directory of Open Access Journals (Sweden)

    Chao Liu

    2011-01-01

    Full Text Available AIM: To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1 isolated from an extract of herbal medicine Sorbaria sorbifolia. METHODS: Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM method. Microvessel density (MVD was determined by staining tissue sections immunohistochemically for CD34 using the Weidner capillary counting method. The mRNA and protein levels of vascular endothelial growth factor (VEGF, vascular endothelialgrowth factor receptor 2 (VEGFR2, Flk-1/KDR, basic fibroblast growth factor (bFGF, cyclo-oxygenase (COX-2 and hypoxia-inducible factor (HIF-1? were detected by quantitative real-time polymerase chain reaction and Western blotting analysis. RESULTS: The TTF1 inhibition rates for CAM were 30.8%, 38.2% and 47.5% with treatment concentrations of 25, 50 and 100 ?g/embryo × 5 d, respectively. The inhibitory rates for tumor size were 43.8%, 49.4% and 59.6% at TTF1 treatment concentrations of 5, 10, and 20 ?mol/kg, respectively. The average MVD was 14.2, 11.2 and 8.5 at treatment concentrations of 5 ?mol/kg, 10 ?mol/kg and 20 ?mol/kg TTF1, respectively. The mRNA and protein levels of VEGF, KDR, bFGF, COX-2 and HIF-1? in mice treated with TTF1 were significantly decreased. CONCLUSION: TTF1 can inhibit tumor angiogenesis, and the mechanism may be associated with the down-regulation of VEGF, KDR, bFGF, HIF-1? and COX-2.

  6. Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Xing-Cheng Zhao

    2013-07-01

    Full Text Available The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD motif targeting endothelial cells (ECs. We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

  7. 64Cu-Labeled tetraiodothyroacetic acid-conjugated liposomes for PET imaging of tumor angiogenesis

    International Nuclear Information System (INIS)

    Introduction: We synthesized and evaluated 64Cu-labeled tetraiodothyroacetic acid (tetrac)-conjugated liposomes for PET imaging of tumor angiogenesis, because tetrac inhibits angiogenesis via integrin ?V?3. Methods: Tetrac-PEG-DSPE and DOTA-PEG-DSPE were synthesized and formulated with other lipids into liposomes. The resulting tetrac/DOTA-liposomes were labeled with 64Cu at 40 °C for 1 h and purified using a PD-10 column. 64Cu-DOTA-liposomes were also prepared for comparison. Human aortic endothelial cell (HAEC) binding studies were performed by incubating the liposomes with the cells at 37 °C. MicroPET imaging followed by tissue distribution study was carried out using U87MG tumor-bearing mice injected with tetrac/64Cu-DOTA-liposomes or 64Cu-DOTA-liposomes. Results: HAEC binding studies exhibited that tetrac/64Cu-DOTA-liposomes were avidly taken up by the cells from 1.02 %ID at 1 h to 11.89 %ID at 24 h, while 64Cu-DOTA-liposomes had low uptake from 0.47 %ID at 1 h to 1.57 %ID at 24 h. MicroPET imaging of mice injected with tetrac/64Cu-DOTA-liposomes showed high radioactivity accumulation in the liver and spleen. ROI analysis of the tumor images revealed 1.93 ± 0.12 %ID/g at 1 h and 2.70 ± 0.36 %ID/g at 22 h. In contrast, tumor ROI analysis of 64Cu-DOTA-liposomes revealed 0.54 ± 0.08 %ID/g at 1 h and 0.52 ± 0.09 %ID/g at 22 h. Tissue distribution studies confirmed that the tumor uptakes of tetrac/64Cu-DOTA-liposomes and 64Cu-DOTA-liposomes were 1.75 ± 0.03 %ID/g and 0.36 ± 0.01 %ID/g at 22 h, respectively. Conclusion: These results demonstrate that tetrac/64Cu-DOTA-liposomes have significantly enhanced tumor uptake compared to 64Cu-DOTA-liposomes due to tetrac conjugation. Further studies are warranted to reduce the liver and spleen uptake of tetrac/64Cu-DOTA-liposomes

  8. 1H-NMR METABONOMICS ANALYSIS OF SERA DIFFERENTIATES BETWEEN MAMMARY TUMOR-BEARING MICE AND HEALTHY CONTROLS

    Science.gov (United States)

    Global analysis of 1H-NMR spectra of serum is an appealing approach for the rapid detection of cancer. To evaluate the usefulness of this method in distinguishing between mammary tumor-bearing mice and healthy controls, we conducted 1H-NMR metabonomic analyses on serum samples ob...

  9. Dissecting the dynamics of dysregulation of cellular processes in mouse mammary gland tumor

    Directory of Open Access Journals (Sweden)

    de la Fuente Alberto

    2009-12-01

    Full Text Available Abstract Background Elucidating the sequence of molecular events underlying breast cancer formation is of enormous value for understanding this disease and for design of an effective treatment. Gene expression measurements have enabled the study of transcriptome-wide changes involved in tumorigenesis. This usually occurs through identification of differentially expressed genes or pathways. Results We propose a novel approach that is able to delineate new cancer-related cellular processes and the nature of their involvement in tumorigenesis. First, we define modules as densely interconnected and functionally enriched areas of a Protein Interaction Network. Second, 'differential expression' and 'differential co-expression' analyses are applied to the genes in these network modules, allowing for identification of processes that are up- or down-regulated, as well as processes disrupted (low co-expression or invoked (high co-expression in different tumor stages. Finally, we propose a strategy to identify regulatory miRNAs potentially responsible for the observed changes in module activities. We demonstrate the potential of this analysis on expression data from a mouse model of mammary gland tumor, monitored over three stages of tumorigenesis. Network modules enriched in adhesion and metabolic processes were found to be inactivated in tumor cells through the combination of dysregulation and down-regulation, whereas the activation of the integrin complex and immune system response modules is achieved through increased co-regulation and up-regulation. Additionally, we confirmed a known miRNA involved in mammary gland tumorigenesis, and present several new candidates for this function. Conclusions Understanding complex diseases requires studying them by integrative approaches that combine data sources and different analysis methods. The integration of methods and data sources proposed here yields a sensitive tool, able to pinpoint new processes with a role in cancer, dissect modulation of their activity and detect the varying assignments of genes to functional modules over the course of a disease.

  10. Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell.

    Science.gov (United States)

    Akrami, Hassan; Aminzadeh, Saman; Fallahi, Hossein

    2015-05-01

    Numerous epidemiological studies have suggested effectiveness of long-term and regular use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, in preventing and treatment of certain cancers including prostate, colon, breast, lung, and gastric cancers. We have studied the potential anti-turmeric effect of ibuprofen in adenocarcinoma gastric cell line (AGS). The effects of ibuprofen were investigated on cell proliferation, apoptosis, angiogenesis, and expression of stemness marker genes using real-time RT-PCR, DNA laddering, and tube formation assays via ECM gel and human umbilical vein endothelial cells (HUVECs). Annexin-V-FLUOS and propidium iodide (PI) were used to stain the apoptotic cells. Our findings indicate that ibuprofen at the concentrations of 100, 200, 300, 400, and 500 ?M is able to reduce the cancerous characteristics of the AGS cells by inducing apoptosis, inhibition of cell proliferation, and angiogenesis. Real-time RT-PCR showed that ibuprofen altered the expression of several genes including Akt, P53, PCNA, Bax, and Bcl2 in the AGS cells. In addition, reduction in CD44 and OCT3/4 transcript levels revealed that ibuprofen reduces the stemness of the AGS cells and therefore it could be used as a potential anti-tumor drug. PMID:25542229

  11. Iron accumulation in mammary tumor suggests a tug of war between tumor and host for the microelement.

    Science.gov (United States)

    Freitas, Isabel; Boncompagni, Eleonora; Vaccarone, Rita; Fenoglio, Carla; Barni, Sergio; Baronzio, Gian Franco

    2007-01-01

    Iron is indispensable for the metabolism and proliferation of both normal and malignant cells. Recycling from senescent erythrocytes in the liver and spleen is critical for iron supply to all tissues. In the liver and spleen from MMTV-neu (erbB-2) mice bearing a mammary carcinoma, we noticed the scarcity of hemosiderin pigment and its abundance in the stroma of the tumor. Thus iron (III) was investigated with the Perls' reaction in tissues from normal and MMTV-neu mice. With respect to normal animals, in MMTV-neu mice, staining for iron was almost absent in the liver and scarce in the red pulp of the spleen. By contrast, iron was abundant in stromal and tumor cells in the invasion, angiogenic, necrotic and hemorrhagic regions and also in the interstitial fluid. These observations suggest that the tumor subverts iron recycling to its own advantage, by directly utilizing iron released from erythrocytes and dead tumor cells. Our findings are in keeping with the development of iron chelating drugs as chemotherapic agents. PMID:17970045

  12. Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer.

    Science.gov (United States)

    Bowman-Colin, Christian; Xia, Bing; Bunting, Samuel; Klijn, Christiaan; Drost, Rinske; Bouwman, Peter; Fineman, Laura; Chen, Xixi; Culhane, Aedin C; Cai, Hong; Rodig, Scott J; Bronson, Roderick T; Jonkers, Jos; Nussenzweig, Andre; Kanellopoulou, Chryssa; Livingston, David M

    2013-05-21

    Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germ-line deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2- or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo. PMID:23657012

  13. Immunohistochemical Localization of Cytokeratin, Vimentin and Alpa-Smooth Muscle Actin Micro and Intermediate Filaments in Canine Mammary Tumors

    OpenAIRE

    Mi?lli?, U?mit H.; Hazirog?lu, R?fk?; Aydin, Y?lmaz

    2000-01-01

    Forty-six formalin-fixed paraffin-embedded canine mammary tumors, 15 benign and 31 malignant, were studied immunohistochemically. Mouse monoclonal anti-alpha-cytokeratin 18, mouse monoclonal anti-alpha-cytokeratin (pan cytokeratin), mouse monoclonal anti-alpha-smooth muscle actin and mouse monoclonal anti-vimentin antibodies were used. The ductal and acinar epithelium stained positively for cytokeratin 18 and pan cytokeratin, although there was no immunoreactivity in some tumors. Metaplast...

  14. The Relationship between Clinicopathological Features and Expression of Epithelial and Mesenchymal Markers in Spontaneous Canine Mammary Gland Tumors

    OpenAIRE

    Yoshida, Kota; Yoshida, Saori; Choisunirachon, Nan; Saito, Tomochika; Matsumoto, Kaori; Saeki, Kohei; Mochizuki, Manabu; Nishimura, Ryohei; Sasaki, Nobuo; Nakagawa, Takayuki

    2014-01-01

    It is known that epithelial mesenchymal transition (EMT) contributes to the acquisition of malignant property in human cancers. However, the role of EMT in canine tumors remains to be elucidated. To evaluate the correlation between expression levels of protein markers involved in EMT and clinicopathological characteristics in canine mammary gland tumors, immunohistochemistry using antibodies against ZO-1, E-cadherin, vimentin, N-cadherin and fibronectin was performed on 119 ...

  15. Misregulation of Stromelysin-1 in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1 dependent Invasive Properties

    Energy Technology Data Exchange (ETDEWEB)

    Lochter, A.; Srebrow, A.; Sympson, C.J.; Terracio, N.; Werb, Z.; Bissell, M.J.

    1997-02-21

    Stromelysin-1 is a member of the metalloproteinase family of extracellular matrix-degrading enzymes that regulates tissue remodeling. We previously established a transgenic mouse model in which rat stromelysin-1 targeted to the mammary gland augmented expression of endogenous stromelysin-1, disrupted functional differentiation, and induced mammary tumors. A cell line generated from an adenocarcinoma in one of these animals and a previously described mammary tumor cell line generated in culture readily invaded both a reconstituted basement membrane and type I collagen gels, whereas a nonmalignant, functionally normal epithelial cell line did not. Invasion of Matrigel by tumor cells was largely abolished by metalloproteinase inhibitors, but not by inhibitors of other proteinase families. Inhibition experiments with antisense oligodeoxynucleotides revealed that Matrigel invasion of both cell lines was critically dependent on stromelysin-1 expression. Invasion of collagen, on the other hand, was reduced by only 40-50%. Stromelysin-1 was expressed in both malignant and nonmalignant cells grown on plastic substrata. Its expression was completely inhibited in nonmalignant cells, but up-regulated in tumor cells, in response to Matrigel. Thus misregulation of stromelysin-1 expression appears to be an important aspect of mammary tumor cell progression to an invasive phenotype. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that have been implicated in a variety of normal developmental and pathological processes, including tumorigenesis. The MMP family comprises at least 15 members with different, albeit overlapping, substrate specificities. During activation of latent MMPs, their propeptides are cleaved and they are converted to a lower molecular weight form by other enzymes, including serine proteinases, and by autocatalytic cleavage. Among the MMPs, stromelysin-1 (SL1) possesses the broadest substrate specificity. Despite increasing knowledge about its enzymatic properties and the regulation of its expression, little is known about its function. We have generated transgenic animals that express an autoactivating mutant of rat SL1 targeted to the epithelial compartment of the mammary gland. Phenotypically, SL1 transgenic mice display increased branching morphogenesis and lactogenic differentiation at prepubertal stages and premature involution during late pregnancy. Branching morphogenesis requires the invasion of epithelial cells into the adipose tissue, a process reminiscent of invasion of stromal compartments by tumor cells. Strikingly, a large number of SL1 transgenic animals also develop mammary tumors of various histotypes, including invasive adenocarcinomas. Because tumor development is a late response of SL1 transgenic mice to overexpression of the transgene, it remains unclear whether SL1 plays a direct role in tumor growth and/or invasion or whether the observed tumors are a consequence of other molecular alterations in the microenvironment of the mammary gland before the onset of tumor growth. Studies performed with synthetic inhibitors of MMP activity and tissue inhibitors of metalloproteinases (TIMPs) have shown that suppression of MMP activity also suppresses tumor growth and metastasis. In many cases, the level of SL1 expression in tumors of the mammary gland and other tissues is positively correlated with the degree of malignancy. However, the only direct evidence for the nature of the MMPs involved was provided by the demonstration that function-blocking antibodies against gelatinase A and antisense inhibition of matrilysin expression decreased the invasiveness of tumor cells in a reconstituted basement membrane assay. These studies encouraged us to investigate whether SL1 plays a direct role in invasion of ECM. We used two carcinoma cell lines, TCL1 and SCg6 that formed rapidly growing, invasive tumors in vivo and migrated through Matrigel and collagen gels in culture. Antisense oligodeoxynucleotides (ODNs) against SL1 inhibited Matrigel invasion by TCL1 and SCg

  16. c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors

    Scientific Electronic Library Online (English)

    A.P., Dutra; N.V.M., Granja; F.C., Schmitt; G.D., Cassali.

    1673-16-01

    Full Text Available The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 ma [...] lignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil) and the Veterinary Faculty of Porto University (Portugal). c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor) in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4%) of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P

  17. A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer.

    Science.gov (United States)

    Zheng, Lixiang; Zhou, Bugao; Meng, Xianming; Zhu, Weifeng; Zuo, Airen; Wang, Xiaomin; Jiang, Runde; Yu, Shiping

    2014-12-01

    Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and muscle tissue. Metastatic spread through blood vessel into liver and lungs was observed by hematoxylin eosin staining. No estrogen receptor (ER) or progesterone receptor (PR) immunoreactivity was detected in their associated malignant tumors, human epidermal growth factor receptor-2 (HER-2) protein weak expression was found by immunohistochemistry. High expression of vascular endothelial growth factor (VEGF), moderate or high expression of c-Myc and cyclin D1 were observed in tumor sections at different stages (2, 4, 6 and 8 weeks after cancer being found) when compared with that of the normal mammary glands. The result showed that the model is of an invasive ductal carcinoma. Remarkably in the mouse model, ER and PR-negative and HER2 weak positivity are observed. The high or moderate expressions of breast cancer markers (VEGF, c-Myc and cyclin D1) in mammary cancer tissue change at different stages. To our knowledge, this is the first report of a spontaneous mammary model displaying colony-strain, outbred mice. This model will be an attractive tool to understand the biology of anti-hormonal breast cancer in women. PMID:25230850

  18. Nuclear localization of long-VEGF is associated with hypoxia and tumor angiogenesis

    International Nuclear Information System (INIS)

    Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has a pivotal role in normal and pathological angiogenesis. VEGF has a long 5' untranslated region harboring an open reading frame (ORF) initiated by a CUG codon that is in-frame with the VEGF coding region. The ORF translation leads to the expression of a long isoform termed L-VEGF that is extended by an additional 180 amino acids. In this communication, we provide evidence that L-VEGF is subjected to proteolytic cleavage leading to the detachment of the 180 aa extension from the VEGF moiety. Using immunofluorescence staining, we show that upon hypoxia this 180 aa extension translocates to the nuclei of expressing cells. Accordingly, immunohistochemical staining of both normal and tumor tissue samples demonstrated restricted nuclear localization of the ORF, which was correlated with cytoplasmic localization of VEGF. This suggests that the 180 aa ORF is involved in VEGF-mediated angiogenic processes

  19. Synthesis of Specific Nanoparticles for Targeting and Imaging Tumor Angiogenesis Using Electron-Beam Irradiation

    International Nuclear Information System (INIS)

    We have succeeded to synthesize PVDF nanoparticles by nanoemulsion polymerization and their functionalization with a peptide that presents an anti-angiogenic activity. Resulted nanoparticles present a radius of 60 nm. From FESEM images and light scattering measurements, we deduced that they were spherical and monodisperse. The alkyl radicals induced from electron beam irradiation combine immediately with the oxygen to form peroxide radicals. Because of a high specific area and small crystallite size, the radical decay with time is evidenced from EPR measurements. Despite this radical decay, electron beam irradiation allows us to graft PAA by radical polymerization onto freshly irradiated PVDF nanoparticles and then to immobilize CBO-P11 by click chemistry via a spacer arm. Evidences of grafting were shown using HRMAS NMR and MALDI-TOF mass spectrometry. Nanoparticles functionalized with an angiogenesis-targeting agent are an attractive option for anti-tumor therapy

  20. Regulation of adipocyte lipid homeostasis by genistein alters mammary epithelial cell differentiation: a paracrine mechanism for mammary tumor protection

    Science.gov (United States)

    Epidemiological and animal studies have shown a negative correlation between breast cancer incidence and intake of soy rich foods. Our laboratory has studied soy protein isolate (SPI), the primary component of soy infant formula, as a paradigm to evaluate diet as a risk factor in mammary cancer. We ...

  1. Expressão dos filamentos intermediários no diagnóstico dos tumores mamários de cadelas / Expression of intermediate filaments in canine mammary tumors diagnosis

    Scientific Electronic Library Online (English)

    D.A.P.C., Zuccari; A.E., Santana; N.S., Rocha.

    2002-12-01

    Full Text Available Foram utilizados anticorpos monoclonais para marcação imunoistoquímica dos tecidos tumorais e obtenção de informações sobre a histogênese dos tumores mamários utilizando-se anti-citoqueratinas para marcação de células epiteliais, e anti-actina e anti-vimentina para células mioepiteliais. O procedime [...] nto imunoistoquímico mostrou-se esclarecedor com relação à histogênese dos tumores mamários, confirmando a marcação de células epiteliais com as citoqueratinas que perdem sua expressão na transformação celular maligna. A alfa-actina e a vimentina mostraram-se eficientes na marcação de células mioepiteliais. A alfa-actina diminuiu a marcação na metaplasia óssea ou cartilaginosa contrariamente à vimentina cuja marcação foi aumentada. Os resultados permitem melhor entendimento da classificação dos tumores mamários de cadelas com a utilização de anticorpos monoclonais como marcadores do citoesqueleto, que se mostraram eficientes nessa caracterização. Abstract in english Immunohistochemical evaluation was performed to study the histogenesis of canine mammary tumors and to contribute to a better understanding of their classification. Monoclonal antibodies specific for different types of intermediate filaments (cytokeratins, vimentin, alpha-actin) were used. Epithelia [...] l cells stained positively for cytokeratins and their expression was lost as the malignant transformation occurs. Myoepithelial cells stained positively for vimentin and alpha-actin. In contrast to vimentin, alpha-actin lost the expression as the cartilaginous or osseous metaplasia occurs. Immunohistochemical evaluation with monoclonal antibodies proved to be efficient for identification of tumor histogenesis. alpha-actin) were used. Epithelial cells stained positively for cytokeratins and their expression was lost as the malignant transformation occurs. Myoepithelial cells stained positively for vimentin and alpha-actin. In contrast to vimentin, alpha-actin lost the expression as the cartilaginous or osseous metaplasia occurs. Immunohistochemical evaluation with monoclonal antibodies proved to be efficient for identification of tumor histogenesis.

  2. Expressão dos filamentos intermediários no diagnóstico dos tumores mamários de cadelas Expression of intermediate filaments in canine mammary tumors diagnosis

    Directory of Open Access Journals (Sweden)

    D.A.P.C. Zuccari

    2002-12-01

    Full Text Available Foram utilizados anticorpos monoclonais para marcação imunoistoquímica dos tecidos tumorais e obtenção de informações sobre a histogênese dos tumores mamários utilizando-se anti-citoqueratinas para marcação de células epiteliais, e anti-actina e anti-vimentina para células mioepiteliais. O procedimento imunoistoquímico mostrou-se esclarecedor com relação à histogênese dos tumores mamários, confirmando a marcação de células epiteliais com as citoqueratinas que perdem sua expressão na transformação celular maligna. A alfa-actina e a vimentina mostraram-se eficientes na marcação de células mioepiteliais. A alfa-actina diminuiu a marcação na metaplasia óssea ou cartilaginosa contrariamente à vimentina cuja marcação foi aumentada. Os resultados permitem melhor entendimento da classificação dos tumores mamários de cadelas com a utilização de anticorpos monoclonais como marcadores do citoesqueleto, que se mostraram eficientes nessa caracterização.Immunohistochemical evaluation was performed to study the histogenesis of canine mammary tumors and to contribute to a better understanding of their classification. Monoclonal antibodies specific for different types of intermediate filaments (cytokeratins, vimentin, alpha-actin were used. Epithelial cells stained positively for cytokeratins and their expression was lost as the malignant transformation occurs. Myoepithelial cells stained positively for vimentin and alpha-actin. In contrast to vimentin, alpha-actin lost the expression as the cartilaginous or osseous metaplasia occurs. Immunohistochemical evaluation with monoclonal antibodies proved to be efficient for identification of tumor histogenesis. alpha-actin were used. Epithelial cells stained positively for cytokeratins and their expression was lost as the malignant transformation occurs. Myoepithelial cells stained positively for vimentin and alpha-actin. In contrast to vimentin, alpha-actin lost the expression as the cartilaginous or osseous metaplasia occurs. Immunohistochemical evaluation with monoclonal antibodies proved to be efficient for identification of tumor histogenesis.

  3. Cloning of partial cDNA encoding differentiation and tumor-associated mucin glycoproteins expressed by human mammary epithelium

    International Nuclear Information System (INIS)

    Human mammary epithelial cells secrete and express on their cell surfaces complex mucin glycoproteins that are developmentally regulated, tumor-associated, and highly immunogenic. Studies using monoclonal antibodies directed to these glycoproteins suggest that their molecular structures can vary with differentiation stages in the normal gland and in malignancy. To analyze the molecular nature of these glycoproteins, milk mucin was affinity-purifed and deglycosylated with hydrogen fluoride, yielding bands at 68 and 72 kDa on silver-stained gels. Polyclonal and monoclonal antibodies to the stripped core protein were developed and used to screen a ?gt11 expression library of cDNA made from mRNA of the mammary tumor cell line MCF-7. Seven crossreacting clones were isolated, with inserts 0.1-1.8 kilobases long. RNA blot analysis, using as a probe the 1.8-kilobase insert subcloned in plasmid pUC8 (pMUC10), revealed transcripts of 4.7 and 6.4 kilobases in MCF-7 and T47D mammary tumor cells, whereas normal mammary epithelial cells from pooled milks have additional transcripts. The expression of mRNA correlates with antigen expression as determined by binding of two previously characterized anti-mucin monoclonal antibodies (HMFG-1 and HMFG-2) to seven cell lines. Restriction enzyme analysis detected a restriction fragment length polymorphism when human genomic DNA was digested with EcoRI or HinfI

  4. Assessment of thermal effects of interstitial laser phototherapy on mammary tumors using proton resonance frequency method

    Science.gov (United States)

    Le, Kelvin; Li, Xiaosong; Figueroa, Daniel; Towner, Rheal A.; Garteiser, Philippe; Saunders, Debra; Smith, Nataliya; Liu, Hong; Hode, Tomas; Nordquist, Robert E.; Chen, Wei R.

    2011-12-01

    Laser immunotherapy (LIT) uses a synergistic approach to treat cancer systemically through local laser irradiation and immunological stimulation. Currently, LIT utilizes dye-assisted noninvasive laser irradiation to achieve selective photothermal interaction. However, LIT faces difficulties treating deeper tumors or tumors with heavily pigmented overlying skin. To circumvent these barriers, we use interstitial laser irradiation to induce the desired photothermal effects. The purpose of this study is to analyze the thermal effects of interstitial irradiation using proton resonance frequency (PRF). An 805-nm near-infrared laser with an interstitial cylindrical diffuser was used to treat rat mammary tumors. Different power settings (1.0, 1.25, and 1.5 W) were applied with an irradiation duration of 10 min. The temperature distributions of the treated tumors were measured by a 7 T magnetic resonance imager using PRF. We found that temperature distributions in tissue depended on both laser power and time settings, and that variance in tissue composition has a major influence in temperature elevation. The temperature elevations measured during interstitial laser irradiation by PRF and thermocouple were consistent, with some variations due to tissue composition and the positioning of the thermocouple's needle probes. Our results indicated that, for a tissue irradiation of 10 min, the elevation of rat tumor temperature ranged from 8 to 11°C for 1 W and 8 to 15°C for 1.5 W. This is the first time a 7 T magnetic resonance imager has been used to monitor interstitial laser irradiation via PRF. Our work provides a basic understanding of the photothermal interaction needed to control the thermal damage inside a tumor using interstitial laser treatment. Our work may lead to an optimal protocol for future cancer treatment using interstitial phototherapy in conjunction with immunotherapy.

  5. Autochthonous mouse melanoma and mammary tumors do not express the pluripotency genes Oct4 and Nanog.

    Science.gov (United States)

    Schreiber, Caroline; Kuch, Vanessa; Umansky, Viktor; Sleeman, Jonathan P

    2013-01-01

    The homeodomain transcription factors Oct4 and Nanog maintain pluripotency and self-renewal in embryonic stem cells. In somatic cells, inappropriate expression of these genes has been associated with loss of differentiation, malignant transformation, and the acquisition of cancer stem cell-like properties. As cancer stem cells have been suggested to underlie the growth and malignancy of tumors, Oct4 and Nanog may represent therapeutic targets. Their expression could also act as a marker of the cancer stem cell population, permitting its isolation and characterisation. Nevertheless, the existence of multiple pseudogenes and isoforms of these genes has complicated the interpretation of the data that supports a role for Oct4 and Nanog in the cancer context. Here we addressed this issue using knockin mice in which IRES elements are used to allow GFP expression under the control of the endogenous Oct4 or Nanog promoters, while maintaining correct expression of the Oct4 or Nanog gene. These mice were crossed with MT/ret mice that develop melanomas, and with MMTV-PyMT mice and MMTV-Neu mice that develop mammary adenocarcinomas. We analysed the tumors that developed in these compound mice for GFP expression. In this way we could assess transcription of Oct4 and Nanog in autochthonous cancers without the complication of factors such as pseudogene expression, alternative splicing and antibody specificity. Both the Oct4 and Nanog knockin tumor-bearing mice expressed GFP in blastocysts and testes as expected. However, we could find no evidence for expression of the GFP reporter above background levels in tumors using FACS, qPCR and immunohistochemistry. Furthermore, cultivation of Oct4GFP and NanogGFP MMTV-PyMT tumor cells either adherently or as spheroids had no effect on the expression of the GFP reporter. Together these data suggest that Oct4 and Nanog are not expressed in tumor cells that arise in the autochthonous cancer models studied here. PMID:23468991

  6. Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy.

    Science.gov (United States)

    Gasparini, G; Biganzoli, E; Bonoldi, E; Morabito, A; Fanelli, M; Boracchi, P

    2001-01-01

    Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed. PMID:11245342

  7. Effect of changing tumor oxygenation on glycolytic metabolism in a murine C3H mammary carcinoma assessed by in vivo nuclear magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Nielsen, Flemming U.; Daugård, Preben

    2001-01-01

    The rate of conversion of D-[1-(13)C]glucose into [3-(13)C]lactate (apparent glycolytic rate) has been determined in C3H murine mammary carcinomas in vivo using tumor-selective (13)C nuclear magnetic resonance spectroscopy with (1)H-(13)C cross-polarization. Under conditions of acute hypoxia induced by breathing carbon monoxide at 660 ppm, the apparent glycolytic rate was 0.0239 +/- 0.0019 min(-1). The proportion of (13)C label incorporated into [4-(13)C]glutamate (measured in tumor extracts) was 25-fold lower than that incorporated into [3-(13)C]lactate, reflecting a very limited oxidative metabolism during this hypoxic episode. For animals breathing air or carbogen (95% O(2) + 5% CO(2)), the calculated glycolytic rates were correspondingly lower (0.0160 +/- 0.0021 min(-1) and 0.0050 +/- 0.0011 min(-1), respectively). Although (13)C labeling of glutamate at C4 was still an order of magnitude lower than that for lactate at C3 (11-fold for air and 9-fold for carbogen), these ratios did show a greater degree ofoxidative metabolism than that seen in animals breathing carbon monoxide at 660 ppm. The marked difference in apparent glycolytic rate for this tumor model between well-oxygenated and hypoxic conditions demonstrates a substantial Pasteur effect (inhibition of glycolysis by oxygen). Dynamic (13)C nuclear magnetic resonance spectroscopy provides a noninvasive estimate of tumor glycolysis that can be used to evaluate the relationship between oxygenation and energy metabolism, and this has potential consequences for the sensitivity of hypoxic cells to treatment and their ability to promote angiogenesis.

  8. (64)Cu-NODAGA-c(RGDyK) Is a Promising New Angiogenesis PET Tracer : Correlation between Tumor Uptake and Integrin ?(V)?(3) Expression in Human Neuroendocrine Tumor Xenografts

    DEFF Research Database (Denmark)

    Oxboel, Jytte; Schjoeth-Eskesen, Christina

    2012-01-01

    Purpose. The purpose of this paper is to evaluate a new PET tracer (64)Cu-NODAGA-c(RGDyK) for imaging of tumor angiogenesis using gene expression of angiogenesis markers as reference and to estimate radiation dosimetry for humans. Procedures. Nude mice with human neuroendocrine tumor xenografts (H727) were administered (64)Cu-NODAGA-c(RGDyK) i.v. for study of biodistribution as well as for dynamic PET. Gene expression of angiogenesis markers integrin ?(V), integrin ?(3), and VEGF-A were analyzed using QPCR and correlated to the tracer uptake in the tumors (%ID/g). From biodistribution data human radiation-absorbed doses were estimated using OLINDA/EXM. Results. Tumor uptake was 1.2%ID/g with strong correlations between gene expression and tracer uptake, for integrin ?(V)?R = 0.76, integrin ?(3)?R = 0.75 and VEGF-A R = 0.81 (all P <0.05). The whole body effective dose for humans was estimated to be 0.038 and 0.029?mSv/MBq for females and males, respectively, with highest absorbed dose in bladder wall. Conclusion. (64)Cu-NODAGA-c(RGDyK) is a promising new angiogenesis PET tracer with potential for human use.

  9. Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction

    Science.gov (United States)

    Ochiya, Takahiro; Takenaga, Keizo; Asagiri, Masataka; Nakano, Kazumi; Satoh, Hitoshi; Watanabe, Toshiki; Imajoh-Ohmi, Shinobu; Endo, Hideya

    2015-01-01

    The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD) indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy. PMID:26029719

  10. Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats.

    Science.gov (United States)

    Kakehashi, Anna; Tago, Yoshiyuki; Yoshida, Midori; Sokuza, Yui; Wei, Min; Fukushima, Shoji; Wanibuchi, Hideki

    2012-03-01

    Our research is focused on modifying effects of an isoflavone aglycones (IAs)-rich extract at a hormonally active dose of 150 mg/kg body weight/day on mammary and endometrial carcinogenesis in female Donryu rats. IA administered for 2 weeks in a phytoestrogen-low diet exerted estrogenic activity and induced cell proliferation in the uterus of ovariectomized rats. Furthermore, administration for 4 weeks resulted in elevation of cell proliferation in the mammary glands of 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals. Forty weeks of postpubertal administration of IA to 5-week-old rats after initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) caused significant increase of incidence and multiplicity of mammary adenocarcinoma, multiplicities of endometrial atypical hyperplasia, adenomatous polyps, and an increased trend of uterine adenocarcinomas. Liquid chromatography with tandem mass spectrometry and immunohistochemical analyses revealed significant elevation of tumorigenesis-related proteins such as S100 calcium-binding protein A8, kininogen 1, and annexins 1 and 2 in mammary adenocarcinomas and cadherin EGF LAG seven-pass G-type receptor 2, DEAD box polypeptide 1, and cysteine- and glycine-rich protein 1 in uterine proliferative lesions of IA-treated animals. Those changes are likely to be related to modulation of estrogen receptor (ER), AP1, nuclear factor-kappa B, and actin signaling pathways. Our results indicate that the postpubertal exposure of Donryu rats to IA at an estrogenic dose results in promotion of mammary and uterine carcinogenesis induced by DMBA and ENNG, which might be related to the activation of ER-dependent signaling and alteration of the molecular tumor environment in the mammary gland and endometrium. PMID:22248470

  11. Versican expression in myoepithelial cells from carcinomas in canine mixed mammary tumors.

    Science.gov (United States)

    Damasceno, Karine A; Bertagnolli, Angélica C; Estrela-Lima, Alessandra; Rabelo, Bruna S; Campos, Liliane C; Ribeiro, Lorena G R; Cassali, Geovanni D

    2014-04-01

    The matrix of canine mixed mammary tumors (CMMTs) consists of proliferating spindle cells of possible myoepithelial origin, as well as myxomatous tissue, cartilage matrix and/or bone. Among the multiple components of this tumor extracellular matrix, versican probably plays a prominent role due to its importance in tumor progression, cell proliferation and differentiation. However, there are few data related to a possible association between versican expression and the state of myoepithelial cell differentiation in CMMTs. Using immunohistochemistry and histochemistry, the objective of this study was to evaluate the expression of versican, sulfated proteoglycans and mucopolysaccharides in myoepithelial cells at different stages of differentiation and to explore a potential relationship with p63 and ?-smooth muscle actin (SMA) expression. A significant difference in versican expression was observed among the different stages of myoepithelial cell differentiation with an inverse correlation between versican and p63/SMA expression. These results suggest that at an early stage of proliferation, myoepithelial cells acquire a phenotype consistent with a role in chondrogenesis. Moreover, myoepithelial cells showed an affinity for safranin and periodic acid-Schiff staining at different stages of proliferation supporting the myoepithelial origin of spindle cells from CMMTs. PMID:24582132

  12. In vivo tumor angiogenesis imaging with site-specific labeled 99mTc-HYNIC-VEGF

    International Nuclear Information System (INIS)

    We recently developed a cysteine-containing peptide tag (C-tag) that allows for site-specific modification of C-tag-containing fusion proteins with a bifunctional chelator, HYNIC (hydrazine nicotinamide)-maleimide. We then constructed and expressed C-tagged vascular endothelial growth factor (VEGF) and labeled it with HYNIC. We wished to test 99mTc-HYNIC-C-tagged VEGF (99mTc-HYNIC-VEGF) for the imaging of tumor vasculature before and after antiangiogenic (low continuous dosing, metronomic) and tumoricidal (high-dose) cyclophosphamide treatment. HYNIC-maleimide was reacted with the two thiol groups of C-tagged VEGF without any effect on biologic activity in vitro. 99mTc-HYNIC-VEGF was prepared using tin/tricine as an exchange reagent, and injected via the tail vein (200-300 ?Ci, 1-2 ?g protein) followed by microSPECT imaging 1 h later. Sequencing analysis of HYNIC-containing peptides obtained after digestion confirmed the site-specific labeling of the two accessible thiol groups of C-tagged VEGF. Tumor vascularity was easily visualized with 99mTc/VEGF in Balb/c mice with 4T1 murine mammary carcinoma 10 days after implantation into the left axillary fat pad in controls (12.3±5.0 tumor/bkg, n=27) along with its decrease following treatment with high (150 mg/kg q.o.d. x 4; 1.14±0.48 tumor/bkg, n=9) or low (25 mg/kg q.d. x 7; 1.03±0.18 tumor/bkg, n=9) dose cyclophosphamide. Binding specificity was confirmed by observing a 75icity was confirmed by observing a 75% decrease in tumor uptake of 99mTc/biotin-inactivated VEGF, as compared with 99mTc-HYNIC-VEGF. 99mTc can be loaded onto C-tagged VEGF in a site-specific fashion without reducing its bioactivity. 99mTc-HYNIC-VEGF can be rapidly prepared for the imaging of tumor vasculature and its response to different types of chemotherapy. (orig.)

  13. The relationship between tumor blood flow, angiogenesis, tumor hypoxia, and aerobic glycolysis

    DEFF Research Database (Denmark)

    Østergaard, Leif; Tietze, Anna

    2013-01-01

    Anti-angiogenic therapies are being pursued as means of starving tumors of their energy supply. While numerous studies show that such therapies render tumors hypoxic, just as many studies have, surprisingly, shown improved tumor oxygenation. These contradicting findings challenge both the original rationale for anti-angiogenic therapy and our understanding of the physiology of tissue oxygenation. The flow-diffusion equation, which describes the relation between blood flow and the extraction of freely diffusible molecules in tissue, was recently extended to take the heterogeneity of capillary transit times (CTH) into account. CTH is likely to be high in the chaotic microvasculature of a tumor, increasing the effective shunting of blood through its capillary bed. We review the properties of the extended flow-diffusion equation in tumor tissue. Elevated CTH reduces the extraction of oxygen, glucose, and cytotoxic molecules. The extent to which their net extraction is improved by anti-angiogenic therapy in turn, depends on the extent to which CTH is normalized by the treatment. The extraction of oxygen and glucose are affected to different extents by elevated CTH, and the degree of aerobic glycolysis - known as the Warburg effect - is thus predicted to represent an adaptation to the CTH of the local microvasculature.

  14. Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.

    Science.gov (United States)

    Gahete, Manuel D; Córdoba-Chacón, José; Lantvit, Daniel D; Ortega-Salas, Rosa; Sanchez-Sanchez, Rafael; Pérez-Jiménez, Francisco; López-Miranda, José; Swanson, Steven M; Castaño, Justo P; Luque, Raúl M; Kineman, Rhonda D

    2014-11-01

    Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[?]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status. PMID:25085903

  15. The hyaluronan synthesis inhibitor 4-methylumbelliferone exhibits antitumor effects against mesenchymal-like canine mammary tumor cells.

    Science.gov (United States)

    Saito, Teruyoshi; Dai, Tamura; Asano, Ryuji

    2013-03-01

    Hyaluronan (HA), a principal constituent of the extracellular matrix (ECM), mediates growth and metastasis of tumor cells. The role of HA in the epithelial-mesenchymal transition (EMT) is well known, and increased ECM remodeling is observed in mesenchymal-like cells. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) is anti-tumorigenic for various malignant tumors. However, the antitumor effect of 4-MU against canine mammary tumor cells that possess a mesenchymal-like phenotype is unclear. We examined the antitumor effect of 4-MU on CF41.Mg mesenchymal-like canine mammary tumor cells. We investigated the influence of 4-MU on the expression of HA synthase (HAS) 1-3 mRNA and observed dose-dependent downregulation of HAS2 mRNA at 24-72 h; in contrast, HAS3 expression was elevated at 24 h. Thus, 4-MU inhibited HA synthesis via HAS2 repression. 4-MU also inhibited cell proliferation and induced apoptosis in the CF41.Mg cells. Our experiments showed that 4-MU-induced apoptosis in CF41.Mg cells involved induction of the pro-apoptotic gene BAX. We also assessed motility and found that 4-MU reduced chemokinesis and chemotaxis in CF41.Mg cells. Our data suggest that 4-MU may serve as a candidate therapeutic agent for the treatment of canine mammary tumors. Since 4-MU exhibits antitumor activity in mesenchymal-like cells, it may also be a useful inhibitor of canine mammary tumor invasion and metastasis. PMID:23426189

  16. Proteínas de fase aguda em cadelas com neoplasia mamária Acute phase proteins in female dogs with mammary tumors

    Directory of Open Access Journals (Sweden)

    Michelly Kheidy Borges Battisti

    2013-05-01

    Full Text Available As proteínas de fase aguda (PFA apresentam concentrações séricas alteradas mediante processos infecciosos, inflamatórios e neoplásicos. Objetivou-se com este trabalho avaliar as variações séricas das PFA em cadelas portadoras de neoplasia mamária, comparando com a avaliação histológica e leucograma. As PFA foram avaliadas em 45 cadelas com tumor de mama, distribuídas nos grupos neoplasia benigna (n=13, maligna não ulcerada (n=24 e maligna ulcerada (n=8. O grupo controle foi composto por 20 cadelas saudáveis. Foram realizados o teste de eletroforese em gel de poliacrilamida contendo dodecil sulfato de sódio (SDS-PAGE para identificar as PFA (albumina, ceruloplasmina, transferrina, haptoglobina Hp, ?-1 antitripsina e ?-1 glicoproteina ácida e o teste ultrassensível para proteína C reativa (PCR. As pacientes com neoplasia mamária maligna ulcerada apresentaram elevações sérica para PCR e Hp e redução da albumina (PAcute phase proteins (APPs are serum proteins whose concentrations change after infectious and inflammatory disease, and cancer. The aims of this study were to evaluate changes in APPs concentration and to correlate these findings with histological classification and WBC in female dogs with mammary tumors. APPs were studied in 45 female dogs with mammary tumor distributed in the following groups: benign (n=13, malignant without tumor ulceration (n=24, and malignant with tumor ulceration (n=8. SDS-polyacrylamide gel (SDS-PAGE electrophoresis was used to measure APPs concentrations (albumin, ceruloplasmin, transferrin, haptoglobinHp, ?-1-acid glycoprotein and ?-1-antitrypsin and ultrasensitive assay was used to evaluate serum C-reactive protein (CRP. Patients with malignant mammary neoplasia plus ulceration had significant increase of CRP and Hp, and had decreased levels of albumin (P<0.05, One-Way ANOVA and Dunn Test. Positive correlation among APPs and inflammatory leukocytosis were observed (P=0.002, Fisher test. No correlation was observed between APPs and histological subtype. In conclusion, combined changes of CRP, Hp and albumin may be used as a prediagnostic tool and prognosis in dogs with mammary tumors.

  17. Coexpression of cytokeratins characteristic for myoepithelial and luminal cell lineages in rat 13762NF mammary adenocarcinoma tumors and their spontaneous metastases.

    Science.gov (United States)

    Lichtner, R B; Julian, J A; North, S M; Glasser, S R; Nicolson, G L

    1991-11-01

    We used immunohistochemical procedures to study the cellular expression and distribution of cytokeratins (CKs) in rat 13762NF mammary adenocarcinoma cells growing at mammary fat pad sites and at spontaneous lymph node and lung sites. In order to establish CK distribution in normal rat mammary epithelia, immature, resting, and lactating rat mammary glands were probed with a panel of monospecific antibodies that recognize individual CKs. Basal/myepithelial cells were distinguished by expression of CKs 5 and 14 and coexpression of vimentin from luminal cells, which expressed CKs 8, 18, and 19. Antibody to CK 7 recognized luminal epithelium of immature and resting, but not lactating, mammary glands. Myoepithelial cells of lactating mammary gland were weakly recognized by antibodies to CKs 7 and 19. Tumors formed by cell lines and clones derived from parental 13762NF tumor (MTPa, MTC, MTA, and MTF7) were not recognized by any of the anti-CK antibodies. Only vimentin was expressed in these tumors and their metastases. In tumors and metastases generated from cell lines and clones derived from lymph node (MTLY) and lung metastases (MTLn2 and MTLn3) of the 13762NF tumor we observed heterogeneous CK phenotypes. Expression of CKs 5 and 18 was greatly reduced or lacking, while CK 14 was coexpressed with CKs 7, 8, and 19 with or without vimentin. Tumors from the highly metastatic clone MTLn3 had a dominant cellular phenotype, expressing CKs 7, 8, 14, and 19 and vimentin, a pattern that did not match normal mammary epithelia, whether luminal, basal/myoepithelial, or the dual-phenotype stem cell, in which CKs 5, 8, 14, and 18 were coexpressed. MTLn3 lymph node and lung metastases expressed the same cellular phenotype as the s.c. growing MTLn3 tumor. The results appear to contradict the belief that malignant mammary tumors may be distinguished from benign tumors or hyperplastic growths by the lack of basal/myoepithelial markers. PMID:1718590

  18. Epithelial Protein-Tyrosine Phosphatase 1B (PTP1B) Contributes to the Induction of Mammary Tumors by HER2/Neu but is not Essential for Tumor Maintenance

    OpenAIRE

    Balavenkatraman, Kamal K.; Aceto, Nicola; Britschgi, Adrian; Mueller, Urs; Bence, Kendra K.; Neel, Benjamin G.; Bentires-Alj, Mohamed

    2011-01-01

    Protein-tyrosine phosphatase 1B (PTP1B), a well-established metabolic regulator, plays an important role in breast cancer. Using whole-body PTP1B knockout mice, recent studies have shown that PTP1B ablation delays HER2/Neu-induced mammary cancer. Whether PTP1B plays a cell-autonomous or a non-cell-autonomous role in HER2/Neu-evoked tumorigenesis and whether it is involved in tumor maintenance was unknown. We generated mice expressing HER2/Neu and lacking PTP1B specifically in the mammary epit...

  19. Tumor angiogenesis, macrophages and mast cell microdensities in endometrioid endometrial carcinoma

    Science.gov (United States)

    SIMIONESCU, CRISTIANA; M?RG?RITESCU, CLAUDIU; STEPAN, ALEX; PIRICI, DANIEL; CIUREA, RALUCA; CERNEA, NICOLAE

    2013-01-01

    The present study aimed to observe and compare the values of microvessel density (MVD), mast cell microdensity (McMD) and macrophage microdensity (MphMD) in intratumoral areas compared with the advancing edges, and to assess any correlations between these values and the degree and stage of the neoplasia. The cases of 52 patients who were diagnosed with endometrial carcinoma between 2003 and 2011 were analyzed, the majority of which were in the first stage of the disease (44 cases). Double sequential immunohistochemistry and the hot-spot counting method were used to assess the MVD (CD105+ MVD), McMD [tryptase+ (Try+) McMD] and MphMD (CD68+ MphMD) densities. The ?2 test, paired Student’s t-test and the Pearson correlation index were used to assess the significance of the results. A weak correlation was observed at the advancing edge only, between CD105+ MVD and Try+ McMD (P=0.039). No significant differences were identified in the analysis of CD105+ MVD, Try+ McMD and CD68+ MphMD, but wide variations in their distribution were observed. Depending on the tumor stage, CD105+ MVD exhibited an intratumoral, indirect correlation with Try+ McMD for stage IA (P=0.026) and II (P=0.013) tumors. CD105+ MVD presented an indirect correlation with CD68+ MphMD in stage IB tumors (P=0.016) and at the advancing edge for well-differentiated tumors (P=0.027). An analysis of the correlation between CD68+ MphMD and Try+ McMD indicated that the intratumoral levels of CD68+ MphMD were directly proportional with the Try+ McMD values in well-differentiated (P=0.005) and stage II (P=0.012) tumors, while at the front of the invasion, this correlation was indirect (P=0.010) in stage II tumors. In endometrioid endometrial carcinoma (EEC), angiogenesis is at its most active at the advancing edge of the tumor, where mast cells play a pro-angiogenic role. PMID:24137338

  20. Selective photothermal laser-tissue interaction with augmentation of immunoadjuvants in treatment of DMBA-4 metastatic mammary tumors in rats

    Science.gov (United States)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-09-01

    Induced anti-tumor immunity can be the most effective and long-term cure for cancers, particularly for metastatic tumors. Laser immunotherapy has been developed to induce such immunological responses in rats bearing DMBA-4 metastatic mammary tumors. It involves an intratumoral administration of a laser-absorbing dye (indocyanine green) and a specially formulated immunoadjuvant (glycated chitosan), followed by an irradiation of a near-infrared laser (805-nm diode laser). To understand the immunity induced in this tumor model, immunization using freeze-thaw cell lysates against the DMBA-4 tumors was performed, followed by the tumor challenge twenty-one days later. Also performed is the surgical removal of the primary tumors of the rats before the observation of metastatic tumors. The immunization only delayed the emergence of the primary and metastases in the rats but did not provide immunity against the tumor challenge. After surgical removal of the primary tumors, the tumors re-emerged at the primary sites and the metastases developed at multiple remote sites. In contrast, laser immunotherapy cured rats experienced tumor regression and eradication. Our research has provided strong support for the working mechanism of laser immunotherapy. The experimental results showed that selective photothermal laser-tissue interaction with a complementary use of immunoadjuvant could be a potential therapy for treatment of metastatic tumors by inducing a tumor-specific, long-lasting immunity.

  1. Tumor-derived hydrogen sulfide, produced by cystathionine-?-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer.

    Science.gov (United States)

    Szabo, Csaba; Coletta, Ciro; Chao, Celia; Módis, Katalin; Szczesny, Bartosz; Papapetropoulos, Andreas; Hellmich, Mark R

    2013-07-23

    The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-?-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-?-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target. PMID:23836652

  2. Contrast enhanced maximum intensity projection ultrasound imaging for assessing angiogenesis in murine glioma and breast tumor models: A comparative study.

    Science.gov (United States)

    Forsberg, Flemming; Ro, Raymond J; Fox, Traci B; Liu, Ji-Bin; Chiou, See-Ying; Potoczek, Magdalena; Goldberg, Barry B

    2011-04-01

    The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from four contrast enhanced ultrasound (US) techniques to four invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic imaging (PSHI), flash-echo imaging (FEI), and Microflow imaging (MFI; a technique creating maximum intensity projection images over time) was performed with an Aplio scanner (Toshiba America Medical Systems, Tustin, CA) and a 7.5MHz linear array. Fractional tumor neovascularity was calculated from digital clips of contrast US, while the relative area stained was calculated from specimens. Results were compared using a factorial, repeated measures ANOVA, linear regression and z-tests. The tortuous morphology of tumor neovessels was visualized better with MFI than with the other US modes. Cell line, implantation method and contrast US imaging technique were significant parameters in the ANOVA model (p0.05). In conclusion, the largest study of contrast US of murine xenografts to date has been conducted and quantitative contrast enhanced US measures of tumor neovascularity in glioma and breast cancer xenograft models appear to provide a noninvasive marker for angiogenesis; although the best method for monitoring angiogenesis was not conclusively established. PMID:21144542

  3. Glucocorticoid receptor-dependent disruption of a specific nucleosome on the mouse mammary tumor virus promoter is prevented by sodium butyrate.

    OpenAIRE

    Bresnick, E. H.; John, S.; Berard, D. S.; Lefebvre, P.; Hager, G. L.

    1990-01-01

    Our laboratory has previously developed cell lines derived from mouse NIH 3T3 fibroblasts and C127 mammary tumor cells that stably express mouse mammary tumor virus (MMTV) long terminal repeat fusion genes in bovine papillomavirus-based episomes. Glucocorticoid hormone strongly activates transcription from episomes and induces the disruption of a single nucleosome in an array of phased nucleosomes on the MMTV promoter. Sodium butyrate inhibits the glucocorticoid hormone-dependent development ...

  4. Molecular portrait-based correlation between primary canine mammary tumor and its lymph node metastasis: possible prognostic-predictive models and/or stronghold for specific treatments?

    OpenAIRE

    Beha Germana; Brunetti Barbara; Asproni Pietro; Muscatello Luisa; Millanta Francesca; Poli Alessandro; Sarli Giuseppe; Benazzi Cinzia

    2012-01-01

    Abstract Background This study aimed to evaluate the relationship between the molecular phenotype of the primary mammary tumor and its related lymph node metastasis in the dog to develop prognostic-predictive models and targeted therapeutic options. Results Twenty mammary tumor samples and their lymph node metastases were selected and stained by immunohistochemistry with anti-estrogen receptor (ER), -progesterone receptor (PR), -human epidermal growth factor receptor 2 (c-erbB-2), -cytokerati...

  5. Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

    OpenAIRE

    Landis, M. D.; Seachrist, D. D.; Abdul-karim, F. W.; Keri, R. A.

    2006-01-01

    Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are requ...

  6. Immunohistochemical and molecular expression of laminin-332 gamma-2 chain in canine mammary tumors Expressão imunoistoquímica e molecular da laminina-332 cadeia gama-2 em tumores mamários de cadelas

    OpenAIRE

    Zuccari, D. A. P. C.; Castro, R.; Jardim, B. V.; Mancini, U. M.; Polachini, G. M.

    2011-01-01

    Forty-eight cases of canine mammary cancer were investigated to evaluate the immunohistochemical distribution of the ?2 chain of laminin-332. Tumor cells were compared to a pool of normal mammary tissues using quantitative RT-PCR. The western blot was performed in eight tumor samples as complementary test to evaluate protein integrity. Immunohistochemistry experiments showed negative, focal, and weak expression of laminin-332 ?2 in tumors with the worst prognosis. Quantitative PCR r...

  7. Rosiglitazone inhibits metastasis development of a murine mammary tumor cell line LMM3

    Directory of Open Access Journals (Sweden)

    Rolando Romina

    2008-02-01

    Full Text Available Abstract Background Activation of peroxisome proliferator-activated receptors ? (PPAR? induces diverse effects on cancer cells. The thiazolidinediones (TZDs, such as troglitazone and ciglitazone, are PPAR? agonists exhibiting antitumor activities; however, the underlying mechanism remains inconclusive. Rosiglitazone (RGZ, a synthetic ligand of PPAR? used in the treatment of Type 2 diabetes, inhibits growth of some tumor cells and is involved in other processes related to cancer progression. Opposing results have also been reported with different ligands on tumor cells. The purpose of this study was to determine if RGZ and 15d-PGJ2 induce antitumor effects in vivo and in vitro on the murine mammary tumor cell line LMM3. Methods The effect on LMM3 cell viability and nitric oxide (NO production of different doses of RGZ, 15-dPGJ2, BADGE and GW9662 were determined using the MTS colorimetric assay and the Griess reaction respectively. In vivo effect of orally administration of RGZ on tumor progression was evaluated either on s.c. primary tumors as well as on experimental metastasis. Cell adhesion, migration (wound assay and invasion in Transwells were performed. Metalloproteinase activity (MMP was determined by zymography in conditioned media from RGZ treated tumor cells. PPAR? expression was detected by inmunohistochemistry in formalin fixed tumors and by western blot in tumor cell lysates. Results RGZ orally administered to tumor-bearing mice decreased the number of experimental lung metastases without affecting primary s.c. tumor growth. Tumor cell adhesion and migration, as well as metalloproteinase MMP-9 activity, decreased in the presence of 1 ?M RGZ (non-cytotoxic dose. RGZ induced PPAR? protein expression in LMM3 tumors. Although metabolic activity -measured by MTS assay- diminished with 1–100 ?M RGZ, 1 ?M-treated cells recovered their proliferating capacity while 100 ?M treated cells died. The PPAR? antagonist Biphenol A diglicydyl ether (BADGE did not affect RGZ activity. On the contrary, the specific antagonist GW9662 completely abrogated RGZ-induced decrease in cell viability. A decrease in NO levels was detected in the presence of either 1 or 100 ?M RGZ. The natural ligand 15d-PGJ2 did not affect metabolic activity although it induced a significant decrease in NO production. Conclusion A significant decrease in the number of experimental LMM3 lung metastasis, but not on primary tumor growth, after oral RGZ administration was observed. In vitro, 100 ?MRGZ also reduced cell viability and NO production, while no changes were observed in the presence of 15d-PGJ2. BADGE did not reverse RGZ effect while the antagonist GW9662 completely abrogated it, suggesting a PPAR?- dependent mechanism. Inhibition of lung metastatic nodules by RGZ administered in vivo, might be associated with the observed decrease in MMP-9 expression, in cell adhesion, migration and invasion. RGZ augmented its expression. PPAR? was detected in cell lysates by western blot and by immunohistochemistry in tumors from RGZ-treated mice. In summary we can suggest that RGZ or any other TZDs might be possible future approaches in the treatment of metastasis of PPAR?-expressing cells.

  8. The rat as animal model in breast cancer research: a histopathological study of radiation- and hormone-induced rat mammary tumors

    International Nuclear Information System (INIS)

    One of the goals of this monograph is to present data on the frequency of mammary neoplasms following irradiation and/or hormone administration in intact and castrated female rats of three strains allowed to live their natural life spans. These data are intended to give an overview of the effects of radiation and hormonal manipulation on the mammary gland based on histological examination of necropsied rats and using standard morphological criteria for mammary tumors. The second goal of this monograph is to provide detailed histological descriptions of the mammary tumors found in the various experimental groups as well as in several groups of untreated control rats. The aims are to examine whether possible strain-related and treatment-related differences in morphology or growth patterns exist, as well as to define the pathogensis of radiation-induced rat mammary tumors through the study of early lesions. An attempt will be made to describe tumor characteristics which may be of comparative value in identifying tumor types (and their induction methods) useful as models for specific human breast neoplasms. A rat mammary tumor classification system reflecting the morphological features useful for comparative purposes is also presented. (Auth.)

  9. Talin regulates moesin–NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis

    Science.gov (United States)

    Wang, Yarong; Bravo-Cordero, Jose Javier; Sharma, Ved P.; Miskolci, Veronika; Hodgson, Louis

    2014-01-01

    Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin–NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis. PMID:24891603

  10. Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis.

    Science.gov (United States)

    Beaty, Brian T; Wang, Yarong; Bravo-Cordero, Jose Javier; Sharma, Ved P; Miskolci, Veronika; Hodgson, Louis; Condeelis, John

    2014-06-01

    Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis. PMID:24891603

  11. Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy

    Directory of Open Access Journals (Sweden)

    Peter Vajkoczy

    1999-04-01

    Full Text Available Vascular endothelial growth factor (VEGF plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.

  12. IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis

    OpenAIRE

    Zhang, Chunyang; Lu, Ling; Li, Yun; Wang, Xianlei; ZHOU, JIANFENG; Liu, Yunzhang; Fu, Ping; Gallicchio, Marisa A; Bach, Leon A.; Duan, Cunming

    2011-01-01

    Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here we report that hypoxia induced the expression of insulin-like growth factor binding protein-6 (IGFBP-6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a HIF-mediated mechanism. Addition of human IGFBP-6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP-6 mutant with at least 10,00...

  13. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin [Department of General Surgery, The Second People' s Hospital of Yueqing, Yueqing 325608 (China); Cai, Liuxin, E-mail: liuxcai08@googlemail.com [Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Linhai 317000 (China)

    2010-12-17

    Research highlights: {yields} Reconstitution of ARHI suppresses the growth of HCC xenografts. {yields} ARHI reexpression impairs tumor angiogenesis in vivo. {yields} Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. {yields} Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  14. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Research highlights: ? Reconstitution of ARHI suppresses the growth of HCC xenografts. ? ARHI reexpression impairs tumor angiogenesis in vivo. ? Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. ? Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  15. Peripheral pulmonary nodules:relationship between multi-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF expression.

    OpenAIRE

    Cheng Xiao-Ling; Xiao Zhuang-Wei; Wang Zhao-Xin; Jia Bao-hui; Le Hong-Bo; Ma Shu-Hua; Mei Wei; Wu Min; Hu Zhi-Guo; Li Yu-Guang

    2008-01-01

    Abstract Background The aim of this study is to investigate the relationship between16-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF (vascular endothelial growth factor) expression in patients with benign and malignant pulmonary nodules, and differential diagnosis between benign and malignant pulmonary nodules. Methods Sixty-four patients with benign and malignant pulmonary nodules underwent 16-slice spiral CT perfusion imaging. The CT perfusion imaging was analyzed for TD...

  16. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.

    Science.gov (United States)

    Ségaliny, Aude I; Mohamadi, Amel; Dizier, Blandine; Lokajczyk, Anna; Brion, Régis; Lanel, Rachel; Amiaud, Jérôme; Charrier, Céline; Boisson-Vidal, Catherine; Heymann, Dominique

    2015-07-01

    Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-?, IL-1?, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases. PMID:25471534

  17. Contrast Enhanced Maximum Intensity Projection Ultrasound Imaging for Assessing Angiogenesis in Murine Glioma and Breast Tumor Models: A Comparative Study

    OpenAIRE

    Forsberg, Flemming; Ro, Raymond J.; Fox, Traci B.; Liu, Ji-bin; Chiou, See-ying; Potoczek, Magdalena; Goldberg, Barry B.

    2010-01-01

    The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from 4 contrast enhanced ultrasound (US) techniques to 4 invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic...

  18. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals

    OpenAIRE

    Gupta, Subash C.; Kim, Ji Hye; Prasad, Sahdeo; Aggarwal, Bharat B.

    2010-01-01

    Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with ...

  19. Formation of higher-order secondary and tertiary chromatin structures by genomic mouse mammary tumor virus promoters

    OpenAIRE

    Georgel, Philippe T.; Fletcher, Terace M.; Hager, Gordon L.; Hansen, Jeffrey C.

    2003-01-01

    Agarose multigel electrophoresis has been used to characterize the structural features of isolated genomic mouse mammary tumor virus (MMTV) promoters. The mouse 3134cells used for these studies contain ?200 stably integrated tandem repeats of a 2.4-kb MMTV promoter fragment. Inactive, basally active, and hormonally activated genomic promoters were liberated by restriction digestion of isolated nuclei, recovered in low-salt nuclear extracts, and electrophoresed in multigels consisting ...

  20. Expression of vimentin filaments in canine malignant mammary gland tumors: A simulation of clinicopathological features of human breast cancer

    OpenAIRE

    Rismanchi, Sanaz; Yadegar, Orly; Muhammadnejad, Samad; Amanpour, Saeid; Taghizadeh-jahed, Masoud; Muhammadnejad, Ahad

    2014-01-01

    Canine malignant mammary gland tumors (CMMGTs) are the most common malignancies observed in females. Several biological similarities have been reported between CMMGTs and human breast cancer (HBC). The present study aimed to assess the correlation of vimentin filaments overexpression, as part of the process of epithelial-mesenchymal transition (EMT) and the clinicopathological characteristics in CMMGTs. The clinicopathological characteristics of 42 CMMGTs were collected. Paraffin-embedded blo...

  1. Activation of the Aryl Hydrocarbon Receptor by TCDD Inhibits Mammary Tumor Metastasis in a Syngeneic Mouse Model of Breast Cancer

    OpenAIRE

    Wang, Tao; Wyrick, Katie L.; Meadows, Gary G.; Wills, Tamara B.; Vorderstrasse, Beth A.

    2011-01-01

    Treatment with aryl hydrocarbon receptor (AhR) agonists can slow or reverse the growth of primary mammary tumors in rodents, which has fostered interest in developing selective AhR modulators for treatment of breast cancer. However, the major goal of breast cancer therapy is to inhibit metastasis, the primary cause of mortality in women with this disease. Studies conducted using breast cancer cell lines have demonstrated that AhR agonists suppress proliferation, invasiveness, and colony forma...

  2. Survival of mouse mammary gland transplants of normal, hyperplastic, and tumor tissues exposed to X-rays

    International Nuclear Information System (INIS)

    Mouse mammary tissues, including ducts, prelactating lobules, hyperplastic outgrowth lines, and tumors, were exposed to varying doses of X-rays and then transplanted to fat pads of nonirradiated BALB/c mice for study. Estimates of the dose of radiation that would allow survival of 50% of the transplants (SD50) were made with the use of probit analysis. Nearly all duct and lobule transplants survived doses of X-rays from 0 to 800 rad. The survival rate declined rapidly following doses above 800 rad, and the calculated SD50 was 1,020 and 1,260 rad for mammary ducts and lobules, respectively. The three hyperplastic outgrowth lines tested gave very different results. Hyperplastic line Z5C1 transplants had better than 90% survival at doses up to 1,200 rad and an SD50 between 1,200 and 1,600 rad. Hyperplastic line Z5D transplants had an SD50 of between 800 and 1,200 rad. Hyperplastic line D1 transplants had a better than 90% survival following doses of 0-600 rad and an SD50 between 600 and 800 rad. The survival of tumor transplants was 100% following doses of X-rays up to 1,200 rad; the SD50 was in excess of 1,600 rad. The mouse mammary transplantation system can be used to study the direct effect of X-rays on normal, premalignant, and malignant mammary tissues and provides a basis for the study of the radiobiology of mammary tissues

  3. Cyclooxygenase-2 Pathway Correlates with VEGF Expression in Head and Neck Cancer. Implications for Tumor Angiogenesis and Metastasis

    Directory of Open Access Journals (Sweden)

    Oreste Gallo

    2001-01-01

    Full Text Available We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs by analyzing COX-2 expression and prostaglandin E2 (PGE2 production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P<0001. Specimens from patients with lymph node metastasis exhibited higher COX-2 protein expression (P=.0074, PGEZ levels (P=.0011 and microvessel density (P<.0001 than specimens from patients without metastasis. A significant correlation between COX-2 and tumor vascularization (rs=0.450, P=.007 as well as between COX-2 and microvessel density with VEGF expression in tumor tissues was found (rs=0.450, P=.007; rs=0.620, P=.0001, respectively. The induction of COX-2 mRNA and PGE2 synthesis by EGF and Escherichia coli lipopolysaccharide (LPS in A-431 and SCC-9 cell lines, resulted in an increase in VEGF mRNA and protein production. Indomethacin and celecoxib reversed the EGF- and LPS-dependent COX-2, VEGF, and PGE2 increases. This study suggests a central role of COX-2 pathway in HNC angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors may be useful in HNC treatment.

  4. Effect of selenodiglutathione on the metabolism of canine mammary tumor cells

    International Nuclear Information System (INIS)

    Selenodiglutathione (SDG) has been shown to be an effective inhibitor of tumor growth. The present studies were designed to evaluate altered metabolism in canine mammary tumor cells (CMT-13) exposed to various concentrations of SDG. Addition of SDG at 0.025 ?g Se/ml did not inhibit growth of CMT-13 cells after 24 h of incubation. At this concentration of SDG, approximately 25% of 75Se-35S-SDG was retained in these tumor cells after 24 h of incubation. The nuclear fraction contained 96% of the 75Se and 35S radioactivity. The ratio of 75Se to 35S was 1 to 4.5 in the whole cell and in the nuclear fraction. SDG increased glutathione peroxidase activity by 40% compared to CMT-13 cells not exposed to SDG. Glutathione reductase activity was decreased by 63% by the addition of SDG. In addition, supplemental SDG resulted in a 55% decrease in GSH content but did not alter GSSG concentrations. After 4d of incubation, SDG at 0.1 and 0.5 ?g Se/ml caused a 43 and 58% inhibition of growth of CMT-13 cells. Addition of GSH (100?M) partially prevented, 68% and 54%, the growth inhibition caused by SDG at concentrations of 0.1 and 0.5 ?g Se per ml respectively during the 4d incubation period. Preincubation of CMT-13 cells with GSH for 48 h before addition of SDG (0.5 ?g Se/ml) completely prevented the growth inhibition caused by this seleno-compound

  5. GM-CSF INHIBITS BREAST CANCER GROWTH AND METASTASIS BY INVOKING AN ANTI-ANGIOGENIC PROGRAM IN TUMOR-EDUCATED MACROPHAGES

    OpenAIRE

    Eubank, Tim D.; Roberts, Ryan D.; Khan, Mahmood; Curry, Jennifer M.; Nuovo, Gerard J.; Kuppusamy, Periannan; Marsh, Clay B.

    2009-01-01

    Tumor-educated macrophages facilitate tumor metastasis and angiogenesis. We discovered that GM-CSF blocked macrophages VEGF activity by producing soluble VEGF receptor-1 (sVEGFR-1) and determined the effect on tumor-associated macrophage behavior and tumor growth. We show GM-CSF treatment of murine mammary tumors slowed tumor growth and slowed metastasis. These tumors had more macrophages, fewer blood vessels, and lower oxygen concentrations. This effect was sVEGFR-1 dependent. In situ hybrid...

  6. Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats

    Directory of Open Access Journals (Sweden)

    Papadopoulos Nikoletta

    2008-04-01

    Full Text Available Abstract Background c-kit is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-kit gene on carcinogenesis. Gain-of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. However, very little is known about pathologies associated with loss-of-function mutations. Regarding breast cancer, c-kit protein and mRNA are highly expressed in normal breast but their expression decreases or is absent in the presence of breast cancer. We studied the role of c-kit in mammary carcinogenesis in the Ws/Ws rats carrying spontaneous lack-of-function mutation in the c-kit gene. Fifty day-old virgin female Ws/Ws rats and their wild type counterparts were injected with either 50 mg/kg body weight of the chemical carcinogen N-nitrosomethylurea or with vehicle. The animals were followed-up for 6 months. Fisher 344 rats were used as positive controls for tumor development. Results Eleven weeks after treatment, palpable tumors were detected in the Ws/Ws rats. The tumor incidence was 80% in Ws/Ws rats, while no tumors were observed in the wild type rats (p = 0.006. Our data show that the lack of c-kit is permissive for the development of mammary tumor in Ws/Ws rats treated with carcinogen. Conclusion We conclude that the lack of c-kit may contribute to an imbalanced homeostatic state in the mammary gland either by affecting signaling between stroma and epithelium, or through the lack of mast cells.

  7. The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.

    Science.gov (United States)

    To, Ciric; Kim, Eun-Hee; Royce, Darlene B; Williams, Charlotte R; Collins, Ryan M; Risingsong, Renee; Sporn, Michael B; Liby, Karen T

    2014-07-01

    Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. PMID:24817481

  8. Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo

    Directory of Open Access Journals (Sweden)

    Vassiliki Kostourou

    2004-07-01

    Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

  9. Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice.

    Science.gov (United States)

    Williams, Terence M; Cheung, Michelle W-C; Park, David S; Razani, Babak; Cohen, Alex W; Muller, William J; Di Vizio, Dolores; Chopra, Neeru G; Pestell, Richard G; Lisanti, Michael P

    2003-03-01

    Caveolin-1 is the principal structural component of caveolae microdomains, which represent a subcompartment of the plasma membrane. Several independent lines of evidence support the notion that caveolin-1 functions as a suppressor of cell transformation. For example, the human CAV-1 gene maps to a suspected tumor suppressor locus (D7S522/7q31.1) that is frequently deleted in a number of carcinomas, including breast cancers. In addition, up to 16% of human breast cancers harbor a dominant-negative mutation, P132L, in the CAV-1 gene. Despite these genetic associations, the tumor suppressor role of caveolin-1 still remains controversial. To directly assess the in vivo transformation suppressor activity of the caveolin-1 gene, we interbred Cav-1 (-/-) null mice with tumor-prone transgenic mice (MMTV-PyMT) that normally develop multifocal dysplastic lesions throughout the entire mammary tree. Herein, we show that loss of caveolin-1 gene expression dramatically accelerates the development of these multifocal dysplastic mammary lesions. At 3 wk of age, loss of caveolin-1 resulted in an approximately twofold increase in the number of lesions (foci per gland; 3.3 +/- 1.0 vs. 7.0 +/- 1.2) and an approximately five- to sixfold increase in the total area occupied by these lesions. Similar results were obtained at 4 wk of age. However, complete loss of caveolin-1 was required to accelerate the appearance of these dysplastic mammary lesions, because Cav-1 (+/-) heterozygous mice did not show any increases in foci development. We also show that loss of caveolin-1 increases the extent and the histological grade of these mammary lesions and facilitates the development of papillary projections in the mammary ducts. Finally, we demonstrate that cyclin D1 expression levels are dramatically elevated in Cav-1 (-/-) null mammary lesions, consistent with the accelerated appearance and growth of these dysplastic foci. This is the first in vivo demonstration that caveolin-1 can function as a transformation suppressor gene. PMID:12631721

  10. Estudo retrospectivo de 207 casos de tumores mamários em gatas / A retrospective study of 207 cases of mammary tumors in queens

    Scientific Electronic Library Online (English)

    Monique, Togni; Eduardo K., Masuda; Glaucia D., Kommers; Rafael A., Fighera; Luiz Francisco, Irigoyen.

    2013-03-01

    Full Text Available Este estudo teve como objetivos determinar os tumores mais prevalentes em gatos e relacionar os tumores mamários a alguns de seus fatores prognósticos. Os arquivos do Laboratório de Patologia Veterinária (LPV) da Universidade Federal de Santa Maria (UFSM) foram revisados e um total de 1.427 protocol [...] os de biopsias e necropsias de felinos, entre 2000 e 2011, foi encontrado. Com base nas informações dos arquivos, foi estabelecida a relação entre os tumores e alguns fatores como sexo, idade, raça, estado reprodutivo, uso de contraceptivos, número e localização das glândulas afetadas, ulcerações, tamanho do neoplasma, metástases distantes e para os linfonodos. Assim, observou-se que os tumores de mama foram o segundo diagnóstico mais prevalente, após os tumores de pele. Todos os gatos com tumores mamários eram fêmeas, sendo os sem raça definida e os idosos os mais afetados. Os neoplasmas malignos foram diagnosticados com maior frequência, seguidos pelos tumores não neoplásicos e pelos neoplasmas benignos. Os tumores menores eram, na sua maioria, carcinomas. Ulcerações estavam presentes não só em neoplasmas malignos, mas também em alterações não neoplásicas. Metástases distantes foram encontradas principalmente nos pulmões e na pele. Abstract in english This study aimed to determine the most prevalent mammary tumors in cats and associate them to some prognostic factors. The files from the Laboratório de Patologia Veterinária (LPV) of the Universidade Federal de Santa Maria (UFSM) were reviewed, and 1.427 feline biopsies and autopsy protocols betwee [...] n the years 2000 and 2011 were found. Based on the information retrieved from the files, a relationship was established among the tumors and some prognostic factors such as sex, age, breed, reproductive status, use of contraceptives, number and location of affected glands, ulcers, size of the neoplasm, distant metastases, and affected lymph nodes. Thus, it was observed that mammary cancer is the second most prevalent diagnosis, following skin tumors. All cats with mammary tumors were female, being the elderly and mixed breed the most affected. Malignant neoplasms were the most frequently diagnosed, followed by non-neoplastic tumors, and benign neoplasms. Smaller tumors were mostly carcinomas. Ulcerations were present not only in malignant neoplasms but also in non-neoplastic changes. Distant metastases were found mainly to the lungs and skin.

  11. Mouse mammary tumor virus (MMTV-like DNA sequences in the breast tumors of father, mother, and daughter

    Directory of Open Access Journals (Sweden)

    Wiernik Peter H

    2008-02-01

    Full Text Available Abstract Background The diagnosis of late onset breast cancer in a father, mother, and daughter living in the same house for decades suggested the possibility of an environmental agent as a common etiological factor. Both molecular and epidemiological data have indicated a possible role for the mouse mammary tumor virus (MMTV, the etiological agent of breast cancer in mice, in a certain percentage of human breast tumors. The aim of this study was to determine if MMTV might be involved in the breast cancer of this cluster of three family members. Results MMTV-like envelope (env and long terminal repeat (LTR sequences containing the MMTV superantigen gene (sag were detected in the malignant tissues of all three family members. The amplified env gene sequences were 98.0%–99.6% homologous to the MMTV env sequences found in the GR, C3H, and BR6 mouse strains. The amplified LTR sequences containing sag sequences segregated to specific branches of the MMTV phylogenetic tree and did not form a distinct branch of their own. Conclusion The presence of MMTV-like DNA sequences in the malignant tissues of all three family members suggests the possibility of MMTV as an etiological agent. Phylogenetic data suggest that the MMTV-like DNA sequences are mouse and not human derived and that the ultimate reservoir of MMTV is most likely the mouse. Although the route by which these family members came to be infected with MMTV is unknown, the possibility exists that such infection may have resulted from a shared exposure to mice.

  12. Mouse mammary tumor virus-like gene sequences are present in lung patient specimens

    Directory of Open Access Journals (Sweden)

    Rodríguez-Padilla Cristina

    2011-09-01

    Full Text Available Abstract Background Previous studies have reported on the presence of Murine Mammary Tumor Virus (MMTV-like gene sequences in human cancer tissue specimens. Here, we search for MMTV-like gene sequences in lung diseases including carcinomas specimens from a Mexican population. This study was based on our previous study reporting that the INER51 lung cancer cell line, from a pleural effusion of a Mexican patient, contains MMTV-like env gene sequences. Results The MMTV-like env gene sequences have been detected in three out of 18 specimens studied, by PCR using a specific set of MMTV-like primers. The three identified MMTV-like gene sequences, which were assigned as INER6, HZ101, and HZ14, were 99%, 98%, and 97% homologous, respectively, as compared to GenBank sequence accession number AY161347. The INER6 and HZ-101 samples were isolated from lung cancer specimens, and the HZ-14 was isolated from an acute inflammatory lung infiltrate sample. Two of the env sequences exhibited disruption of the reading frame due to mutations. Conclusion In summary, we identified the presence of MMTV-like gene sequences in 2 out of 11 (18% of the lung carcinomas and 1 out of 7 (14% of acute inflamatory lung infiltrate specimens studied of a Mexican Population.

  13. The relationship between clinicopathological features and expression of epithelial and mesenchymal markers in spontaneous canine mammary gland tumors.

    Science.gov (United States)

    Yoshida, Kota; Yoshida, Saori; Choisunirachon, Nan; Saito, Tomochika; Matsumoto, Kaori; Saeki, Kohei; Mochizuki, Manabu; Nishimura, Ryohei; Sasaki, Nobuo; Nakagawa, Takayuki

    2014-10-01

    It is known that epithelial mesenchymal transition (EMT) contributes to the acquisition of malignant property in human cancers. However, the role of EMT in canine tumors remains to be elucidated. To evaluate the correlation between expression levels of protein markers involved in EMT and clinicopathological characteristics in canine mammary gland tumors, immunohistochemistry using antibodies against ZO-1, E-cadherin, vimentin, N-cadherin and fibronectin was performed on 119 clinical tissue samples. Consequently, loss of ZO-1 and E-cadherin, and gain of vimentin and N-cadherin were more frequently observed in malignant tumors than in benign tumors. However, there was no correlation among expression of these molecules. Univariate and multivariate analysis identified that loss of E-cadherin independently had a low one-year survival rate (adjusted odds ratio: 2.3, P=0.02). These results suggested that EMT might relate to acquisition of malignancy, and additionally, E-cadherin was strongly correlated with malignant behavior in canine mammary gland tumors. PMID:24931646

  14. Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats

    International Nuclear Information System (INIS)

    Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further tested with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues

  15. Proteínas de fase aguda em cadelas com neoplasia mamária / Acute phase proteins in female dogs with mammary tumors

    Scientific Electronic Library Online (English)

    Michelly Kheidy Borges, Battisti; Daniella Matos da, Silva; Mhayara Samile de Oliveira, Reusing; Olair Carlos, Beltrame; Elizabeth Moreira dos Santos, Schmidt; José Jurandir, Fagliari; Rosângela Locatelli, Dittrich; Simone Domit, Guérios.

    2013-05-01

    Full Text Available As proteínas de fase aguda (PFA) apresentam concentrações séricas alteradas mediante processos infecciosos, inflamatórios e neoplásicos. Objetivou-se com este trabalho avaliar as variações séricas das PFA em cadelas portadoras de neoplasia mamária, comparando com a avaliação histológica e leucograma [...] . As PFA foram avaliadas em 45 cadelas com tumor de mama, distribuídas nos grupos neoplasia benigna (n=13), maligna não ulcerada (n=24) e maligna ulcerada (n=8). O grupo controle foi composto por 20 cadelas saudáveis. Foram realizados o teste de eletroforese em gel de poliacrilamida contendo dodecil sulfato de sódio (SDS-PAGE) para identificar as PFA (albumina, ceruloplasmina, transferrina, haptoglobina Hp, ?-1 antitripsina e ?-1 glicoproteina ácida) e o teste ultrassensível para proteína C reativa (PCR). As pacientes com neoplasia mamária maligna ulcerada apresentaram elevações sérica para PCR e Hp e redução da albumina (P Abstract in english Acute phase proteins (APPs) are serum proteins whose concentrations change after infectious and inflammatory disease, and cancer. The aims of this study were to evaluate changes in APPs concentration and to correlate these findings with histological classification and WBC in female dogs with mammary [...] tumors. APPs were studied in 45 female dogs with mammary tumor distributed in the following groups: benign (n=13), malignant without tumor ulceration (n=24), and malignant with tumor ulceration (n=8). SDS-polyacrylamide gel (SDS-PAGE) electrophoresis was used to measure APPs concentrations (albumin, ceruloplasmin, transferrin, haptoglobinHp, ?-1-acid glycoprotein and ?-1-antitrypsin) and ultrasensitive assay was used to evaluate serum C-reactive protein (CRP). Patients with malignant mammary neoplasia plus ulceration had significant increase of CRP and Hp, and had decreased levels of albumin (P

  16. Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging

    Science.gov (United States)

    Pysz, Marybeth A.; Guracar, Ismayil; Foygel, Kira; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Purpose To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system. Materials and methods The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis. Results MIP percent contrast area was significantly different (P correlated significantly (P correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05). Conclusion Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts. PMID:22535383

  17. Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Elena I. Deryugina

    2014-10-01

    Full Text Available According to established notion, one of the major angiogenesis-inducing factors, pro-matrix metalloproteinase-9 (proMMP-9, is supplied to the tumor microenvironment by tumor-associated macrophages (TAMs. Accumulated evidence, however, indicates that tumor-associated neutrophils (TANs are also critically important for proMMP-9 delivery, especially at early stages of tumor development. To clarify how much angiogenic proMMP-9 is actually contributed by TAMs and TANs, we quantitatively evaluated TAMs and TANs from different tumor types, including human xenografts and syngeneic murine tumors grown in wild-type and Mmp9-knockout mice. Whereas host MMP-9 competence was required for full angiogenic potential of both normal and tumor-associated leukocytes, direct comparisons of neutrophils versus macrophages and TANs versus TAMs demonstrated that macrophages and TAMs secrete 40- to 50-fold less proMMP-9 than the same numbers of neutrophils or TANs. Correspondingly, the levels of MMP-9–mediated in vivo angiogenesis induced by neutrophils and TANs substantially exceeded those induced by macrophages and TAMs. MMP-9–delivering TANs were also required for development of metastasis-supporting intratumoral vasculature, characterized by ?11-?m size lumens and partial coverage with stabilizing pericytes. Importantly, MMP-9–producing TAMs exhibit M2-skewed phenotype but do not express tissue inhibitor of metalloproteinases-1 (TIMP-1, a novel characteristic allowing them to secrete TIMP-1–free, neutrophil-like MMP-9 zymogen unencumbered by its natural inhibitor. Together, our findings support the notion whereby TANs, capable of immediate release of their pre-stored cargo, are the major contributors of highly angiogenic MMP-9, whereas tumor-influxing precursors of macrophages require time to differentiate, polarize into M2-skewed TAMs, shut down their TIMP-1 expression, and only then, initiate relatively low-level production of TIMP-free MMP-9 zymogen.

  18. Correlation of tumor-infiltrating lymphocytes to histopathological features and molecular phenotypes in canine mammary carcinoma: A morphologic and immunohistochemical morphometric study

    OpenAIRE

    Kim, Jong-hyuk; Chon, Seung-ki; Im, Keum-soon; Kim, Na-hyun; Sur, Jung-hyang

    2013-01-01

    Abundant lymphocyte infiltration is frequently found in canine malignant mammary tumors, but the pathological features and immunophenotypes associated with the infiltration remain to be elucidated. The aim of the present study was to evaluate the relationship between lymphocyte infiltration, histopathological features, and molecular phenotype in canine mammary carcinoma (MC). The study was done with archived formalin-fixed, paraffin-embedded samples (n = 47) by histologic and immunohistochemi...

  19. Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design

    OpenAIRE

    Kmieciak, Maciej; Morales, Johanna K.; Morales, Joshua; Bolesta, Elizabeth; Grimes, Margaret; Manjili, Masoud H.

    2008-01-01

    Using parental FVB mice and their neu transgenic counterparts, FVBN202, we showed for the first time that dangerous hyperplasia of mammary epithelial cells coincided with breaking immunological tolerance to the neu “self” tumor antigen, though such immune responses failed to prevent formation of spontaneous neu-overexpressing mammary carcinoma (MMC) or to reject transplanted MMC in FVBN202 mice. On the other hand, neu-specific immune responses appeared to be effective against MMC in paren...

  20. An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

    Science.gov (United States)

    Fagiani, Ernesta; Bill, Ruben; Pisarsky, Laura; Ivanek, Robert; Rüegg, Curzio; Christofori, Gerhard

    2015-07-01

    Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer. PMID:26021306

  1. Deleted in Malignant Brain Tumors 1 is Present in the Vascular Extracellular Matrix and Promotes Angiogenesis

    DEFF Research Database (Denmark)

    Müller-Enbergs, Helmut; Hu, Jiong

    2012-01-01

    OBJECTIVE: Deleted in malignant brain tumors 1 (DMBT1) belongs to the scavenger receptor cysteine-rich superfamily of proteins and is implicated in innate immunity, cell polarity, and differentiation. Here we studied the role of DMBT1 in endothelial cells. METHODS AND RESULTS: DMBT1 was secreted into the extracellular matrix (ECM) by endothelial cells in vitro and in situ and the presence of DMBT1 in the ECM increased endothelial cell adherence. Endothelial cell-derived DMBT1 associated with galectin-3 (coprecipitation), and human recombinant DMBT1 bound EGF, vascular endothelial growth factor and Delta-like (Dll) 4 (specific ELISAs). Compared to cells from wild-type mice, endothelial cells from DMBT1(-/-) mice demonstrated reduced migration, proliferation, and tube formation. In vivo recovery from hindlimb ischemia was attenuated in DMBT1(-/-) animals as was vascular endothelial growth factor -induced endothelial sprouting from isolated aortic rings; the latter response could be rescued by the addition of recombinant DMBT1. The Notch pathway is involved in multiple aspects of vascular development, including arterial-venous differentiation and we found that endothelial cells from DMBT1(-/-) mice expressed more EphrinB2 than cells from wild-type mice. Levels of Dll1, Dll4, Hes1, Hey1, and EphB4, on the other hand, were increased. CONCLUSIONS: Taken together, the results of this study indicate that DMBT1 functions as an important endothelium-derived ECM protein that is able to bind angiogenic factors and promote adhesion, migration, proliferation, and angiogenesis as well as vascular repair. Mechanistically, DMBT1 interacts with galectin-3 and modulates the Notch signaling pathway as well as the differential expression of ephrin-B2 and EphB4.

  2. Significance of ER?, HER2, and CAV1 expression and molecular subtype classification to canine mammary gland tumor.

    Science.gov (United States)

    Shinoda, Hitomi; Legare, Marie E; Mason, Gary L; Berkbigler, Jennifer L; Afzali, Maryam F; Flint, Alfred F; Hanneman, William H

    2014-04-23

    Canine mammary gland tumor (CMT) and human breast cancer (HBC) share many similarities regarding their risk factors, histological features, and behavior. Despite the increasing evidence of molecular marker expression as a prognostic indicator for HBC, few studies have applied this approach to CMT. The aim of the present study is to evaluate the significance of the expression of estrogen receptor-alpha (ER?), human epidermal growth factor receptor 2 (HER2), and caveolin-1 (CAV1) to the behavior and the clinical outcome of CMT. Additionally, the correlation between subtype classification (luminal A, luminal B, HER2-overexpressing, basal-like, and normal-like) and tumor behavior prognosis were assessed. Canine mammary gland tissues were immunohistochemically stained for ER?, HER2, and CAV1 and evaluated and classified into 5 subtypes on the basis of immunoreactivity. Although there were no statistically significant differences in the molecular marker immunoreactivity of different subtypes, the degree of positive staining for ER?, extranuclear ER?, HER2, and CAV1 showed significant correlations (P tumor. The current study indicates the prognostic value of immunohistochemical staining status of ER?, HER2, and CAV1 for CMT. In addition, some trends were seen in subtype classification on the prognosis of the tumor, implying that, although further analysis is needed, there is potential clinical application of 5-subtype classification for CMT. PMID:24760135

  3. Endogenous Mouse Mammary Tumor Viruses (Mtv: New Roles for an Old Virus in Cancer, Infection and Immunity

    Directory of Open Access Journals (Sweden)

    GeorgePunkosdy

    2013-11-01

    Full Text Available Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV and endogenous (Mtv forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.

  4. Benzyl isothiocyanate suppresses high-fat diet-stimulated mammary tumor progression via the alteration of tumor microenvironments in obesity-resistant BALB/c mice.

    Science.gov (United States)

    Kim, Minhee; Cho, Han Jin; Kwon, Gyoo Taik; Kang, Young-Hee; Kwon, Seung-Hae; Her, Song; Park, Taesung; Kim, Yongkang; Kee, Yun; Park, Jung Han Yoon

    2015-01-01

    We previously reported that a high-fat diet (HFD) and M2-macrophages induce changes in tumor microenvironments and stimulate tumor growth and metastasis of 4T1 mammary cancer cells in BALB/c mice. In this study, we attempted to determine whether benzyl isothiocyanate (BITC) inhibits HFD-induced changes in tumor progression and in tumor microenvironments. Four groups of female BALB/c mice (4-week-old) were fed on a control diet (CD, 10?kcal% fat) and HFD (60?kcal% fat) containing BITC (0, 25, or 100?mg/kg diet) for 20 weeks. Following 16 weeks of feeding, 4T1 cells (5×10(4) cells) were injected into the mammary fat pads, and animals were killed 30 d after the injection. HFD feeding increased solid tumor growth and the number of tumor nodules in the lung and liver, as compared to the CD group, and these increases were inhibited by BITC supplementation. The number of lipid vacuoles, CD45+ leukocytes and CD206+ M2-macrophages, expression of Ki67, levels of cytokines/chemokines, including macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1, and mRNA levels of F4/80, CD86, Ym1, CD163, CCR2, and M-CSF receptor were increased in the tumor tissues of HFD-fed mice, and these increases were inhibited by BITC supplementation. In vitro culture results demonstrated that BITC inhibited macrophage migration as well as lipid droplet accumulation in 3T3-L1 cells. These results suggest that suppression of lipid accumulation and macrophage infiltration in tumor tissues may be one of the mechanisms by which BITC suppresses tumor progression in HFD-fed mice. PMID:24729546

  5. Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands / Identificação de mutações nos exons 4 a 8 do gene p53 supressor de tumor em glândulas mamárias caninas

    Scientific Electronic Library Online (English)

    D.M.B., Souza; M.G.O., Barros; J.S.C., Silva; M.B., Silva; Z.F., Coleto; G.C., Jimenez; M., Adrião; A., Wischral.

    2012-04-01

    Full Text Available Para estudar as mutações nos exos 4 a 8 do gene p53, foram utilizados 15 tumores mamários, mamas normais das mesmas cadelas e seis mamas de cadelas normais. O DNA extraído das amostras de tecido foi sequenciado e analisado para a presença de mutações. Em 71,8% das amostras obtidas foram observadas m [...] utações, sendo as "missense" as mais frequentes. Os exons mais comprometidos foram 5, 7 e 8 com 23,4, 31,6 e 23,4% de mutações, respectivamente. O estudo conclui que tumores mamários caninos têm relação com mutações no gene p53 e que as mutações ocorrem com maior frequência nas regiões da proteína que estão ligadas ao DNA no núcleo celular. Isto pode alterar a funcionalidade da proteína e propiciar o crescimento do tumor. As mamas adjacentes aos tumores, apesar da aparência macroscópica normal, apresentaram mutações, que podem representar recidivas se a mama não for retirada juntamente com o tumor. Abstract in english Fifteen female canines with mammary tumors and 6 normal females were used to study mutations in exons 4 to 8 of the p53 gene. DNA samples from the tumors, respective adjacent normal mammary tissue and mammary glands from healthy animals were sequenced and analyzed for the presence of mutations. Muta [...] tions were found in 71.8% of the samples and the most frequent were missense mutations. The most attacked exons in the mammary tumor were 5, 7 and 8, with 23.4, 31.6 and 23.4% mutations, respectively. Canine mammary tumors are related to mutations in gene p53 and mutations mostly occur in the region of the protein that is linked to the DNA in the cell nucleus, which can change the functionality of the cell and propitiate tumor growth. Despite being macroscopically normal, the mammary tissue adjacent to the tumors has mutations that can lead to recurrence if not removed together with the tumor.

  6. Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands Identificação de mutações nos exons 4 a 8 do gene p53 supressor de tumor em glândulas mamárias caninas

    Directory of Open Access Journals (Sweden)

    D.M.B. Souza

    2012-04-01

    Full Text Available Fifteen female canines with mammary tumors and 6 normal females were used to study mutations in exons 4 to 8 of the p53 gene. DNA samples from the tumors, respective adjacent normal mammary tissue and mammary glands from healthy animals were sequenced and analyzed for the presence of mutations. Mutations were found in 71.8% of the samples and the most frequent were missense mutations. The most attacked exons in the mammary tumor were 5, 7 and 8, with 23.4, 31.6 and 23.4% mutations, respectively. Canine mammary tumors are related to mutations in gene p53 and mutations mostly occur in the region of the protein that is linked to the DNA in the cell nucleus, which can change the functionality of the cell and propitiate tumor growth. Despite being macroscopically normal, the mammary tissue adjacent to the tumors has mutations that can lead to recurrence if not removed together with the tumor.Para estudar as muta??es nos exos 4 a 8 do gene p53, foram utilizados 15 tumores mamários, mamas normais das mesmas cadelas e seis mamas de cadelas normais. O DNA extraído das amostras de tecido foi sequenciado e analisado para a presença de mutações. Em 71,8% das amostras obtidas foram observadas mutações, sendo as "missense" as mais frequentes. Os exons mais comprometidos foram 5, 7 e 8 com 23,4, 31,6 e 23,4% de mutações, respectivamente. O estudo conclui que tumores mamários caninos têm relação com mutações no gene p53 e que as mutações ocorrem com maior frequência nas regiões da proteína que estão ligadas ao DNA no núcleo celular. Isto pode alterar a funcionalidade da proteína e propiciar o crescimento do tumor. As mamas adjacentes aos tumores, apesar da aparência macroscópica normal, apresentaram mutações, que podem representar recidivas se a mama não for retirada juntamente com o tumor.

  7. Catalyser-21TM, a mineral water derived from leaf soil, inhibits tumor cell invasion and angiogenesis

    OpenAIRE

    Ye, Jun; Li, Yuping; Hamasaki, Takeki; Nakamichi, Noboru; Kawahara, Takeshi; Osada, Kazuhiro; Teruya, Kiichiro; Kato, Yuko; Toh, Kazuko; Abe, Masumi; Katakura, Yoshinori; Noguchi, Katsumi; Shirahata, Sanetaka

    2007-01-01

    Catalyser-21TM is a mineral water derived from natural leaf soil containing various organic and inorganic substances. Previous reports suggested a possibility that Catalyser-21TM has antioxidative potential and could inhibit angiogenesis and cancer cell invasiveness. Angiogenesis is a prerequisite for cancer cells to spread to surrounding tissues. Vascular endothelial growth factor (VEGF) is a major angiogenic factor in the formation of blood capillaries by cancer cells to supply nutrients an...

  8. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPAR? mediated mechanism

    OpenAIRE

    Garrido-urbani, Sarah; Jemelin, Ste?phane; Deffert, Christine; Carnesecchi-acker, Ste?phanie; Basset, Olivier; Szyndralewiez, Ce?dric; Heitz, Freddy; Page, Patrick; Montet, Xavier Ce?dric Rodolphe; Michalik, Liliane; Arbiser, Jack; Ru?egg, Curzio; Krause, Karl-heinz; Imhof, Beat

    2011-01-01

    Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon an...

  9. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

    OpenAIRE

    ZHANG, GUODONG; PANIGRAHY, DIPAK; Mahakian, Lisa M; Yang, Jun; Liu, Jun-Yan; Stephen Lee, Kin Sing; Wettersten, Hiromi I.; Ulu, Arzu; Hu, Xiaowen; Tam, Sarah; Hwang, Sung Hee; Ingham, Elizabeth S.; Mark W. Kieran; Weiss, Robert H; Ferrara, Katherine W.

    2013-01-01

    Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vi...

  10. Canine malignant mammary gland neoplasms with advanced clinical staging treated with carboplatin and cyclooxygenase inhibitors.

    Science.gov (United States)

    Lavalle, Gleidice Eunice; De Campos, Cecília Bonolo; Bertagnolli, Angélica Cavalheiro; Cassali, Geovanni Dantas

    2012-01-01

    Surgery remains the treatment of choice for female dogs with mammary gland tumors. Chemotherapy is not commonly used as an adjuvant therapy. Cyclooxygenase 2 (COX-2) has been related to angiogenesis development in tumors, disease progression and worse prognosis. The aim of this prospective study was to compare overall survival periods of female dogs diagnosed with advanced mammary tumors submitted to different treatment protocols, including surgery, chemotherapy and cyclooxygenase inhibitors. Twenty-nine female dogs were evaluated and treated with four different protocols. The overall survival of patients with low COX-2 scores was longer when compared to patients with high COX-2 scores. Different proposed adjuvant treatments associated with surgery led to a statistically significant longer overall survival when compared to surgical treatment alone. Canine patients presenting malignant mammary gland neoplasms with advanced clinical staging should be submitted to complementary therapeutic medication based on clinical staging and immunophenotypical characteristics of the disease. PMID:22523289

  11. Characterization of S?bp-2 as a mouse mammary tumor virus promoter-binding protein

    International Nuclear Information System (INIS)

    A cDNA encoding a rat S?bp-2 has been cloned from a ?gt11 library by South-Western blot screening using a 50-bp tannic acid responsive element [J. Biol. Chem. 273 (1998) 12499] of the mouse mammary tumor virus (MMTV) promoter region as a probe. The full-length cDNA encodes a protein with a predicted size of 108 kDa. Northern blot analysis revealed that the gene expression of S?bp-2 is comparatively high in testis, moderate in brain, and low in other tissues. The recombinant S?bp-2 protein was expressed as a GST- or Trx-fusion protein in Escherichia coli and purified by affinity column chromatography. Gel mobility shift competition analysis indicated that the recombinant S?bp-2 protein binds to region II (containing the ACTG-motif) in the 50-bp element in the MMTV promoter. A transient transfection assay of the S?bp-2 expression vector with MMTV promoter-containing Luciferase (Luc) reporter plasmids into mouse cells suggested that S?bp-2 is a negative transcription factor. Furthermore, the MMTV promoter activity was suppressed in cells expressing high levels of S?bp-2. Insertion of the 50-bp element upstream of the SV40 promoter negatively responded to the induced expression of S?bp-2. These results suggest that the negative transcriptional effect of S?bp-2 arises from its binding to the 50-bp element located in the MMTV promoter region

  12. Immunohistochemical expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in canine simple mammary gland adenocarcinomas

    OpenAIRE

    Al-dissi, Ahmad N.; Haines, Deborah M.; Singh, Baljit; Kidney, Beverly A.

    2010-01-01

    The expression of 5 markers associated with angiogenesis, proliferation, and apoptosis was studied in 26 canine simple mammary gland adenocarcinomas (SMGAs). The adenocarcinomas were graded histologically, and tissue sections were immunohistochemically stained for the expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), intra-tumor microvessel density, and tumor proliferation (PI) using antibodies against VEGF, VEGFR-2, von Willebrand factor, and Ki-67 antigen, ...

  13. ?1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer

    OpenAIRE

    Lahlou, Hicham; Muller, William J

    2011-01-01

    Consistent with their essential role in cell adhesion to the extracellular matrix, integrins and their associated signaling pathways have been shown to be involved in cell proliferation, migration, invasion and survival, processes required in both tumorigenesis and metastasis. ?1-integrins represent the predominantly expressed integrins in mammary epithelial cells and have been proven crucial for mammary gland development and differentiation. Here we provide an overview of the studies that h...

  14. Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis.

    Science.gov (United States)

    Heidegger, Isabel; Kern, Johann; Ofer, Philipp; Klocker, Helmut; Massoner, Petra

    2014-05-15

    We scrutinized the effect of insulin receptor (INSR) in addition to IGF1R in PCa using in vitro and in vivo models. In-vitro overexpression of IGF1R and INSRA, but not INSRB increased cell proliferation, colony formation, migration, invasion and resistance to apoptosis in prostate cancer cells (DU145, LNCaP, PC3). Opposite effects were induced by downregulation of IGF1R and total INSR, but not INSRB. In contrast to tumor cells, non-cancerous epithelial cells of the prostate (EP156T, RWPE-1) were inhibited on overexpression and stimulated by knockdown of receptors. In-vivo analyses using the chicken allantoic membrane assay confirmed the tumorigenic effects of IGF1R and INSR. Apart of promoting tumor growth, IGF1R and INSR overexpression also enhanced angiogenesis indicated by higher vessel density and increased number of desmin-immunoreactive pericytes. Our study underscores the oncogenic impact of IGF1R including significant effects on tumor growth, cell migration, sensitivity to apoptotic/chemotherapeutic agents and angiogenesis, and characterizes the INSR, in particular the isoform INSRA, as additional cancer-promoting receptor in prostate cancer. Both, the insulin-like growth factor receptor 1 and the insulin receptor exert oncogenic functions, thus proposing that both receptors need to be considered in therapeutic settings. PMID:24809298

  15. Association of preoperative radiation effect with tumor angiogenesis and vascular endothelial growth factor in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    This study examined the relationship between tumor angiogenesis and the radiation-induced response, evaluated based on pathological changes, in oral squamous cell carcinoma patients treated with preoperative radiation therapy. Forty-one cases of squamous cell carcinoma treated with preoperative radiation therapy were investigated. Tumor angiogenesis was assessed by scoring the intratumor microvessel density (IMVD). Expression of vascular endothelial growth factor (VEGF) was also evaluated before and after preoperative radiotherapy. There was no correlation between IMVD in the specimens before therapy and the pathological response to radiation therapy. However, radiation therapy decreased IMVD in the specimens after therapy. A significant association was observed between VEGF expression and resistance to radiation therapy: only 4 of the 21 patients whose tumors exhibited a high level (2+ or 3+) of VEGF staining experienced a major (3+ or 4+) pathological response to radiation therapy. Furthermore, an increasing level of VEGF expression after radiation therapy was observed in non-effective (0 to 2+) response cases. These results suggest that VEGF expression and the induction of this protein are related to radiosensitivity and could be used to predict the effects of preoperative radiation therapy on oral squamous cell carcinoma. (author)

  16. Association of preoperative radiation effect with tumor angiogenesis and vascular endothelial growth factor in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Shintani, Satoru; Kiyota, Akihisa; Mihara, Mariko; Nakahara, Yuuji; Terakado, Nagaaki; Ueyama, Yoshiya; Matsumura, Tomohiro [Okayama Univ. (Japan). Dental School

    2000-10-01

    This study examined the relationship between tumor angiogenesis and the radiation-induced response, evaluated based on pathological changes, in oral squamous cell carcinoma patients treated with preoperative radiation therapy. Forty-one cases of squamous cell carcinoma treated with preoperative radiation therapy were investigated. Tumor angiogenesis was assessed by scoring the intratumor microvessel density (IMVD). Expression of vascular endothelial growth factor (VEGF) was also evaluated before and after preoperative radiotherapy. There was no correlation between IMVD in the specimens before therapy and the pathological response to radiation therapy. However, radiation therapy decreased IMVD in the specimens after therapy. A significant association was observed between VEGF expression and resistance to radiation therapy: only 4 of the 21 patients whose tumors exhibited a high level (2+ or 3+) of VEGF staining experienced a major (3+ or 4+) pathological response to radiation therapy. Furthermore, an increasing level of VEGF expression after radiation therapy was observed in non-effective (0 to 2+) response cases. These results suggest that VEGF expression and the induction of this protein are related to radiosensitivity and could be used to predict the effects of preoperative radiation therapy on oral squamous cell carcinoma. (author)

  17. MiR-128 Inhibits Tumor Growth and Angiogenesis by Targeting p70S6K1

    OpenAIRE

    Shi, Zhu-Mei; Wang, Jing; Yan, Zhiping; You, Yong-ping; Li, Chong-Yong; Qian, Xu; Yin, Yu; Zhao, Peng; Wang, Ying-ying; Wang, Xie-Feng; Li, Ming-na; Liu, Ling-Zhi; LIU Ning; Jiang, Bing-Hua

    2012-01-01

    MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that miR-128 expression levels were decreased in glioma, and identified p70S6K1 as a novel direct target of miR-128. Overexpression of miR-128 suppressed p70S6K1 and its downstream signaling molecules such as HIF-1 and VEGF expression, and attenuated cell proliferation, tumor growth and angiogenesis. Forced expres...

  18. Lack of association between level of Plasminogen Activator Inhibitor-1 and estimates of tumor angiogenesis in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Riisbro, Rikke

    2007-01-01

    Plasminogen Activator Inhibitor type-1 (PAI-1) is involved in tumor invasion and progression. High levels of PAI-1 are associated with poor prognosis in breast cancer, and PAI-1 has been shown to play a role in angiogenic processes. Since estimates of tumor angiogenesis may predict poor prognosis we studied the relationship between PAI-1 and estimates of angiogenesis in breast cancer. Tumor tissue specimens from 438 breast cancer patients were included. Median follow-up was 10.3 years. Protein levels of PAI-1 were measured using an ELISA. Angiogenesis scores were performed using a Chalkley grid. Median PAI-1 level was 0.70 ng/mg protein (range, 0 - 90 ng/mg protein) and median Chalkley count was 5.00 (range, 2.67 - 12.00). Chalkley counts were not correlated with PAI-1. In univariate analysis both increasing PAI-1 and increasing Chalkley counts evaluated as continuous parameters were significantly associated with poor disease-specific survival with RR 1.04 (95% CI 1.02 - 1.07) (p<0.0001) and RR 1.11 (95% CI 1.01 - 1.22) (p=0.04), respectively. High tertiles of PAI-1 were borderline significantly correlated with poor disease-specific survival (p=0.06), whereas high tertiles of Chalkley counts were significantly associated with poor disease-specific survival (p=0.004). Combining low/low versus high/high tertiles of Chalkley counts and PAI-1 showed actuarial 10-year survival rates of 82% versus 52% (p=0.004). High N-stage (p<0.0001), grade (p<0.0001) and increasing levels of PAI-1 (p=0.009) were independent markers of death from breast cancer. This study confirms high PAI-1 or high Chalkley counts as markers of poor prognosis in breast cancer patients, and suggests that the prognostic impact of PAI-1 is independent of its supposed involvement in tumor angiogenesis. Udgivelsesdato: 2007-null

  19. Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis

    OpenAIRE

    Salvati, Erica; Zizza, Pasquale; Rizzo, Angela; Iachettini, Sara; Cingolani, Chiara; D’Angelo, Carmen; Porru, Manuela; Randazzo, Antonio; Pagano, Bruno; Novellino, Ettore; Pisanu, Maria Elena; Stoppacciaro, Antonella; Spinella, Francesca; Bagnato, Anna; Gilson, Eric

    2013-01-01

    Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an antiparallel G-quadruplex (G4) structure. This G4 structure can be efficiently stabilized by small molecules with the consequent inhibition of vegfr-2 expression. Functionally, the G4-mediated red...

  20. Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Roos, W.; Fabbro, D.; Kueng, W.; Costa, S.D.; Eppenberger, U.

    1986-02-01

    The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors, whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors. TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines, as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 M with the exception of the T-47-D cells. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cells.

  1. Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells

    International Nuclear Information System (INIS)

    The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors, whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors. TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines, as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 ?M with the exception of the T-47-D cells. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cellsmmary carcinoma cells

  2. Sustained inhibition of PKC? reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model

    OpenAIRE

    Kim, Jeewon; Thorne, Stephen H.; Sun, Lihan; Huang, Baocheng; Mochly-rosen, Daria

    2010-01-01

    Metastasis is the major reason for breast cancer-related deaths. Although there is a host of indirect evidence for a role of PKC? in primary breast cancer growth, its role in the molecular pathways leading to metastasis have not been comprehensively studied. By treating mice with ?V5-3, a novel peptide inhibitor selective for PKC?, we were able to determine how PKC? regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affect...

  3. A comparison of 3D-CTA and 4D-CE-MRA for the dynamic monitoring of angiogenesis in a rabbit VX2 tumor

    International Nuclear Information System (INIS)

    Purpose: To compare three-dimensional computed tomography angiography (3D-CTA) and four-dimensional contrast-enhanced magnetic resonance angiography (4D-CE-MRA) for the in vivo monitoring of tumor angiogenesis. Materials and methods: VX2 tumors were implanted into the right thigh muscle of 30 New Zealand white rabbits. The animals were randomly assigned to 5 groups, which, respectively, were scanned by 3D-CTA and 4D-CE-MRA on day 4, 7, 10, 13, or 16 after tumor implantation. After scanning, tumors were resected and processed for conventional histology and CD-31 immunohistochemistry. Tumor volume measurements derived from CT and MR imaging were compared with histopathological data. The minimum tumor diameter and the number of new tumor blood vessels detectable by 3D-CTA and 4D-CE-MRA were also compared. Results: There were no significant differences in the tumor volume measurements derived from CT, MR, and histological analysis. The minimum diameter of tumor vessels detectable by 3D-CTA (0.68 ± 0.07 mm) was significantly less than that by 4D-CE-MRA (0.85 ± 0.12 mm) (P = 0.005). The number of tumor vessels detected by each imaging method was not significantly different until day 13 after implantation, when 3D-CTA detected a greater number (P < 0.001). The morphologic process of tumor angiogenesis was demonstrated dynamically by 3D-CTA and 4D-CE-MRA in vivo. Conclusions: Tumor angiogenesis can be dynamically monitored in vivo by 3D-CTA and 4D-CE-MRA. Of the two methods3D-CTA and 4D-CE-MRA. Of the two methods, 3D-CTA has better spatial resolution, but 4D-CE-MRA allows temporal resolution of tumor angiogenesis.

  4. Dietary fat modulation of mammary tumor growth and metabolism demonstrated by 31P-nuclear magnetic resonance

    International Nuclear Information System (INIS)

    The relationship of dietary fat concentration and saturation on the growth and metabolic activity of line 168 was studied using syngeneic mice fed 6 experimental diets before and during tumor growth. Tumor latency was significantly greater for mice fed a diet containing the minimum of essential fatty acids (EFA, 0.5% corn oil) or 8% coconut oil (SF) than for mice fed 8 or 20% safflower oil (PUF) or 20% SF. Changes in dietary fat resulted in alterations of tumor cell and serum fatty acid composition but not the number of inflammatory cells infiltrating the tumor. 31P-surface coil NMR was used to measure possible changes in tumor metabolism in vivo. Although pH decreased from 7.2 to 6.6 as the tumor volume increased, there was no difference in pH among dietary groups. There was an inverse relationship between both sugar phosphate (SP)/Pi and ATP/Pi ratios and tumor volume; those ratios for mice fed an EFA deficient or minimal EFA diet decreased at a different rate than ratios for mice fed diets with additional fat. Tumors of mice fed diets containing no or a low level (0.3%) of 18:2 had higher SP/ATP ratios than mice fed diets containing a moderate level (? 4%) of 18:2. Thus, high levels of dietary fat had a significant effect on promotion of mammary tumors during early stages of tumor growth. Differences in tumor volume associated with dietary fat may be related to changes in the levels of high energy phosphate metabolites

  5. Myeloid cell leukemia-1 is associated with tumor progression by inhibiting apoptosis and enhancing angiogenesis in colorectal cancer.

    Science.gov (United States)

    Lee, Wan-Sik; Park, Young-Lan; Kim, Nuri; Oh, Hyung-Hoon; Son, Dong-Jun; Kim, Mi-Young; Oak, Chan-Young; Chung, Cho-Yun; Park, Hyung-Chul; Kim, Jong-Sun; Myung, Dae-Seong; Cho, Sung-Bum; Kim, Hyun-Soo; Joo, Young-Eun

    2015-01-01

    Myeloid cell leukemia-1 (Mcl-1) is a highly expressed anti-apoptotic Bcl-2 protein in cancer. Therefore, inhibition of its expression induces apoptosis in cancer cells and enhances sensitivity to cancer treatment. The aims of this study were to evaluate whether Mcl-1 affects the oncogenic behaviors of colorectal cancer cells, and to document the relationship of its expression with various clinicopathological parameters in colorectal cancer. Mcl-1 knockdown induced apoptosis by activating cleaved caspase-3 and -9, and increasing the expression of the pro-apoptotic protein, PUMA. Mcl-1 knockdown induced cell cycle arrest by decreasing cyclin D1, CDK4 and 6, and by increasing p27 expression. Mcl-1 knockdown decreased both endothelial cell invasion and tube formation, and decreased the expression of VEGF. The phosphorylation level of STAT3 was decreased by Mcl-1 knockdown. The mean apoptotic index value of Mcl-1 positive tumors was significantly lower than that of Mcl-1 negative tumors. The mean microvessel density value of Mcl-1 positive tumors was significantly higher than that of negative tumors. Mcl-1 expression was significantly increased in colorectal cancer, also associated with tumor stage, lymph node metastasis, and poor survival. These results indicate Mcl-1 is associated with tumor progression through its inhibition of apoptosis and enhancement of angiogenesis in colorectal cancer. PMID:25628923

  6. Total alkaloids of Rubus alceifolius Poir inhibit tumor angiogenesis through suppression of the Notch signaling pathway in a mouse model of hepatocellular carcinoma.

    Science.gov (United States)

    Zhao, Jinyan; Lin, Wei; Cao, Zhiyun; Zhuang, Qunchuan; Zheng, Liangpu; Peng, Jun; Hong, Zhenfeng

    2015-01-01

    Angiogenesis, which has a critical role in human tumor growth and development, is tightly regulated by the Notch signaling pathway. Total alkaloids are active components of the plant Rubus alceifolius Poir, which is used for the treatment of various types of cancer. A previous study by our group showed that the total alkaloids of Rubus alceifolius Poir (TARAP) induced hepatocellular carcinoma (HCC) cell apoptosis through the activation of the mitochondria-dependent pathway in vitro and in vivo, as well as inhibited angiogenesis in a chick embryo chorioallantoic membrane model. In the present study, to further analyze the specific mechanisms underlying the antitumor activity of TARAP, a HCC xenograft mouse model was used to assess the effect of TARAP on angiogenesis in vivo. TARAP was found to suppress the expression of vascular endothelial growth factor (VEGF) A and VEGF receptor-2 in tumor tissues, which resulted in the inhibition of tumor angiogenesis. In addition, TARAP treatment was observed to inhibit the expression of Notch1, delta-like ligand 4 and jagged 1, which are key mediators of the Notch signaling pathway. The present study identified that the inhibition of tumor angiogenesis through the suppression of the Notch signaling pathway may be one of the mechanisms through which TARAP may be effective in the treatment of cancer. PMID:25333354

  7. Heat shock protein 70 and nitric oxide concentrations in non-tumorous and neoplastic canine mammary tissues: preliminary results - Short communication.

    Science.gov (United States)

    Szczubia?, Marek; Urban-Chmiel, Renata; ?opuszy?ski, Wojciech

    2015-06-01

    The concentrations of heat shock protein 70 (Hsp70) and nitric oxide ions (NO), measured as nitrite, were determined in canine mammary tumours and nontumorous mammary gland tissues. The concentrations of Hsp70 and NO were significantly higher in both benign and malignant tumours than in non-tumorous mammary tissues. Hsp70 concentration decreased with the increase in the grade of histological malignancy. A strong positive correlation was found between the concentrations of Hsp70 and NO in the benign tumours as well as in grade I and grade II malignant tumours. The results indicate that the process of neoplastic transformation in the canine mammary gland is related to a significant increase in Hsp70 and NO concentration in tumour tissues, and an interdependence between Hsp70 and nitrite ion production can be observed. PMID:26051259

  8. Immunophenotypic features of tumor infiltrating lymphocytes from mammary carcinomas in female dogs associated with prognostic factors and survival rates

    Directory of Open Access Journals (Sweden)

    Serakides Rogéria

    2010-06-01

    Full Text Available Abstract Background The immune system plays an important role in the multifactorial biologic system during the development of neoplasias. However, the involvement of the inflammatory response in the promotion/control of malignant cells is still controversial, and the cell subsets and the mechanisms involved are poorly investigated. The goal of this study was to characterize the clinical-pathological status and the immunophenotyping profile of tumor infiltrating lymphocytes and their association with the animal survival rates in canine mammary carcinomas. Methods Fifty-one animals with mammary carcinomas, classified as carcinomas in mixed tumors-MC-BMT = 31 and carcinomas-MC = 20 were submitted to systematic clinical-pathological analysis (tumor size; presence of lymph node and pulmonary metastasis; clinical stage; histological grade; inflammatory distribution and intensity as well as the lymphocytic infiltrate intensity and survival rates. Twenty-four animals (MC-BMT = 16 and MC = 8 were elected to the immunophenotypic study performed by flow cytometry. Results Data analysis demonstrated that clinical stage II-IV and histological grade was I more frequent in MC-BMT as compared to MC. Univariate analysis demonstrated that the intensity of inflammation (moderate/intense and the proportion of CD4+ (? 66.7% or CD8+ T-cells (P = 0.02 remained as independent prognostic factor. Despite the clinical manifestation, the lymphocytes represented the predominant cell type in the tumor infiltrate. The percentage of T-cells was higher in animals with MC-BMT without metastasis, while the percentage of B-lymphocytes was greater in animals with metastasized MC-BMT (P + T-cells was significantly greater in metastasized tumors (both MC-BMT and MC, (P + T-cells was higher in MC-BMT without metastasis. Consequently, the CD4+/CD8+ ratio was significantly increased in both groups with metastasis. Regardless of the tumor type, the animals with high proportions of CD4+ and low CD8+ T-cells had decreased survival rates. Conclusion The intensity of lymphocytic infiltrate and probably the relative abundance of the CD4+ and CD8+ T-lymphocytes may represent important survival prognostic biomarkers for canine mammary carcinomas.

  9. Exogenous mouse mammary tumor virus proviral DNA isolated from a kidney adenocarcinoma cell line contains alterations in the U3 region of the long terminal repeat.

    OpenAIRE

    Wellinger, R. J.; Garcia, M.; Vessaz, A.; Diggelmann, H.

    1986-01-01

    Mouse mammary tumor virus (MMTV) is a B-type retrovirus which induces predominantly mammary carcinomas after a relatively long latency period. To date, very little is known about the reasons for the strict tissue specificity of MMTV. The BALB/cf/Cd strain of mice, which was infected with milk-borne MMTV (C3H), shows a high incidence of kidney adenocarcinomas, and our data suggest that MMTV might be involved in the formation of these tumors. Newly integrated exogenous MMTV proviruses were foun...

  10. EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer

    OpenAIRE

    Milliken, Erin L.; Zhang, Xiaoxue; Flask, Chris; Duerk, Jeffrey L.; Macdonald, Paul N.; Keri, Ruth A.

    2005-01-01

    1,25-Dihydroxyvitamin D3 and several of its analogs, such as EB1089, induce growth arrest and apoptosis of breast cancer cells in culture. EB1089 has also been shown to limit growth of xenografts in nude mice and carcinogen-induced mammary tumors in rats. Coupled with the fact that the vitamin D receptor is highly expressed in a large proportion of breast tumors, these data suggest that it may be a broad spectrum therapeutic target. We utilized a transgenic model of hormone-induced mammary ca...

  11. Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors.

    Science.gov (United States)

    Landis, M D; Seachrist, D D; Abdul-Karim, F W; Keri, R A

    2006-06-01

    Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation. PMID:16434967

  12. Assessment of cell proliferation and prognostic factors in canine mammary gland tumors Avaliação da proliferação celular e fatores prognósticos em tumores mamários caninos

    Directory of Open Access Journals (Sweden)

    A.P. Dutra

    2008-12-01

    Full Text Available Three methods for the analysis of cell proliferation, mitotic index/10 high-power fields (10 HPF, mitotic index/four sets of 10 HPF (40 HPF, and MIB-1 index were evaluated in a series of canine mammary gland tumors, as well as the possible correlation between them. Fifty-six canine mammary gland tumors, including 23 benign and 33 malignant, were studied. In addition, the prognostic impact of mitotic index/10 HPF, and histological malignancy grade were evaluated in 17 malignant tumors, being seven ductal and 10 metaplastic carcinomas. The three methods used to evaluate cell proliferation were correlated with the prognostic impact of mitotic index/10 HPF and histological malignancy grade. The results showed a strong association between mitotic figure counts and MIB-1 index (PAvaliaram-se três métodos de proliferação celular, índice mitótico/10 campos de grande aumento (10 CGA, quatro vezes 10 CGA (40 CGA e índice de marcação por MIB-1, em uma série de tumores mamários caninos, e as possíveis correlações entre estes métodos. Foram estudados 56 tumores mamários caninos, 23 benignos e 33 malignos. Foi também avaliado o impacto prognóstico do índice mitótico (10 CGA e o grau histológico maligno em 17 tumores malignos, sete carcinomas ductais e 10 carcinomas metaplásicos. A correlação entre os três métodos para avaliar a proliferação celular e o impacto prognóstico do índice mitótico por 10 CGA e o grau histológico maligno foi realizada. Os resultados mostraram que existe uma forte associação entre contagem de mitose e o índice de marcação por MIB-1(P<0,0001 e correlação entre contagem de mitoses em 40 CGA e índice de marcação por MIB-1 e entre índice mitótico em 10 CGA e 40 CGA (P<0,05. Observou-se correlação entre os três métodos de avaliação da proliferação celular e os fatores prognósticos semelhante aos estudos de câncer de mama humano.

  13. Effect of an estrogen antagonist (tamoxifen) on the initiation and progression of ?-irradiation-induced mammary tumors in female Sprague-Dawley rats

    International Nuclear Information System (INIS)

    One hundred and sixty-eight female Sprague-Dawley rats were divided among 4 groups (42 rats/group) and were irradiated with 400 rad [137Cs] ? rays to the whole body when 59 days old. The estrogen antagonist tamoxifen was injected s.c. daily from 29-89 days of age (Series 1) or from 89-149 days of age (Series 2), prior to the onset of palpable mammary tumors. Two groups of rats were injected with the diluent and served as controls. All rats were palpated bi-weekly for mammary tumors and killed 37 weeks after ?-irradiation. The number of mammary carcinomas which developed in each group and their significance levels were: series 1, controls, 31; tamoxifen treated, 11, P < 0.01; series 2, controls, 33; tamoxifen treated, 17, P < 0.01. Tamoxifen treatment did not significantly influence the incidence of benign mammary tumors (fibroadenomas) nor the rate of body weight gain. Thus, the effective use of an estrogen antagonist for the prophylaxis of radiogenic mammary carcinomas has been demonstrated in this study. (author)

  14. Mouse mammary tumor virus in hybrids from strains C57BL and GR: breeding test of backcross segregants.

    Science.gov (United States)

    Heston, W E; Smith, B; Parks, W P

    1976-10-01

    F1 and F2 and first backcross hybrids and second backcross families of the high mammary tumor incidence strain GR and the low incidence strain C57BL were examined for the segregation of mouse mammary tumor viral (MMTV) expression. Although GR has been reported to transmit MMTV as a single dominant gene, several lines of evidence suggest there are multiple genetic factors that influence MMTV expression, MMTV expression as measured by double antibody radioimmunoassay for MMTV p14 segregated in 106 first backcross progeny at a 60:40 ratio, intermediate between what would be expected for either a single or two gene hypothesis. In female second backcross progeny of either male or female first backcross, a heterogeneous pattern of expression was noted that does not fit any simple Mendalian pattern. From an analysis of serial lactations of first backcross and second backcross families, it appears that all hybrid females contain MMTV proviral information that may be expressed either at late lactations or in a variable proportion of progeny mice. These combined results are most consistent with a vertically transmitted genome regulated by multiple factors in these crosses. PMID:185316

  15. Bone marrow stromal cell antigen 2 (BST-2 restricts mouse mammary tumor virus (MMTV replication in vivo

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    Jones Philip H

    2012-01-01

    Full Text Available Abstract Background Bone marrow stromal cell antigen 2 (BST-2 is a cellular factor that restricts the egress of viruses such as human immunodeficiency virus (HIV-1 from the surface of infected cells, preventing infection of new cells. BST-2 is variably expressed in most cell types, and its expression is enhanced by cytokines such as type I interferon alpha (IFN-?. In this present study, we used the beta-retrovirus, mouse mammary tumor virus (MMTV as a model to examine the role of mouse BST-2 in host infection in vivo. Results By using RNA interference, we show that loss of BST-2 enhances MMTV replication in cultured mammary tumor cells and in vivo. In cultured cells, BST-2 inhibits virus accumulation in the culture medium, and co-localizes at the cell surface with virus structural proteins. Furthermore, both scanning electron micrograph (SEM and transmission electron micrograph (TEM show that MMTV accumulates on the surface of IFN?-stimulated cells. Conclusions Our data provide evidence that BST-2 restricts MMTV release from naturally infected cells and that BST-2 is an antiviral factor in vivo.

  16. CdS-Cd(OH)2 core shell quantum dots functionalized with Concanavalin A lectin for recognition of mammary tumors

    International Nuclear Information System (INIS)

    We report the use of CdS/Cd(OH)2 quantum dots functionalized with glutaraldehyde and conjugated to concanavalin-A (Con-A) lectin to investigate cell alterations regarding carbohydrate profile in human mammary tissues diagnosed as fibroadenoma (benigne tumor). The Con-A lectin is a biomolecule which binds specifically to glucose/mannose residues present in the cellular membrane. These bioconjugated-particles were incubated with tissue sections of normal and to Fibroadenoma, a benign type of mammary tumor. The tissue sections were deparafinized, hydrated in graded alcohol and treated with a solution of Evans Blue in order to avoid autofluorescence. The fluorescence intensity of QD-Con-A stained tissues showed different patterns which reflect the carbohydrate expression of glucose/mannose in fibroadenoma when compared to the detection of the normal carbohydrate expression. The pattern of inespecific labeling of the tissues with glutharaldehyde functionalized CdS/Cd(OH)2 quantum dots is compared to the targeting driven by the Con-A lectin. The preliminary findings reported here support the use of CdS/Cd(OH)2 quantum dots as specific probes of cellular alterations possibiliting their use in diagnostics. (copyright 2006 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  17. STAT5b as Molecular Target in Pancreatic Cancer—Inhibition of Tumor Growth, Angiogenesis, and Metastases

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    Christian Moser

    2012-10-01

    Full Text Available The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC. We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC.

  18. Development of a New Positron Emission Tomography Tracer for Targeting Tumor Angiogenesis: Synthesis, Small Animal Imaging, and Radiation Dosimetry

    Directory of Open Access Journals (Sweden)

    David S. Lalush

    2013-05-01

    Full Text Available Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET. To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c. Lewis lung carcinoma (LLC mouse model and conducted tissue distribution, small animal PET/CT imaging study, autoradiography, histology, fluorescence imaging, and dosimetry assessments. The results from this study show that, in the context of the s.c. LLC immunocompetent mouse model, the QFP-tracer can target tumor blood vessels selectively. However, further optimization of the biodistribution and dosimetry profile of the tracer is necessary to ensure efficient radiopharmaceutical applications enabled by the biological specificity of the QFP-peptide.

  19. Transforming growth factor-? transiently induces vimentin expression and invasive capacity in a canine mammary gland tumor cell line.

    Science.gov (United States)

    Yoshida, K; Saito, T; Kamida, A; Matsumoto, K; Saeki, K; Mochizuki, M; Sasaki, N; Nakagawa, T

    2013-06-01

    The epithelial-mesenchymal transition (EMT) is a crucial event that occurs during cancer metastasis and can be induced by transforming growth factor-? (TGF-?) in various tumor cells in vitro. However, little is known about the effects of TGF-? in canine mammary gland tumors (CMGTs). Here, we investigated the role of TGF-? in CMGT. We observed that treatment of the CMGT cell line CHMp13a with TGF-?1 leads to transient induction of the mesenchymal marker vimentin. Real-time measurements of cellular electrical impedance also showed that CMGT invasiveness is transiently increased by TGF-?1 treatment, but is reversed after prolonged stimulation. This phenomenon is similar to the mesenchymal-epithelial transition (MET, the reverse phenomenon of EMT), and a process that is implicated in the establishment of secondary metastatic lesions. PMID:23182613

  20. Comparison of Expression Profiles of Metastatic versus Primary Mammary Tumors in MMTV-Wnt-1 and MMTV-Neu Transgenic Mice

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    Shixia Huang

    2008-02-01

    Full Text Available Distant metastases of human breast cancers have been suggested to be more different from each other than from their respective primary tumors, based on expression profiling. The mechanism behind this lack of similarity between individual metastases is not known. We used cDNA microarrays to determine the expression profiles of pulmonary metastases and primary mammary tumors in two distinct transgenic models expressing either the Neu or the Wnt-1 oncogene from the mouse mammary tumor virus long terminal repeat (MMTV LTR. We found that pulmonary metastases are similar to each other and to their primary tumors within the same line. However, metastases arising in one transgenic mouse line are very different from either metastases or primary tumors arising in the other line. In addition, we found that, like their primary tumors, lung metastases in Wnt-1 transgenic mice harbor both epithelial and myoepithelial tumor cells and cells that express the putative progenitor cell marker keratin 6. Our data suggest that both gene expression profiles and cellular heterogeneity are preserved after breast cancer has spread to distant sites, and that metastases are similar to each other when their primary tumors were induced by the same oncogene and from the same subset of mammary cells.

  1. Tumstatin, the NC1 domain of ?3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth

    International Nuclear Information System (INIS)

    Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen ?3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to ?V?3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors

  2. Physiological levels of Pik3ca(H1047R) mutation in the mouse mammary gland results in ductal hyperplasia and formation of ER?-positive tumors.

    Science.gov (United States)

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A

    2012-01-01

    PIK3CA, the gene coding for the p110? subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3ca(H1047R), into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin(-); CD29(lo); CD24(+); CD61(+)) cell population. The Pik3ca(H1047R) expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ER?-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3ca(H1047R) in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3ca(H1047R) mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336

  3. Physiological Levels of Pik3caH1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ER?-Positive Tumors

    Science.gov (United States)

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G.; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A.

    2012-01-01

    PIK3CA, the gene coding for the p110? subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3caH1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin?; CD29lo; CD24+; CD61+) cell population. The Pik3caH1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ER?-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3caH1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336

  4. Obesity and perinatal TCDD exposure increases mammary tumors in FVB mice

    Science.gov (United States)

    Risk of breast cancer has been consistently shown to correlate to total lifetime exposure to estrogens. Because both TCDD exposure and the state of obesity interact with the estrogen pathway, we wanted to investigate how TCDD and obesity interact with mammary cancer susceptibili...

  5. Obesity and perinatal TCDD exposure increases mammary tumor incidence in FVB mice

    Science.gov (United States)

    Breast cancer risk consistently correlates with total lifetime exposure to estrogens. Because both TCDD and adipocytes impact the estrogen pathway, we examined how TCDD and obesity interact to alter mammary cancer susceptibility. At 12.5 days post conception, we exposed FVB fema...

  6. Preferential induction of mammary tumors in p53 hemizygous BALB/c mice by fractionated irradiation of a sub-lethal dose of X-rays

    International Nuclear Information System (INIS)

    BALB/c mice are susceptible to radiation-induced mammary tumors as well as lymphomas. We investigated the effects of the p53 deficient allele and of X-irradiation on the tumor spectrum in the BALB/c background. Substantially all p53 -/- animals died of thymic lymphomas before 36 weeks of age, while none of the p53 +/+ animals died during that period. At this age, mortalities of p53 +/- females and males were 5% (1/22) and 11% (1/9), respectively, due to non-thymic lymphoma and sarcoma. When exposed to 4 Gy of X-irradiation, 100% (44/44) and 95% (18/19) of p53 +/- mice died with tumors within 36 weeks. Among these, the predominant cause of death was lymphoma in either sex [26/44 (59%) in females; 13/19 (68%) in males]; mammary adenocarcinoma (15/44, 34%) and sarcoma (3/19, 16%) were semi-dominant in females and males, respectively. The mortalities of similarly treated p53 +/+ mice were 16% (5/31) in females and 17% (3/18) in males: virtually all deaths were due to thymic lymphomas in either sex. When exposed to 4 x 0.7 Gy of X-irradiation at weekly intervals, 23/23 (100%) of the p53 +/- females died of tumors within 36 weeks. In these animals, mammary adenocarcinoma (15/23, 65%), instead of lymphoma (7/23, 30%), was dominant. None of the similarly treated p53 +/+ females developed malignant tumors during the period. Mammary adenocarcinomas generated in p53 +/- females exposed or non-exposed to radiation showed a frequent loss of the p53 wild-type allele. Hence, we provf the p53 wild-type allele. Hence, we provided a useful experimental system to study radiation-induced mammary tumors in mice. (author)

  7. The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

    Science.gov (United States)

    Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature an...

  8. Antigenic determinants in a virus-induced mouse mammary tumor recognized by cell-mediated immune assays.

    Science.gov (United States)

    Lopez, P F; Parks, W P; Lopez, D M

    1984-03-01

    Purified tumor cell membrane (PTCM) fractions from spontaneous BALB/cfC3H mammary adenocarcinomas elicit blastogenic responses in spleen cells of tumor-bearing mice. Previous studies have demonstrated that splenic T-cells are the major responding cell population but have not clarified whether the antigens responsible for the reactions are exclusively viral in origin or may involve nonviral tumor-associated antigens (TAA). Pretreatment of PTCM preparations with polyvalent anti-murine mammary tumor virus (MuMTV) completely obliterated the ability of PTCM to stimulate an innocent bystander cytotoxicity reaction; however, it reduced the blastogenic response by only 60%, suggesting that the two assays may measure different antigenic reactivities. The specificity of the anti-MuMTV blocking for viral antigens was demonstrated by the complete absorption of the serum-blocking reaction with purified MuMTV particles in the cytotoxicity assay; however, absorption was only partial in the blastogenesis assay. Incubation with purified Rauscher murine leukemia virus particles failed to absorb the neutralizing effect of the sera. These data suggest that putative TAA can be detected in the blastogenesis assay but not in the cytotoxicity reaction. Ammonium sulfate-precipitated immunoglobulin fractions of sera from tumor-bearing BALB/cfC3H mice (TBMS) completely blocked the stimulatory potential of PTCM in both the blastogenesis and the cytotoxicity assays. In the reciprocal experiment to that described above, preabsorption of TBMS immunoglobulins with purified MuMTV completely removed the inhibition of the cytotoxicity but again only partially restored the blastogenic response. The reaction could be completely restored by preabsorption of TBMS with PTCM. These results support the contention of nonvirion antigen involvement in the blastogenesis reaction. In conclusion, these two assay systems detect different antigenic determinants on the MuMTV-expressing tumor cell membranes. Both viral and other antigens appear to be relevant in this model system, and serum factors present in the immunoglobulin fractions of tumor-bearing mice can inhibit T-cell responses directed at either kind of antigenic moieties. PMID:6199544

  9. Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via ?9?1 integrin.

    Science.gov (United States)

    Kale, S; Raja, R; Thorat, D; Soundararajan, G; Patil, T V; Kundu, G C

    2014-05-01

    Tumor-associated macrophages (TAMs) have multifaceted roles in tumor development, particularly linked with tumor angiogenesis and invasion, but the molecular mechanism underlying this association remains unclear. In this study, we report that lack of osteopontin (OPN) suppresses melanoma growth in opn(-/-) mice and macrophages are the crucial component responsible for OPN-regulated melanoma growth. In tumor microenvironment, OPN activates macrophages and influences angiogenesis by enhancing cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in an autocrine manner. Furthermore, we identify ?9?1 integrin as a functional receptor for OPN that mediates its effect and activates ERK and p38 signaling, which ultimately leads to COX-2 expression in macrophages. The major role played by OPN and PGE2 in angiogenesis are further amplified by upregulation of MMP-9. OPN-activated macrophages promote the migration of endothelial and cancer cells via PGE2. These findings provide evidence that TAMs serve as source of key components such as OPN and COX-2-derived PGE2 and MMP-9 in melanoma microenvironment. Clinical specimens analyses revealed that increased infiltration of OPN-positive TAMs correlate with melanoma growth and angiogenesis. These data provide compelling evidence that OPN and COX-2 expressing macrophages are obligatory factors in melanoma growth. We conclude that OPN signaling is involved in macrophage recruitment into tumor, and our results emphasize the potential role of macrophage in modulation of tumor microenvironment via secretion of OPN, PGE2 and MMP-9, which trigger angiogenesis and melanoma growth. Thus, blockade of OPN and its regulated signaling network provides unique strategy to eradicate melanoma by manipulating TAMs. PMID:23728342

  10. SNS-032 Prevents Tumor Cell-Induced Angiogenesis By Inhibiting Vascular Endothelial Growth Factor

    Directory of Open Access Journals (Sweden)

    M. Aktar Ali

    2007-05-01

    Full Text Available Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs and human glioblastoma cells (U87MG. SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle. In this study, we examined the proliferation and viability of HUVECs and U87MG cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 inhibited threedimensional capillary network formations of endothelial cells. In a coculture study, SNS-032 completely prevented U87MG cell-mediated capillary formation of HUVECs. This inhibitor also prevented the migration of HUVECs when cultured alone or cocultured with U87MG cells. In addition, SNS-032 significantly prevented the production of vascular endothelial growth factor (VEGF in both cell lines, whereas SNS-032 was less effective in preventing capillary network formation and migration of endothelial cells when an active recombinant VEGF was added to the medium. In conclusion, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF.

  11. Promoting Effects of Milk on the Development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced Mammary Tumors in Rats

    International Nuclear Information System (INIS)

    To assess the effect of milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, 48 female Sprague-Dawley rats treated with DMBA were divided into 3 groups and given 1 of 3 test solutions for 20 weeks as their drinking liquid: milk, estrone sulfate solution or tap water. The milk group showed a significantly great incidence (75%) in tumor development compared with the water group (38%) and was comparable to the estrone sulfate group (69%). Mean tumor number per rat in the milk group was significantly higher than that in the water group (p=0.009). We classified the mammary tumors into three histological types: intraductal papilloma, fibroadenoma, and adenocarcinoma. Although the percent of intraductal papilloma and fibroadenoma was almost same among the three groups, malignant tumor was found only in the milk and estrone sulfate groups. In conclusion, our results indicate that milk as well as estrone sulfate promotes the development of DMBA-induced mammary tumors in rat and could be associated with the occurrence of adenocarcinoma

  12. Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

    Directory of Open Access Journals (Sweden)

    Chen X-C

    2008-10-01

    Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

  13. Investigation into the cancer protective effect of flaxseed in Tg.NK (MMTV/c-neu) mice, a murine mammary tumor model

    DEFF Research Database (Denmark)

    Birkved, Franziska Kramer; Mortensen, Alicja

    2011-01-01

    The aim of the present study was to investigate whether low flaxseed doses relevant to human dietary exposure can prevent mammary tumors in transgenic Tg.NK mice, a model of breast cancer. Animals were exposed to flaxseed through the diet at human relevant levels. Tumor-related parameters and tumor development were evaluated. Hepatic cytochrome P450 and glutathione S-transferase activities were significantly reduced in animals receiving low flaxseed doses. An incidence of palpable tumors before sacrifice, a number of tumors per mouse, and a number of large tumors (>6 mm diameter) at necropsy were statistically significantly lower in the high flaxseed group compared to controls, suggesting a beneficial effect on tumor progression of small dietary doses of flaxseed. However, the number of tumor-bearing mice and multiplicity of tumors at necropsy were not statistically significantly lower compared to the controls. Thus, the effect of small dietary doses of flaxseed on mammary tumor development in Tg.NK mice remains to be established.

  14. Neoplasias mamárias em cadelas: influência hormonal e efeitos da ovario-histerectomia como terapia adjuvante Canine mammary tumors: hormonal influence and effects of ovariohiysterectomy as an adjuvant therapy

    Directory of Open Access Journals (Sweden)

    Cláudia Sampaio Fonseca

    2000-08-01

    Full Text Available As neoplasias mamarias constituem aproximadamente 50% dos tumores diagnosticados em cadelas. Apesar dosharmónios sexuais femininos desempenharem papel fundamental no desenvolvimento desses tumores em mamíferos, o valor da supressão hormonal pela ovário-histerectomia como auxiliar no tratamento do tumor de mama em caninos permanece controverso. Discute-se ainda se a realização da ovário-histerectomia após o diagnóstico influencia ou não o crescimento e progressão do tumor na glândula afetada ou em outras glândulas mamarias. O objetivo desta revisão é discutir alguns aspectos relacionados à influência hormonal na etiologia de tumores mamarias em cadelas, assim como o valor terapêutico da castração, quando realizada no momento da mastectomia.The mammary neoplasms comprises aproximatel 50% ofthe diagnosed tumor s m the bitch. Although female sexual honnones play a fundamental role in the development of these tumors in mammals, the value of the suppression hormonal (ovariohysterectomy as an adjuvam treatment remains controversial. There are still arguments on whether the ovariohysterectomy after diagnosis of the tumor possesses influences lhe growth and progression of the tumor on the affected gland or on other mammary glands. The objective ofthis review is to discuss some aspects related to the hormonal influence in the pathogenesis of the canine tumor, as well as the therapeutic value ofspaying. when accomplished in the moment ofthe mastectomy.

  15. Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival

    OpenAIRE

    Kovacheva, Vesela P.; Davison, Jessica M.; Mellott, Tiffany J.; Rogers, Adrianne E.; Yang, Shi; O'Brien, Michael J; Blusztajn, Jan Krzysztof

    2009-01-01

    Choline is an essential nutrient that serves as a donor of metabolic methyl groups used during gestation to establish the epigenetic DNA methylation patterns that modulate tissue-specific gene expression. Because the mammary gland begins its development prenatally, we hypothesized that choline availability in utero may affect the gland’s susceptibility to cancer. During gestational days 11–17, pregnant rats were fed a control, choline-supplemented, or choline-deficient diet (8, 36, and 0 mmol...

  16. Lentivirus-Mediated Oncogene Introduction into Mammary Cells In Vivo Induces Tumors12

    OpenAIRE

    Siwko, Stefan K.; Bu, Wen; Gutierrez, Carolina; Lewis, Brian; Jechlinger, Martin; Schaffhausen, Brian; Li, Yi

    2008-01-01

    We recently reported the introduction of oncogene-expressing avian retroviruses into somatic mammary cells in mice susceptible to infection by transgenic expression of tva, encoding the receptor for subgroup A avian leukosis-sarcoma virus (ALSV). Because ALSV-based vectors poorly infect nondividing cells, they are inadequate for studying carcinogenesis initiated from nonproliferative cells (e.g., stem cells). Lentivirus pseudotyped with the envelope protein of ALSV infects nondividing TVA-pro...

  17. Peripheral pulmonary nodules: Relationship between multi-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF expression

    Directory of Open Access Journals (Sweden)

    Cheng Xiao-Ling

    2008-06-01

    Full Text Available Abstract Background The aim of this study is to investigate the relationship between16-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF (vascular endothelial growth factor expression in patients with benign and malignant pulmonary nodules, and differential diagnosis between benign and malignant pulmonary nodules. Methods Sixty-four patients with benign and malignant pulmonary nodules underwent 16-slice spiral CT perfusion imaging. The CT perfusion imaging was analyzed for TDC (time density curve, perfusion parametric maps, and the respective perfusion parameters. Immunohistochemical findings of MVD (microvessel density measurement and VEGF expression was evaluated. Results The shape of the TDC of peripheral lung cancer was similar to those of inflammatory nodule. PH (peak height, PHpm/PHa (peak height ratio of pulmonary nodule to aorta, BF (blood flow, BV (blood volume value of peripheral lung cancer and inflammatory nodule were not statistically significant (all P > 0.05. Both showed significantly higher PH, PHpm/PHa, BF, BV value than those of benign nodule (all P 0.05. In the case of adenocarcinoma, BV, BF, PS, PHpm/PHa, and MVD between poorly and well differentiation and between poorly and moderately differentiation were statistically significant (all P 0.05. PH, PHpm/PHa, BV, and PS of benign nodule were significantly lower than those of peripheral lung cancer (all P Conclusion Multi-slice spiral CT perfusion imaging closely correlated with tumor angiogenesis and reflected MVD measurement and VEGF expression. It provided not only a non-invasive method of quantitative assessment for blood flow patterns of peripheral pulmonary nodules but also an applicable diagnostic method for peripheral pulmonary nodules.

  18. Alterations in c-Src/HER1 and estrogen receptor ? signaling pathways in mammary gland and tumors of hexachlorobenzene-treated rats

    International Nuclear Information System (INIS)

    Hexachlorobenzene (HCB) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents. The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors. We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells, in an estrogen receptor ? (ER?)-dependent manner, and of migration in MDA-MB-231 breast cancer cell line. In the present study, we examined HCB effect on c-Src/human epidermal growth factor receptor (HER1) and ER? signaling pathways in mammary glands and in N-nitroso-N-methylurea (NMU)-induced mammary tumors in rats. Furthermore, we evaluated histopathological changes and serum hormone levels. Rats were separated into four groups: control, HCB (100 mg/kg b.w.), NMU (50 mg/kg b.w.) and NMU-HCB. Our data show that HCB increases c-Src and HER1 activation, c-Src/HER1 association, and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands. HCB also enhances Y537-ER? phosphorylation and ER?/c-Src physical interaction. In tumors, HCB also induces c-Src and HER1 activation, c-Src/HER1 association, as well as T308-Akt and Y699-STAT5b phosphorylation. In addition, the pesticide increases ER? protein content and decreases p-Y537-ER? levels and ER?/c-Src association in tumors. HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone, FSH and LH levels in rats without tumors, while the opposite effect was observed in rats with tumors. Taken together, our results indicate that HCB induces an estrogenic effect in mammary gland, increasing c-Src/HER1 and ER? signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ER? activity in tumors, appearing to shift them towards a higher malignancy phenotype.

  19. Functional and structural analysis of the DNA sequence conferring glucocorticoid inducibility to the mouse mammary tumor virus gene

    International Nuclear Information System (INIS)

    In the first part of my thesis I show that the DNA element conferring glucocorticoid inducibility to the Mouse Mammary Tumor Virus (HRE) has enhancer properties. It activates a heterologous promoter - that of the ?-globin gene, independently of distance, position and orientation. These properties however have to be regarded in relation to the remaining regulatory elements of the activated gene as the recombinants between HRE and the TK gene have demonstrated. In the second part of my thesis I investigated the biological significance of certain sequence motifs of the HRE, which are remarkable by their interaction with transacting factors or sequence homologies with other regulatory DNA elements. I could confirm the generally postulated modular structure of enhancers for the HRE and bring the relevance of the single subdomains for the function of the element into relationship. (orig.)

  20. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: ? Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. ? Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. ? These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. ? Anti-SEMA4D blocking antibody inhibits Plexin-B1 activation. ? SEMA4D is a valid anti-angiogenic target in the treatment of OSCC.

  1. Evaluation of tumor angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma: Results of RTOG 9505

    International Nuclear Information System (INIS)

    Purpose: The objective of this study was to evaluate tumor angiogenesis as measured by microvessel density (MVD) as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy alone. Methods and materials: Eligible patients included those with NPC treated with radiotherapy. Paraffin blocks of the primary tumor had a hematoxylin and eosin-stained section prepared at the block face. One representative section for tumor was stained for factor VIII-related antigen using a standard immunoperoxidase staining technique. MVD was determined by light microscopy in areas of invasive tumor containing the highest numbers of capillaries and microvessels per area. Individual microvessel counts were made on a 200x field within the area of most intense tumor neovascularization. Results were expressed as the highest number of microvessels identified within any single 200x field. Using a breakpoint of MVD < 60 vs. ?60, the distributions between the two MVD groups were compared by the method of Gray. Overall survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. A multivariate Cox proportional hazard model was employed to examine the relationship between MVD and disease outcomes while adjusting for other concomitant variables. Results: One hundred sixty-six were eligible, of whom 123 had values determined for MVD. The MVD values ranged from 9 to 243 with a median of 70. In the multivariate analysis of oof 70. In the multivariate analysis of overall survival, distant metastases, and local-regional failure, MVD did not significantly improve the model containing T stage, N stage, age, radiation dose, and World Health Organization class. Conclusions: We found no significant differences in overall survival, time to distant metastasis, or time to local-regional failure using a breakpoint of MVD < 60 vs. MVD ?60. The study was perhaps limited by the small size of the NPC samples

  2. Neoplasias mamárias em cadelas: influência hormonal e efeitos da ovario-histerectomia como terapia adjuvante / Canine mammary tumors: hormonal influence and effects of ovariohiysterectomy as an adjuvant therapy

    Scientific Electronic Library Online (English)

    Cláudia Sampaio, Fonseca; Carlos Roberto, Daleck.

    2000-08-01

    Full Text Available As neoplasias mamarias constituem aproximadamente 50% dos tumores diagnosticados em cadelas. Apesar dosharmónios sexuais femininos desempenharem papel fundamental no desenvolvimento desses tumores em mamíferos, o valor da supressão hormonal pela ovário-histerectomia como auxiliar no tratamento do tu [...] mor de mama em caninos permanece controverso. Discute-se ainda se a realização da ovário-histerectomia após o diagnóstico influencia ou não o crescimento e progressão do tumor na glândula afetada ou em outras glândulas mamarias. O objetivo desta revisão é discutir alguns aspectos relacionados à influência hormonal na etiologia de tumores mamarias em cadelas, assim como o valor terapêutico da castração, quando realizada no momento da mastectomia. Abstract in english The mammary neoplasms comprises aproximatel 50% ofthe diagnosed tumor s m the bitch. Although female sexual honnones play a fundamental role in the development of these tumors in mammals, the value of the suppression hormonal (ovariohysterectomy) as an adjuvam treatment remains controversial. There [...] are still arguments on whether the ovariohysterectomy after diagnosis of the tumor possesses influences lhe growth and progression of the tumor on the affected gland or on other mammary glands. The objective ofthis review is to discuss some aspects related to the hormonal influence in the pathogenesis of the canine tumor, as well as the therapeutic value ofspaying. when accomplished in the moment ofthe mastectomy.

  3. Apoptosis as a prognostic marker in canine mammary tumors by TUNEL / A apoptose como marcador prognóstico em tumores mamários caninos pelo método TUNEL

    Scientific Electronic Library Online (English)

    Kariny Sanches, Pereira; Débora Aparecida Pires de Campos, Zuccari; Patrícia Maluf, Cury; José Antônio, Cordeiro.

    Full Text Available A apoptose, como evento celular, tem uma participação importante na tumorigênese, determinando o crescimento tumoral e sua agressividade. O presente estudo, teve como objetivo, examinar a relação entre a apoptose, o diagnóstico histopatológico e o prognóstico na neoplasia mamária canina. Trinta cade [...] las foram submetidas a exérese tumoral e o fragmento tumoral submetido ao método de marcação das células apoptóticas, que marca fragmentos de DNA da célula em apoptose, conhecido como desoxinucleotídeo terminal transferase (TdT) mediado pela 5' desoxiuridina trifosfato (dUTP) ou TUNEL. As células em apoptose foram contadas em 10 campos de maior aumento (10HPF) sendo que os resultados estatísticos demonstraram uma correlação positiva entre a apoptose e o prognóstico ruim (p= 0,0005). Dessa forma, a apoptose pode ser considerada um marcador prognóstico nas neoplasias mamárias caninas. Abstract in english Apoptosis plays an important role in oncogenesis determining tumor growth and aggressiveness. The aim of this study was to examine the relationship between apoptosis, diagnosis and prognosis in canine mammary tumors. Thirty bitches were submitted to tumor extirpation and a method of labeling apoptot [...] ic cells, that labels DNA fragments, by terminal deoxynucleotidyl-tranferase (TdT) mediated by 5' deoxy-uridine-triphosphate (dUTP) nick and labeling (TUNEL) was used. The apoptotic cells were counted in ten high power fields (10HPF). Statistical results showed that when there are more than 30 apoptotic cells/10HPF the prognosis is worse (p= 0,0005). Thus suggesting that apoptosis can be used as a prognostic marker in canine breast tumors.

  4. Correlação entre a citologia aspirativa por agulha fina e a histologia no diagnóstico de tumores mamários de cadelas / Fine needle aspiration cytologic and histologic correlation in canine mammary tumors

    Scientific Electronic Library Online (English)

    Debora Aparecida Pires de Campos, ZUCCARI; Aureo Evangelista, SANTANA; Noeme Souza, ROCHA.

    Full Text Available Foram estudados tumores de mama em cadelas, comparando o seu padrão citológico, obtido através da Citologia Aspirativa por Agulha Fina (CAAF), com os resultados da histopatologia. Num período de um ano, as cadelas trazidas ao Hospital Veterinário -- UNESP -- Câmpus de Jaboticabal foram submetidas a [...] exérese cirúrgica dos tumores mamários. As amostras foram avaliadas de acordo com parâmetros estruturais utilizados nos tumores mamários humanos, como grau de atipia, critérios nucleares, padrão de cromatina e nucléolos, alta celularidade e pouca coesão intercelular. Utilizaram-se estes critérios para diferenciar tumores mamários benignos de malignos com 63% de diagnósticos concordantes, sensibilidade de 73% e especificidade de 83%. Nossos dados mostraram ter uma correlação positiva com o prognóstico, demonstrando que é possível reconhecer variáveis estruturais de malignidade na citopatologia para obter um diagnóstico precoce e um prognóstico seguro. Abstract in english Cytologic and histologic examination of 35 canine mammary masses was performed over a year period, from dogs that underwent mastectomy for mammary neoplasms at the UNESP Veterinary Medical Teaching Hospital -- Jaboticabal (SP) Brazil. The mastectomy specimens were evaluated according to structural p [...] arameters found to be prognostically significant in human mammary tumors, such as grade of atypia, nuclear criteria (shape, size, form, abnormal mitotic figures), chromatin and nucleolar patterns, high cellularity and poor intercellular cohesions. These criteria were used for differentiation of benign from malignant mammary tumors with 63% of a concordant diagnosis and sensibility of 73% and specificity of 83%. The "fine needle aspiration" technique is discussed as a tool to perform early diagnosis. Our data were found to have a positive correlation to the prognosis indicating that we can recognize structural variables of malignancy by citopathology. Application of the described parameters should facilitate comparative studies of histopathologic diagnosis with biologic behavior of canine mammary tumors using this technique to obtain early diagnosis and a secure prognosis.

  5. In Utero Exposure to Low-Dose Alcohol Induces Reprogramming of Mammary Development and Tumor Risk in MMTV-erbB-2 Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Zhikun Ma

    2015-04-01

    Full Text Available There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ER? signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation.

  6. Effects of mitomycin C alone and in combination with X-rays on EMT6 mouse mammary tumors in vivo

    International Nuclear Information System (INIS)

    The effects of mitomycin C alone and in combination with radiation on the cells of EMT6 mouse mammary tumors in BALB/cKaRw mice were examined. At doses near the toxic level, approximately 98% of the tumor cells were killed by a single injection of mitomycin C. Both proliferating and quiescent cells and both hypoxic and aerobic cells were killed by the drug. Cytotoxicity with mitomycin C occurred rapidly and was apparently complete within 30 minutes after injection of the drug. No evidence was found for repair of potentially lethal mitomycin C damage or sublethal mitomycin C damage by the tumor cells. Mitomycin C and radiation in combination produced an additive cytotoxicity; neither agent was found to alter significantly the shape of the dose-response curve for the other agent. The cytotoxicity of mitomycin C and radiation in combination depended on the sequence and timing of the treatments; additive toxicities were obtained when mitomycin C was given just after, just before, or up to 24 hours before irradiation, but the combination was less effective when mitomycin C was given 2-12 hours after irradiation

  7. Progesterone receptor isoform analysis by quantitative real-time polymerase chain reaction in formalin-fixed, paraffin-embedded canine mammary dysplasias and tumors

    DEFF Research Database (Denmark)

    Guil-Luna, S.; Stenvang, Jan

    2014-01-01

    Cloning and sequencing of the progesterone receptor gene in dogs have revealed 2 isoforms, A and B, transcribed from a single gene. Distribution of isoforms A and B in canine mammary lesions has hitherto been investigated only by Western blot analysis. This study analyzed progesterone receptor and its isoforms in formalin-fixed, paraffin-embedded tissue samples from canine mammary lesions (4 dysplasias, 10 benign tumors, and 46 carcinomas) using 1-step SYBR Green quantitative real-time polymerase chain reaction (RT-qPCR). Progesterone receptor was expressed in 75% of dysplasias, all benign tumors, and 59% of carcinomas. Carcinomas, and particularly simple epithelial-type carcinomas, displayed the lowest levels of expression. A high rate of agreement was recorded between RT-qPCR and immunohistochemical labeling. Isoforms A and B were successfully amplified, with correlation coefficients of 0.99 and amplification efficiencies close to 2, and were expressed in all lesion types analyzed. Predominance of A over B expression was observed in carcinomas and complex adenomas. Low-grade tumors exhibited higher progesterone receptor messenger RNA (mRNA) levels, but no difference was observed in the expression of isoform A versus B. Analysis of progesterone receptor mRNA isoforms by RT-qPCR was successful in routinely formalin-fixed, paraffin-embedded tissue samples and enabled the distribution of isoforms A and B to be identified for the first time in dysplasias, benign tumors, and malignant tumors of the canine mammary gland. These findings will facilitate future research into the role of progesterone receptor isoforms in the progression of canine mammary tumors.

  8. Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis.

    Science.gov (United States)

    Fontanella, Andrew N; Boss, Mary-Keara; Hadsell, Michael; Zhang, Jian; Schroeder, Thies; Berman, Katherine G; Dewhirst, Mark W; Chang, Sha; Palmer, Gregory M

    2015-02-01

    Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects. PMID:25574586

  9. Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: Invasion, angiogenesis, metastasis and therapy.

    Science.gov (United States)

    Santos, A A; Matos, A J F

    2015-08-01

    Significant advances have been made recently in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly the interactions of neoplastic cells with stromal and immune cells, is crucial for the development of novel effective therapeutic agents and strategies. This second part of a two-part review discusses some of the latest advances in the understanding of the clinically relevant genetic and molecular pathways involved in metastasis and in the interactions between tumour and stromal cells, including inflammatory and immune cells, cancer-associated fibroblasts, and endothelial cells. Recent experimental data on the role of matrix-degrading proteases and angiogenic factors are also discussed. Finally, the clinical utility of different non-surgical therapeutic modalities is reviewed. PMID:25933828

  10. Influence of Ganoderma lucidum polysaccharide on the inhibitory effects of cisplatin on the tumor growth and angiogenesis in bladder cancer (T24 cells -bearing nude mice

    Directory of Open Access Journals (Sweden)

    Peng-rong GUO

    2014-08-01

    Full Text Available Objective?To explore the chemo-sensitizing effect and inhibitory effect of Ganoderma lucidum polysaccharide (GLP on tumor angiogenesis of bladder cancer. Methods?The effect of GLP combined with cisplatin on the in vitro proliferation of human bladder cancer cell lines T24 was determined by MTS assay. The interaction between the two drugs was evaluated using the Chou-Talalay method. A T24 (bladder cancer-bearing nude mouse model was established, and then the therapeutic effect of GLP combined with cisplatin was evaluated. The microvessel density (MVD and the expressions of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF in the tumor tissue were determined by immunohistochemical staining, and the expression levels of VEGF and bFGF in tumor tissue were determined by real-time fluorescence quantitative PCR and Western blotting. Results?GLP combined with cisplatin markedly inhibited T24 cells proliferation in vitro showing a synergistic effect (CI<1. Immunohistochemical staining showed that GLP could enhance the inhibitory effect of cisplatin on the tumor growth in the tumorbearing nude mice (P<0.05, and it could also inhibit the angiogenesis and expressions of VEGF and bFGF in the tumor tissue. The real-time fluorescence quantitative PCR and Western blotting showed that the expression levels of VEGF and bFGF in tumor tissue significantly decreased in the tumor-bearing nude mice after being treated with GLP combined with cisplatin as compared with those treated by cisplatin alone. Conclusions?GLP combined with cisplatin could inhibit the proliferation of T24 cells in vitro synergically. GLP could enhance the inhibitory effect of cisplatin on tumor growth and angiogenesis in T24 tumor-bearing nude mice, and the mechanism may be related to the down-regulation of VEGF and bFGF expressions. DOI: 10.11855/j.issn.0577-7402.2014.06.09

  11. Establishment of a human multiple myeloma xenograft model in the chicken to study tumor growth, invasion and angiogenesis.

    Science.gov (United States)

    Martowicz, Agnieszka; Kern, Johann; Gunsilius, Eberhard; Untergasser, Gerold

    2015-01-01

    Multiple myeloma (MM), a malignant plasma cell disease, remains incurable and novel drugs are required to improve the prognosis of patients. Due to the lack of the bone microenvironment and auto/paracrine growth factors human MM cells are difficult to cultivate. Therefore, there is an urgent need to establish proper in vitro and in vivo culture systems to study the action of novel therapeutics on human MM cells. Here we present a model to grow human multiple myeloma cells in a complex 3D environment in vitro and in vivo. MM cell lines OPM-2 and RPMI-8226 were transfected to express the transgene GFP and were cultivated in the presence of human mesenchymal cells and collagen type-I matrix as three-dimensional spheroids. In addition, spheroids were grafted on the chorioallantoic membrane (CAM) of chicken embryos and tumor growth was monitored by stereo fluorescence microscopy. Both models allow the study of novel therapeutic drugs in a complex 3D environment and the quantification of the tumor cell mass after homogenization of grafts in a transgene-specific GFP-ELISA. Moreover, angiogenic responses of the host and invasion of tumor cells into the subjacent host tissue can be monitored daily by a stereo microscope and analyzed by immunohistochemical staining against human tumor cells (Ki-67, CD138, Vimentin) or host mural cells covering blood vessels (desmin/ASMA). In conclusion, the onplant system allows studying MM cell growth and angiogenesis in a complex 3D environment and enables screening for novel therapeutic compounds targeting survival and proliferation of MM cells. PMID:25993267

  12. Improved Magnetic Resonance Molecular Imaging of Tumor Angiogenesis by Avidin-Induced Clearance of Nonbound Bimodal Liposomes

    Directory of Open Access Journals (Sweden)

    Geralda A.F. van Tilborg

    2008-12-01

    Full Text Available Angiogenic, that is, newly formed, blood vessels play an important role in tumor growth and metastasis and are a potential target for tumor treatment. In previous studies, the ?v?3 integrin, which is strongly expressed in angiogenic vessels, has been used as a target for Arg-Gly-Asp (RGD-functionalized nanoparticulate contrast agents for magnetic resonance imaging-based visualization of angiogenesis. In the present study, the target-to-background ratio was increased by diminishing the nonspecific contrast enhancement originating from contrast material present in the blood pool. This was accomplished by the use of a so-called avidin chase, which allowed rapid clearance of non-bound paramagnetic RGD-biotin-liposomes from the blood circulation. C57BL/6 mice, bearing a B16F10 mouse melanoma, received RGD-functionalized or untargeted biotin-liposomes, which was followed by avidin infusion or no infusion. Precontrast, postcontrast, and postavidin T1-weighted magnetic resonance images were acquired at 6.3 T. Postcontrast images showed similar percentages of contrast-enhanced pixels in the tumors of mice that received RGD-biotin-liposomes and biotin-liposomes. Post avidin infusion this percentage rapidly decreased to precontrast levels for biotin-liposomes, whereas a significant amount of contrast-enhanced pixels remained present for RGD-biotin-liposomes. These results showed that besides target-associated contrast agent, the circulating contrast agent contributed significantly to the contrast enhancement as well. Ex vivo fluorescence microscopy confirmed association of the RGD-biotin-liposomes to tumor endothelial cells both with and without avidin infusion, whereas biotin-liposomes were predominantly found within the vessel lumen. The clearance methodology presented in this study successfully enhanced the specificity of molecular magnetic resonance imaging and opens exciting possibilities for studying detection limits and targeting kinetics of site-directed contrast agents in vivo.

  13. Molecular portrait-based correlation between primary canine mammary tumor and its lymph node metastasis: possible prognostic-predictive models and/or stronghold for specific treatments?

    Directory of Open Access Journals (Sweden)

    Beha Germana

    2012-11-01

    Full Text Available Abstract Background This study aimed to evaluate the relationship between the molecular phenotype of the primary mammary tumor and its related lymph node metastasis in the dog to develop prognostic-predictive models and targeted therapeutic options. Results Twenty mammary tumor samples and their lymph node metastases were selected and stained by immunohistochemistry with anti-estrogen receptor (ER, -progesterone receptor (PR, -human epidermal growth factor receptor 2 (c-erbB-2, -cytokeratin 5/6 (CK 5/6, -cytokeratin 14 (CK14, -cytokeratin 19 (CK 19 and -protein 63 (p63 antibodies. Four phenotypes (luminal A, luminal B, c-erbB2 overexpressing and basal-like were diagnosed in primary tumors and five (luminal A, luminal B, c-erbB-2 overexpressing, basal-like and normal-like in the lymph node metastases. Phenotypic concordance was found in 13 of the 20 cases (65%, and seven cases (35% showed discordance with different lymph node phenotypic profile from the primary tumor. Conclusions The phenotype of the primary tumor assumes a predictive-therapeutic role only in concordant cases, meaning that both the primary tumor and its lymph node metastasis should be evaluated at the same time. A treatment plan based only on the primary tumor phenotype could lead to therapeutic failures if the phenotype of the lymph node metastasis differs from that of the primary tumor.

  14. Promoting Effects of Milk on the Development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced Mammary Tumors in Rats

    OpenAIRE

    Ma, De-Fu; Katoh, Ryohei; Zhou, Hong; Wang, Pei-Yu

    2007-01-01

    To assess the effect of milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, 48 female Sprague-Dawley rats treated with DMBA were divided into 3 groups and given 1 of 3 test solutions for 20 weeks as their drinking liquid: milk, estrone sulfate solution or tap water. The milk group showed a significantly great incidence (75%) in tumor development compared with the water group (38%) and was comparable to the estrone sulfate group (69%). Mean tumor number per...

  15. Transgenic mice with mammary gland targeted expression of human cortactin do not develop (pre-malignant breast tumors: studies in MMTV-cortactin and MMTV-cortactin/-cyclin D1 bitransgenic mice

    Directory of Open Access Journals (Sweden)

    van Krieken Johan HJM

    2006-03-01

    Full Text Available Abstract Background In human breast cancers, amplification of chromosome 11q13 correlates with lymph node metastasis and increased mortality. To date, two genes located within this amplicon, CCND1 and EMS1, were considered to act as oncogenes, because overexpression of both proteins, respectively cyclin D1 and cortactin, correlated well with 11q13 amplification. Cyclin D1 is involved in cell cycle regulation and the F-actin-binding protein cortactin in cytoskeletal dynamics and cell migration. To study the role of cortactin in mammary gland tumorigenesis, we examined mouse mammary tumor virus (MMTV-cortactin transgenic mice and MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice. Methods MMTV-cortactin transgenic mice were generated and intercrossed with previously described MMTV-cyclin D1 transgenic mice. Immunohistochemical, Northern and Western blot analyses were performed to study the expression of human transgene cortactin during mammary gland development and in mammary tumors. For tumor incidence studies, forced-bred, multiparous mice were used to enhance transgene expression in the mammary gland. Microscopical examination was performed using haematoxylin and eosin staining. Results Mammary gland tumors arose stochastically (incidence 21% with a mean age of onset at 100 weeks. This incidence, however, did not exceed that of aged-matched control FVB/N mice (38%, which unexpectedly, also developed spontaneous mammary gland tumors. We mimicked 11q13 amplification by generating MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice but did not observe any synergistic effect of cortactin on cyclin D1-induced mammary hyperplasias or carcinomas, nor development of distant metastasis. Conclusion From this study, we conclude that development of (pre-malignant breast tumors in either wild type or MMTV-cyclin D1 mice was not augmented due to mammary gland targeted overexpression of human cortactin.

  16. Influence of hormonal environment in induction of hepatic, mammary and pituitary tumors in male rats treated with radiation or chemical carcinogen

    International Nuclear Information System (INIS)

    Diethylstilbestrol (DES) pellets (5 mg) were implanted in the backs of Wistar Furch strain rats castrated 40 days after birth. Two weeks after the implantation, the rat were treated for carcinogenesis with either a single dose of 200 rad of 14.1 MeV fast neutrons or with N-nitrosobutylurea (NBU) (5 mg/day) for 30 days. Moreover, a prolactin-secreting pituitary tumor was grafted in some of the rats. Both mammary and hepatic tumors occurred in 3 of 7 irradiated rats given DES. Pituitary tumor also occurred in 5 of 7 rats. Mammary, hepatic, and pituitary tumors occurred simultaneously in half of the rats given prolactin. The same results as those obtained in the rats irradiated with fast neutrons were obtained in the rats treated with NBU. These results suggest that only the mammary gland in the rats treated previously with DES was subject to malignant transformation as the target of radiation and a chemical carcinogen and that transformed cells reacted to the high levels of prolactin proliferated, and formed gross carcinoma. (Tsunoda, M.)

  17. Mouse Mammary Tumor Virus Promoter-Containing Retroviral Promoter Conversion Vectors for Gene-Directed Enzyme Prodrug Therapy are Functional in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Christine Hohenadl

    2008-04-01

    Full Text Available Gene directed-enzyme prodrug therapy (GDEPT is an approach for sensitization of tumor cells to an enzymatically activated, otherwise nontoxic, prodrug. Cytochrome P450 2B1 (CYP2B1 metabolizes the prodrugs cyclophosphamide (CPA and ifosfamide (IFA to produce the cytotoxic substances phosphoramide mustard and isophosphoramide mustard as well as the byproduct acrolein. We have constructed a retroviral promoter conversion (ProCon vector for breast cancer GDEPT. The vector allows expression of CYP2B1 from the mouse mammary tumor virus (MMTV promoter known to be active in the mammary glands of transgenic animals. It is anticipated to be used for the generation of encapsulated viral vector producing cells which, when placed inside or close to a tumor, will act as suppliers of the therapeutic CYP2B1 protein as well as of the therapeutic vector itself. The generated vector was effectively packaged by virus producing cells and allowed the production of high levels of enzymatically active CYP2B1 in infected cells which sensitized them to killing upon treatment with both IFA and CPA. Determination of the respective IC50 values demonstrated that the effective IFA dose was reduced by sixteen folds. Infection efficiencies in vivo were determined using a reporter gene-bearing vector in a mammary cancer cell-derived xenograft tumor mouse model.

  18. DNA flow cytometry of canine mammary tumors: comparative aspects with human breast tumors Citometria de fluxo de DNA em tumores mamários da cadela: aspectos comparativos com tumores mamários humano

    Directory of Open Access Journals (Sweden)

    G.D. Cassali

    2007-10-01

    Full Text Available Flow cytometric analysis of DNA content was performed on 28 samples of canine mammary tumors. Nine of them were benign and 19 were malignant. All benign tumors and 11 malignant tumors (57.9% were diploid (P0.05. Using the flow cytometry analysis and immunohistochemistry, it was found a close relationship between aneuploidy and malignant character of neoplasias, progesterone receptor (PR negative immunostaining and higher microvases density. No correlation between DNA content and S phase or immunoreactivity for the markers MIB-1, p53, c-erbB2 and Cyclin D1 was observed.Análise por citometria de fluxo de DNA foi realizada em 28 amostras de tumores mamários de cadela. Nove eram benignos e 19 malignos, sendo todos os benignos e 11 malignos (57,9% diplóides (P0,05. Pela citometria de fluxo e pela imunoistoquímica verificaram-se uma relação entre aneuploidia e características malignas das neoplasias, receptor de progesterona imunoreação negativa e alta densidade de microvascular. Não foi observada correlação entre conteúdo de DNA e a fase S ou imunorreatividade para os marcadores MIB-1, c-erbB-2, p53 e Ciclina D1.

  19. Morphological studies of metastatic mammary rat tumors after laser immunotherapy treatment

    Science.gov (United States)

    Nordquist, Robert E.; Nordquist, John A.; Agee, James C.; Blomquist, Chad M.; Chen, Wei R.

    1998-05-01

    Laser immunotherapy, using a combination of 805 nm diode laser, photosensitizer indocyanine green and immunoadjuvant glycated chitosan, has shown an induced anti-tumor immune response in treatment of metastatic rat tumors. In additional to an apparent systemic, long-term humoral immunological reaction, there could also be laser induced local cellular immune responses. A morphological study was performed to study the immune cells and their infiltration to tumor tissue after this laser immunotherapy treatment. Tumor-bearing rats were terminated at designated times after the treatment; both the tumor and the surrounding normal tissue were collected. The tissue samples were observed under electron microscope. The number and types of infiltrating cells at the tumor site were studied after treatment to determine the contribution of these cells in the elimination of tumors. The tumor cell structural changes resulted from laser-tissue photothermal interaction was investigated. The morphology of tumor development and activities of immune cells including both lymphocytes and plasma cells could shed light on the mode of action of laser treatment of tumors.

  20. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors

    OpenAIRE

    Roussos, Evanthia T.; Wang, Yarong; Wyckoff, Jeffrey B.; Sellers, Rani S.; Wang, Weigang; Li, Jiufeng; Pollard, Jeffrey W.; Gertler, Frank B.; Condeelis, John S.

    2010-01-01

    Introduction The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression ...

  1. Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer.

    Science.gov (United States)

    Chen, Yongshun; Li, Xiaohong; Guo, Leiming; Wu, Xiaoyuan; He, Chunyu; Zhang, Song; Xiao, Yanjing; Yang, Yuanyuan; Hao, Daxuan

    2015-08-01

    Radiotherapy is an effective treatment for esophageal cancer; however, tumor resistance to radiation remains a major biological problem. The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation. The effects of the autophagy inhibitor 3?methyladenine (3?MA) on radiosensitivity were tested in the EC9706 human esophageal squamous cell carcinoma cell line by colony formation assay. Furthermore, the synergistic cytotoxic effects of 3?MA and radiation were assessed in a tumor xenograft model in nude mice. Mechanistic studies were performed using flow cytometry, immunohistochemistry and western blot analysis. The results of the present study demonstrated that radiation induced an accumulation of autophagosomes and 3?MA effectively inhibited radiation?induced autophagy. Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo. The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3?MA, alongside ionizing radiation. In addition, autophagy inhibition increased apoptosis and reduced tumor cell proliferation. The combination of radiation and autophagy inhibition resulted in a significant reduction in tumor volume and vasculature in the murine model. The present study demonstrated in vitro and in vivo that radiation?induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma. PMID:25891159

  2. Prokaryotically and eukaryotically expressed interleukin-24 induces breast cancer growth suppression via activation of apoptosis and inhibition of tumor angiogenesis.

    Science.gov (United States)

    Wei, Shaohua; Cao, Hua; Zhou, Xiaoyan; Wu, Haorong; Yang, Jicheng

    2015-05-01

    Melanoma differentiation?associated?7 (mda?7)/interleukin?24 (IL?24), a unique cytokine?tumor suppressor, exerts tumor?selective killing activity in numerous types of cancer cell. Although eukaryotically and prokaryotically expressed recombinant human (rh)IL?24 proteins have been previously shown to produce potent antitumor effects, to the best of our knowledge, no side?by?side study has been conducted that compares the two proteins directly. In the present study, rhIL?24 protein was expressed in BL21 Escherichia coli transformed with the pET?21a(+)?hIL?24 plasmid by isopropyl???D?1?thiogalactopyranoside induction. Following a denaturing and renaturing process, the soluble rhIL?24 was purified using a Q?Sepharose column. rhIL?24 protein was also expressed in Chinese hamster ovary mammalian cells stably transfected with the pcDNA3?hIL?24 plasmid. The in vitro antitumor efficacies of the two treatments were compared using the MDA?MB?231 human breast cancer cell line. Furthermore, the therapeutic efficacies of the bacteria?derived rhIL?24 protein and the liposome?coated pcDNA3?hIL?24 naked plasmid were evaluated in athymic nude mice with subcutaneously xenografted MDA?MB?231 cell tumors. The prokaryotically expressed/purified rhIL?24 protein and the eukaryotically expressed rhIL?24 in the cell supernate were revealed to be capable of efficiently suppressing MDA?MB?231 tumor growth in vitro. Similarly, the administration of bacteria?derived rhIL?24 protein and pcDNA3?hIL?24 naked plasmid also provided therapeutic benefits in the treatment of in vivo MDA?MB?231 xenografted tumors. The retarded in vitro and in vivo breast cancer growth elicited by rhIL?24 was closely associated with the upregulation of the ratio of anti?apoptotic B cell lymphoma 2 (Bcl?2) to pro?apoptotic Bcl?2?associated X protein (Bax), as well as the activation of caspase?3 followed by marked induction of apoptosis, and the notable inhibition of tumor angiogenesis. Thus, the results of the present study indicate that prokaryotically expressed rhIL?24 protein may be an alternate and promising antitumor agent in human breast cancer or other types of cancer. PMID:25544477

  3. Effect of laser immunotherapy and surgery on the treatment of mouse mammary tumors

    Science.gov (United States)

    Chen, Vivian A.; Le, Henry; Li, Xiaosong; Wolf, Roman F.; Ferguson, Halie; Sarkar, Akhee; Liu, Hong; Nordquist, Robert E.; Chen, Wei R.

    2010-02-01

    Laser immunotherapy using laser photothermal therapy and immunological stimulation could achieve tumor-specific immune responses, as indicated by our previous pre-clinical and preliminary clinical studies. To further study the effect of laser immunotherapy, we conducted an investigation combining laser immunotherapy and surgery. After laser immunotherapy, treated tumors were surgically removed at different time points. The survival rates of treated mice were compared among different groups. Furthermore, the cured mice were rechallenged to test the immunity induced by laser immunotherapy. Our results showed that the mice treated with surgical removal one week after laser immunotherapy had the highest survival rate (77%). When the tumors were removed immediately after laser immunotherapy treatment, the survival rate was 57%. Most cured mice withstood tumor rechallenges, indicating an induction of tumor immunity by laser immunotherapy. The differentiations between different surgery groups indicate that the treated tumors have contributed to the immunological responses of the hosts.

  4. MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide

    International Nuclear Information System (INIS)

    We have previously labeled cyclic RGD peptide c(RGDyK) with fluorine-18 through conjugation labeling via a prosthetic 4-[18F]fluorobenzoyl moiety and applied this [18F]FB-RGD radiotracer for ?v-integrin expression imaging in different preclinical tumor models with good tumor-to-background contrast. However, the unfavorable hepatobiliary excretion and rapid tumor washout rate of this tracer limit its potential clinical applications. The aims of this study were to modify the [18F]FB-RGD tracer by inserting a heterobifunctional poly(ethylene glycol) (PEG, M.W. =3,400) between the 18F radiolabel and the RGD moiety and to test this [18F]FB-PEG-RGD tracer for brain tumor targeting and in vivo kinetics. [18F]FB-PEG-RGD was prepared by coupling the RGD-PEG conjugate with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) under slightly basic conditions (pH=8.5). The radiochemical yield was about 20-30% based on the active ester [18F]SFB, and specific activity was over 100 GBq/?mol. This tracer had fast blood clearance, rapid and high tumor uptake in the subcutaneous U87MG glioblastoma model (5.2±0.5%ID/g at 30 min p.i.). Moderately rapid tumor washout was observed, with the activity accumulation decreased to 2.2±0.4%ID/g at 4 h p.i. MicroPET and autoradiography imaging showed a very high tumor-to-background ratio and limited activity accumulation in the liver, kidneyvity accumulation in the liver, kidneys and intestinal tracts. U87MG tumor implanted into the mouse forebrain was well visualized with [18F]FB-PEG-RGD. Although uptake in the orthotopic tumor was significantly lower (P18F]FB-PEG-RGD gave improved tumor retention and in vivo kinetics compared with [18F]FB-RGD. (orig.)

  5. Unilateral femoral arterial thrombosis in a dog with malignant mammary gland tumor: clinical and thermographic findings, and successful treatment with local intra-arterial administration of streptokinase.

    Science.gov (United States)

    Kim, Jung-Hyun; Park, Hee-Myung

    2012-05-01

    An 8-year-old intact female dog presented with a sudden onset of unilateral hindlimb paralysis of 3 days duration. Based on the history and results of physical, neurological, and histopathological examinations, and blood work, an arterial thrombosis was suspected as a complication of the hypercoagulability from a malignant mammary gland tumor. Thermography provided evidence of the unilateral femoral thrombus. Initially, thrombolysis with streptokinase administered by intravenous infusion was ineffective. Thereafter, the direct delivery of streptokinase to the site of thrombus was attempted. The approach was curative. These results suggest that thermography could describe the site of the arterial thrombus, and local intra-arterial administration of streptokinase may be an effective therapy for the canine arterial thrombosis complicated by malignant mammary gland tumor. PMID:22185771

  6. DNA flow cytometry of canine mammary tumors: comparative aspects with human breast tumors / Citometria de fluxo de DNA em tumores mamários da cadela: aspectos comparativos com tumores mamários humano

    Scientific Electronic Library Online (English)

    G.D., Cassali; A., Salvador; C., Freitas; A.P., Dutra; F.C., Schmitt.

    1163-11-01

    Full Text Available Análise por citometria de fluxo de DNA foi realizada em 28 amostras de tumores mamários de cadela. Nove eram benignos e 19 malignos, sendo todos os benignos e 11 malignos (57,9%) diplóides (P[...] de e um (5,3%) multiploide. A análise dos marcadores de expressão PR e CD31 revelaram significativa diferença entre tumores diploides e aneuploides (P0,05). Pela citometria de fluxo e pela imunoistoquímica verificaram-se uma relação entre aneuploidia e características malignas das neoplasias, receptor de progesterona imunoreação negativa e alta densidade de microvascular. Não foi observada correlação entre conteúdo de DNA e a fase S ou imunorreatividade para os marcadores MIB-1, c-erbB-2, p53 e Ciclina D1. Abstract in english Flow cytometric analysis of DNA content was performed on 28 samples of canine mammary tumors. Nine of them were benign and 19 were malignant. All benign tumors and 11 malignant tumors (57.9%) were diploid (P[...] e (5.3%) near triploid and one (5.3%) multiploid. The analysis of the expression of the markers PR and CD31 revealed a significant difference between diploid and aneuploid tumors (P0.05). Using the flow cytometry analysis and immunohistochemistry, it was found a close relationship between aneuploidy and malignant character of neoplasias, progesterone receptor (PR) negative immunostaining and higher microvases density. No correlation between DNA content and S phase or immunoreactivity for the markers MIB-1, p53, c-erbB2 and Cyclin D1 was observed.

  7. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging

    International Nuclear Information System (INIS)

    The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P6 NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 106 parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast agents, and the accumulation of these labeled cells in murine tumors can be monitored in vivo with MR imaging. This MR cell tracking technique may be applied to monitor NK-cell based immunotherapies in patients in order to assess the presence and extent of NK-cell tumor accumulations and, thus, to determine therapy response early and non-invasively. (orig.)

  8. Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors

    Directory of Open Access Journals (Sweden)

    Campbell Craig I

    2011-11-01

    Full Text Available Abstract Background Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFR? and PDGFR?. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice, it was demonstrated that PDGFR? and to a lesser extent PDGFR? was important for cell migration and invasion as RNAi knockdown of PDGFR? alone or PDGFR? and PDGFR? in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFR? and PDGFR? resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.

  9. Tumor interstitial fluid as modulator of cancer inflammation, thrombosis, immunity and angiogenesis.

    Science.gov (United States)

    Baronzio, Gianfranco; Schwartz, Laurent; Kiselevsky, Mikhail; Guais, Adeline; Sanders, Edward; Milanesi, Gloria; Baronzio, Miriam; Freitas, Isabel

    2012-02-01

    Tumor interstitial fluid (TIF) is a watery phase that accumulates inside the tumor interstitium. Its genesis and fate depend on various factors, namely tumor type, metabolic state of the tumor, expression of vascular endothelial growth factor, and absence of lymphatic system. For almost 30 years TIF remained a neglected entity until it was demonstrated that TIF, and in particular its high pressure, constitutes an important obstacle to drug delivery and immunotherapy. The present review not only summarizes the abundant literature on the processes of TIF genesis and on its effects on therapy but it also presents data that, in our opinion, point towards what is perhaps the real physiological purpose of TIF: a primitive means of providing nourishment, oxygen, cytokines and matrikines to tumor cells that furthermore promotes the invasion of the normal surrounding tissue and passive metastatization through lymphatics. It is also an inducer of inflammation through increased osmolarity due to albumin loss. Recently, a role for TIF as a possible source of biomarkers has also been suggested. PMID:22287726

  10. I?B kinase ? kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells

    OpenAIRE

    Cao, Yixue; Luo, Jun-li; Karin, Michael

    2007-01-01

    NF-?B is constitutively active in many solid tumors, including breast cancer. However, the role of NF-?B in breast carcinogenesis is unknown. Ikk?AA/AA “knockin” mice in which activation of I?B kinase ? (IKK?) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKK? activity is required for cyclin D1 induction and proliferation of lobuloalveolar epithelial cells. Given the role of cyclin D1 in breast an...

  11. Short-term Prophylactic Tamoxifen Reduces Incidence of Antiestrogen-resistant/Estrogen Receptor-positive/Progesterone Receptor-negative Mammary Tumors

    OpenAIRE

    Rose-hellekant, Teresa A.; Skildum, Andrew J.; Zhdankin, Olga; Greene, Amy L.; Regal, Ronald R.; Kundel, Katherine D.; Kundel, Donald W.

    2009-01-01

    Although many estrogen-receptor positive (ER+) breast cancers are effectively treated with selective estrogen-receptor modulators and down-regulators (SERMs/SERDs), some are highly resistant. Resistance is more likely if primary cancers are devoid of progesterone receptors (PR-) or have high levels of growth factor activity. In this study, a transgenic mouse line that expresses the growth factor TGF? (NRL-TGF? mice) and that develops ER+/PR- mammary tumors was used to assess the possible ef...

  12. Neo-angiogenesis metabolic biomarker of tumor-genesis tracking by infrared joystick contact imaging in personalized homecare system

    Science.gov (United States)

    Szu, Harold; Hoekstra, Philip; Landa, Joseph; Vydelingum, Nadarajen A.

    2014-05-01

    We describe an affordable, harmless, and administrative (AHA) metabolic biomarker (MBM) for homecare cancer screening. It may save hundreds of thousands of women's and thousands of men's lives every year from breast cancer and melanoma. The goal is to increase the specificity of infrared (IR) imagery to reduce the false alarm rate (FAR). The patient's hands are immersed in icy cold water, about 11oC, for 30 seconds. We then compare two IR images, taken before and after the cold stimulus, and the difference reveals an enhanced signal and noise ratio (SNR) at tumorigenesis sites since the contraction of capillaries under cold challenge is natural to healthy capillaries, except those newly built capillaries during angiogenesis (Folkman, Nature 1995). Concomitant with the genome and the phenome (molecular signaling by phosphor-mediate protein causing inflammation by platelet activating factor (PAF) that transform cells from benign to malignant is the amplification of nitric oxide (NO) syntheses, a short-lived reactive oxygen species (ROS) that dilates regional blood vessels; superseding normal autonomic nervous system regulation. A rapidly growing tumor site might implicate accumulation of ROS, for which NO can rapidly stretch the capillary bed system usually having thinning muscular lining known as Neo-Angiogenesis (NA) that could behave like Leaky In-situ Faucet Effect (LIFE) in response to cold challenge. To emphasize the state of art knowledge of NA, we mentioned in passing the first generation of an anticapillary growth drug, Avastin by Genetech; it is an antibody protein that is injected for metastasis, while the second generation drug; Sorafenib by Bayers (2001) and Sutent by Pfizer (2000) both target molecular signaling loci to block receptor associated tyrosine kinase induced protein phosphorylation in order to reverse the angiogenesis. Differentiating benign from malignant in a straightforward manner is required to achieve the wellness protocol, yet would become prohibitively expensive and impossible to follow through. For example, given the probability of detection (PD) about 0.1% over unspecified number of years (e.g. menopause years for breast cancer), one might need hundred thousand volunteers. We suggested a Time Reversal Invariant Paradigm (TRIP) (a private communication with Vatican) for gathering equivalent cancer symptom imagery from recovery histories of dozens of patients. We further mixed it with few % of recovered/non-sick cases for negative controls. Creating Virtual images and running videos of these, frame by frame, in two directions (forward and backward in time) resulted in identical Receiver Operation Characteristics (ROC) for both the computer Aided Target Recognition (AiTR) algorithm and the human radiological experts; namely PD versus FAR within the standard deviation; even though the physiology could be entirely different. Such a TRIP would be true taken by any memory-less instantaneous imagery devices (IR, ultrasound, X-rays, MRI excluding magnetic hysteresis memory). In summary, such an affordable, harmless, and administrative, neo-angiogenesis metabolic biomarker can help monitor the transitioning from benign to malignant states of high-risk home alone seniors and also monitor the progress of home alone seniors treatment at home. Therefore, Smartphone equipped with a day camera having IR spectral filtering for

  13. Cytological diagnosis of a metastatic canine mammary tumor in pleural effusion

    Directory of Open Access Journals (Sweden)

    Cassali G.D.

    1999-01-01

    Full Text Available Descrevem-se os achados citomorfológicos de um tumor maligno de mama em uma cadela Poodle de sete anos de idade, o qual foi observado inicialmente pelo exame citológico do derrame pleural. Comparam-se os aspectos citológicos do derrame pleural e punção aspirativa com agulha fina do tumor com aqueles descritos para o câncer de mama na espécie humana.

  14. Cytological diagnosis of a metastatic canine mammary tumor in pleural effusion

    OpenAIRE

    Cassali G.D.; Gärtner F.; Vieira da Silva M.J.; Schmitt F.C.

    1999-01-01

    Descrevem-se os achados citomorfológicos de um tumor maligno de mama em uma cadela Poodle de sete anos de idade, o qual foi observado inicialmente pelo exame citológico do derrame pleural. Comparam-se os aspectos citológicos do derrame pleural e punção aspirativa com agulha fina do tumor com aqueles descritos para o câncer de mama na espécie humana.

  15. pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis.

    Science.gov (United States)

    Choi, Joung-Woo; Jung, Soo-Jung; Kasala, Dayananda; Hwang, June Kyu; Hu, Jun; Bae, You Han; Yun, Chae-Ok

    2015-05-10

    Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX. PMID:25575865

  16. The comparative study of tumor angiogenesis and CT enhancement in pancreatic carcinoma

    International Nuclear Information System (INIS)

    Purpose: The purpose of this work was to study the correlation of pancreatic phase Computed tomography (CT) enhancement, intratumoral microvessel density (MVD) and pathologic grades in pancreatic carcinoma and to evaluate the relationship between CT enhancement degree and the malignancy degree of pancreatic carcinoma. Methods: 34 patients with pancreatic carcinoma underwent CT scanning before resection. The enhancement degrees and forms of tumor were observed in pancreatic phase. The operational sample was stained with HE and CD34 marked by immunohistochemistry. MVD and histopathological grades of pancreatic carcinoma were examined. CT enhancement of the tumor, MVD counting in hot spot areas of neoplastic parenchymal cells and pathological grades of pancreatic carcinoma were comparatively analyzed. Result: Highly differentiated pancreatic adenocarcinoma was identified in 16 patients, moderately differentiated tumor in seven and poorly differentiated tumor in 11. Isodensity CT enhancement was demonstrated in 13 cases, slight low density enhancement in nine, slight low density enhancement along with small cyst lesion in nine and slight low density enhancement along with large cyst lesion in three. The counting of MVD with CD34 marked by immunohistochemistry in hot spot areas of neoplastic parenchyma cells were small in ten cases, medium in 16 and large in eight. The pathological grades correlated with CT enhancement of tumor (r=0.7857, P<0.001). The pathological grade c0.7857, P<0.001). The pathological grade correlated with MVD counting of tumor (r=0.3613, P<0.05). The CT enhancement of tumor correlated with MVD (r=0.6768, P<0.001). Conclusion: There was obvious and significant correlation between CT enhancement, pathological grades and MVD numbers in the hot spot areas of tumor. The extent of CT enhancement was inversely proportional to the malignancy degree of pancreatic carcinoma, and inversely proportional to MVD numbers in the hot spot areas of neoplastic parenchyma. The MVD in the hot spot areas of neoplastic parenchyma cells could also reflect the prognosis of the patients, and was directly proportional to malignancy degree of pancreatic carcinoma

  17. Activation of tumor cell integrin ?v?3 controls angiogenesis and metastatic growth in the brain

    OpenAIRE

    Lorger, Mihaela; Krueger, Joseph S.; O Neal, Melissa; Staflin, Karin; Felding-habermann, Brunhilde

    2009-01-01

    The incidence of brain metastasis is rising and poses a severe clinical problem, as we lack effective therapies and knowledge of mechanisms that control metastatic growth in the brain. Here we demonstrate a crucial role for high-affinity tumor cell integrin ?v?3 in brain metastatic growth and recruitment of blood vessels. Although ?v?3 is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the ?v?3 activation state that is c...

  18. Evaluación de una técnica inmunohistoquímica para el diagnóstico de neoplasias mamarias mixtas en caninos / Evaluation of an immunohistochemical technique for the diagnosis of mixed mammary tumors in bitches

    Scientific Electronic Library Online (English)

    Cyntia, Rodríguez C.; Gilberto, Santillán A.; Rosa, Perales C.; Alfonso, Chavera C..

    2013-04-01

    Full Text Available El objetivo del presente estudio fue evaluar una técnica inmunohistoquímica (IHQ) para el diagnóstico de neoplasias mamarias mixtas (NMM) en caninos, usando anticuerpos monoclonales anti-citoqueratina AE1/AE3 y anti-vimentina, que son empleados en el diagnóstico de neoplasias mamarias en humanos. Se [...] tomaron 20 muestras de tejidos parafinados de neoplasias caninas diagnosticadas histológicamente por hematoxilina y eosina (HE) como NMM. Cada muestra fue cortada a 4 µm de espesor, obteniéndose tres láminas por muestra. Una fue coloreada con HE para confirmar la viabilidad del tejido y en las otras dos láminas se realizó la IHQ mediante el método de Streptavidina-Biotina. Las células epiteliales reaccionaron de manera positiva con el anticuerpo anti-citoqueratina AE1/AE3 dando una coloración marrón a nivel citoplasmático. El anticuerpo anti-vimentina reaccionó de manera positiva con los fibroblastos, el tejido conectivo, las células mioepiteliales y las células cartilaginosas, dando una coloración semejante al anterior. Todas las neoplasias benignas reaccionaron contra ambos anticuerpos, mientras que el 73% de las neoplasias malignas reaccionaron de manera positiva contra el anticuerpo anti-citoqueratina. Se concluye que las NMM en caninos pueden ser diagnosticadas mediante la técnica de IHQ usando los anticuerpos monoclonales empleados en humanos. Abstract in english The aim of the study was to evaluate an immunohistochemical technique for the diagnosis of canine mixed mammary tumors (CMMT) using anti-cytokeratin AE1/AE3 and anti-vimentin monoclonal antibodies that are routinely used in the diagnosis of human mammary tumors. Twenty paraffin tissue blocks of cani [...] ne mixed mammary tumors, previously diagnosed by hematoxilin-eosin (HE) histopathology were used. Three slides sets, 4 µm thick, were obtained per tissue block. One was stained with HE to confirm the viability of the tissue, and the other two were used for the immunohistochemistry through the Streptavidin-Biotin-labeled method. Epithelial cells positively reacted against the anti-cytokeratin AE1/AE3 showing a brown colour at the cytoplasma level. Fibroblasts, connective tissue, myoepithelial cells, cartilage cells and bone areas showed a brown colour against the anti-vimentin antibody. All benign tumors reacted positively to both antibodies, whereas 73% malign tumors were positive with the anti-cytokeratin antibody. It is concluded that mixed mammary neoplasm in dogs may be diagnosed by the technique of immunohistochemistry using monoclonal antibodies used in the detection of human mammary tumors

  19. Induction of tumors in the small intestine and mammary gland of female Donryu rats by continuous oral administration of N-carboxymethyl-N-nitrosourea.

    Science.gov (United States)

    Maekawa, A; Ogiu, T; Matsuoka, C; Onodera, H; Furuta, K; Tanigawa, H; Odashima, S

    1983-01-01

    The carcinogenicity of N-carboxymethyl-N-nitrosourea (CMNU), a naturally occurring N-nitroso compound, was tested in female Donryu rats. Four groups of female Donryu rats were given 400, 200, 100, or 0 ppm of CMNU solution continuously as drinking water. The incidence of tumors was highest and the mean survival time shortest in the 400 ppm group. A dose-effect relationship was observed in the tumor incidence and the mean survival time and the incidences of tumors in all experimental groups were significantly different from those in the control group. In the 400 ppm group, tumors were detected most frequently in the small intestine, followed by the mammary gland. In contrast, most tumors were observed in the mammary gland in the other two experimental groups, although dose-dependent induction of tumors of the small intestine was also detected in these two groups. The organ specificity of CMNU is compared with that of other N-alkyl-N-nitrosourea derivatives. PMID:6885894

  20. Enhanced antiproliferative and apoptotic response to combined treatment of ?-tocotrienol with erlotinib or gefitinib in mammary tumor cells

    Directory of Open Access Journals (Sweden)

    Sylvester Paul W

    2010-03-01

    Full Text Available Abstract Background Aberrant ErbB receptor signaling is associated with various types of malignancies. ?-Tocotrienol is a member of the vitamin E family of compounds that displays potent anticancer activity that is associated with suppression in ErbB receptor phosphorylation and mitogenic signaling. Erlotinib and gefitinib are tyrosine kinase inhibitors that block ErbB1 receptor activation, whereas trastuzumab is a monoclonal antibody that has been designed to specifically inhibit ErbB2 receptor activation. However, the clinical effectiveness of these agents have been disappointing because of cooperation between different ErbB family members that can rescue cancer cells from agents directed against a single ErbB receptor subtype. It was hypothesized that targeting multiple ErbB receptor subtypes with combined treatment of ?-tocotrienol and ErbB receptor inhibitors would provide greater anticancer effects than monotherapy targeting only a single ErbB receptor subtype. Methods Highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined media containing 10 ng/ml EGF as a mitogen. Cell viability wase determined by MTT assay, whereas Western blot and immunofluorescent staining was used to determine treatment effects on ErbB receptor subtype level and activation. Treatment-induced apoptosis was determined using annexin V staining and Western blot analysis of cleaved caspase-3 and PARP levels. Results Treatment with 3.5 ?M ?-tocotrienol, 0.5 ?M erlotinib or 1.0 ?M gefitinib alone, significantly inhibited +SA tumor cell growth. Combined treatment with subeffective doses of erlotinib (0.25 ?M or gefitinib (0.5 ?M with subeffective doses of ?-tocotrienol (0.5-3.0 ?M significantly inhibited the growth and induced apoptosis in a dose-responsive manner. Trastuzumab treatment alone or in combination had no effect on +SA cell growth and viability. Combined treatment of ?-tocotrienol with erlotinib or gefitinib also cause a large decrease in ErbB3, ErbB4, and to a lesser extent ErbB2 receptor levels, and EGF-dependent ErbB2-4 tyrosine phosphorylation (activation, but had no effect on ErbB1 receptor levels or activation. Conclusion Combination treatment of ?-tocotrienol with specific ErbB receptor inhibitors is more effective in reducing mammary tumor cell growth and viability than high dose monotherapy, suggesting that targeting multiple ErbB receptors with combination therapy may significantly improve the therapeutic response in breast cancer patients.

  1. Evaluation of Tumor Angiogenesis Using Dynamic Enhanced Magnetic Resonance Imaging: Comparison of Plasma Vascular Endothelial Growth Factor, Hemodynamic, and Pharmacokinetic Parameters

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, O.; Nishimura, R.; Miyayama, H.; Yasunaga, T.; Ozaki, Y.; Tuji, A.; Yamashita, Y. [Kumamoto Univ. Graduate School of Medical and Pharmaceutical Sciences, Kumamoto (Japan). Dept. of Diagnostic Radiology

    2004-07-01

    Purpose: To assess whether tumor angiogenesis of breast cancers can be predicted on the basis of dynamic magnetic resonance imaging (MRI). Material and Methods: Seventy-one patients with 71 breast cancers underwent Gd-DTPA enhanced dynamic MRI. Two regions of interest measurements were obtained in the periphery and in the center of the breast cancers. Hemodynamic parameters obtained by dynamic MRI included peak time, contrast enhancement ratio (CE ratio), and washout ratio. The triexponential concentration curve of Gd-DTPA was fitted to a theoretical model based on compartmental analysis. The transfer constant (or permeability surface product per unit volume of compartment 'k') was obtained using this method. Tumor angiogenesis was assessed by plasma vascular endothelial growth factor (P-VEGF). Results: The P-VEGF was positive in 28 of 71 tumors (39%). The CE ratio, washout ratio, and k in the periphery in P-VEGF positive breast cancers (mean 178%, 18%, and 1.5x10{sup -2} (s-1)) were significantly greater (P<0.01, P<0.05, and P<0.03)) than those for P-VEGF negative breast cancers (mean: 151%, 14%, and 1.1x10{sup -2} (s-1)). The peak time in the periphery in P-VEGF positive breast cancers was more marked than for P-VEGF negative breast cancers, but this difference was not significant. Conclusion: The hemodynamic and pharmacokinetic analysis of MRI provides valuable information about angiogenesis of breast cancers.

  2. Evaluation of Tumor Angiogenesis Using Dynamic Enhanced Magnetic Resonance Imaging: Comparison of Plasma Vascular Endothelial Growth Factor, Hemodynamic, and Pharmacokinetic Parameters

    International Nuclear Information System (INIS)

    Purpose: To assess whether tumor angiogenesis of breast cancers can be predicted on the basis of dynamic magnetic resonance imaging (MRI). Material and Methods: Seventy-one patients with 71 breast cancers underwent Gd-DTPA enhanced dynamic MRI. Two regions of interest measurements were obtained in the periphery and in the center of the breast cancers. Hemodynamic parameters obtained by dynamic MRI included peak time, contrast enhancement ratio (CE ratio), and washout ratio. The triexponential concentration curve of Gd-DTPA was fitted to a theoretical model based on compartmental analysis. The transfer constant (or permeability surface product per unit volume of compartment 'k') was obtained using this method. Tumor angiogenesis was assessed by plasma vascular endothelial growth factor (P-VEGF). Results: The P-VEGF was positive in 28 of 71 tumors (39%). The CE ratio, washout ratio, and k in the periphery in P-VEGF positive breast cancers (mean 178%, 18%, and 1.5x10-2 (s-1)) were significantly greater (P-2 (s-1)). The peak time in the periphery in P-VEGF positive breast cancers was more marked than for P-VEGF negative breast cancers, but this difference was not significant. Conclusion: The hemodynamic and pharmacokinetic analysis of MRI provides valuable information about angiogenesis of breast cancers

  3. Expressão dos filamentos intermediários no diagnóstico dos tumores mamários de cadelas Expression of intermediate filaments in canine mammary tumors diagnosis

    OpenAIRE

    Zuccari, D. A. P. C.; Santana, A. E.; Rocha, N. S.

    2002-01-01

    Foram utilizados anticorpos monoclonais para marcação imunoistoquímica dos tecidos tumorais e obtenção de informações sobre a histogênese dos tumores mamários utilizando-se anti-citoqueratinas para marcação de células epiteliais, e anti-actina e anti-vimentina para células mioepiteliais. O procedimento imunoistoquímico mostrou-se esclarecedor com relação à histogênese dos tumores mamários, confirmando a marcação de células epiteliais com as citoqueratinas que perdem sua ...

  4. Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis

    Science.gov (United States)

    Salvati, Erica; Zizza, Pasquale; Rizzo, Angela; Iachettini, Sara; Cingolani, Chiara; D’Angelo, Carmen; Porru, Manuela; Randazzo, Antonio; Pagano, Bruno; Novellino, Ettore; Pisanu, Maria Elena; Stoppacciaro, Antonella; Spinella, Francesca; Bagnato, Anna; Gilson, Eric; Leonetti, Carlo; Biroccio, Annamaria

    2014-01-01

    Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an antiparallel G-quadruplex (G4) structure. This G4 structure can be efficiently stabilized by small molecules with the consequent inhibition of vegfr-2 expression. Functionally, the G4-mediated reduction of VEGFR-2 protein causes a switching off of signaling components that, converging on actin cytoskeleton, regulate the cellular events leading to endothelial cell proliferation, migration and differentiation. As a result of endothelial cell function impairment, angiogenic process is strongly inhibited by G4 ligands both in vitro and in vivo. Interestingly, the G4-mediated antiangiogenic effect seems to recapitulate that observed by using a specific interference RNA against vegfr-2, and it is strongly antagonized by overexpressing the vegfr-2 gene. In conclusion, we describe the evidence for the existence of G4 in the promoter of vegfr-2, whose expression and function can be markedly inhibited by G4 ligands, thereby revealing a new, and so far undescribed, way to block VEGFR-2 as target for anticancer therapy. PMID:24335081

  5. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    Science.gov (United States)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  6. Activated Abl kinase inhibits oncogenic transforming growth factor-? signaling and tumorigenesis in mammary tumors

    OpenAIRE

    Allington, Tressa M.; Galliher-beckley, Amy J.; Schiemann, William P.

    2009-01-01

    Transforming growth factor-? (TGF-?) is a ubiquitous cytokine with dual roles in tumor suppression and promotion, and these dichotomous functions have frustrated the development of therapies targeting oncogenic signaling by TGF-?. In comparison, Abl is well established as an initiator of hematopoietic cancers; however, a clear role for Abl in regulating solid tumor development remains elusive. Here, we investigated the role of Abl in TGF-?-mediated epithelial-mesenchymal transition (EMT) ...

  7. Direct cytosolic siRNA delivery by reconstituted high density lipoprotein for target-specific therapy of tumor angiogenesis.

    Science.gov (United States)

    Ding, Yang; Wang, Yazhe; Zhou, Jianping; Gu, Xiaochen; Wang, Wei; Liu, Congyan; Bao, Xiuli; Wang, Cheng; Li, Yuanru; Zhang, Qiang

    2014-08-01

    We described here the mechanisms by which small interfering RNA (siRNA) molecules incorporated in reconstituted high density lipoprotein (rHDL) were efficiently transferred into the cytoplasm of cells to perform target-specific therapy of tumor angiogenesis. Using fluorescent-tagged apolipoprotein A-I (apoA-I) and cholesterol-conjugated siRNA (Chol-siRNA), it was confirmed with FACS and confocal microscopic measurements that Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were successfully established and apoA-I certainly was attached to the surface of Chol-siRNA-loaded lipoplexes (Lipos/Chol-siRNA complexes). Stably assembled rHDL/Chol-siRNA complexes demonstrated proper nanosize, quasi-spherical shape and improved nuclease protection over naked Chol-siRNA. It was also interesting to note that rHDL provided a highly effective approach to transfer Chol-siRNA across the membrane directly into the cytoplasm via the scavenger receptor BI (SR-BI)-mediated non-endocytotic mechanism, thereby bypassing endo-lysosomal trapping. We also showed clear evidence that the in vitro implementation of rHDL for Chol-siRNA-VEGF (Chol-siRNA targeting vascular endothelial growth factor gene) delivery markedly promoted RNA interference (RNAi)-mediated degradation of VEGF mRNA, resulting in down-regulation of secreted VEGF protein. In vivo fluorescence imaging indicated that near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) displayed long circulation time, SR-BI positive tumor-selective targeting, and efficient cytosolic delivery capabilities. Furthermore, intravenous administration of Chol-siRNA-VEGF-loaded rHDL nanoparticles (rHDL/Chol-siRNA-VEGF complexes) significantly enhanced anti-tumor efficacy against breast cancer, decreased VEGF expression level, and inhibited formation of intratumoral microvessels at the tumor tissue. It was concluded that rHDL possessed therapeutic potential and versatility in mediating Chol-siRNA-VEGF direct cytosolic delivery for target-specific anti-angiogenic therapy in breast cancer. PMID:24875759

  8. One-step radiosynthesis of {sup 18}F-AlF-NOTA-RGD{sub 2} for tumor angiogenesis PET imaging

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shuanglong; Liu, Hongguang; Xu, Yingding; Cheng, Zhen [Stanford University, Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Bio-X Program, Department of Radiology, Stanford, CA (United States); Jiang, Han [Stanford University, Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Bio-X Program, Department of Radiology, Stanford, CA (United States); Institute of Nuclear Medicine and Molecular Imaging, and the Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Department of Nuclear Medicine, Medical PET Center, Hangzhou, Zhejiang (China); Zhang, Hong [Institute of Nuclear Medicine and Molecular Imaging, and the Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Department of Nuclear Medicine, Medical PET Center, Hangzhou, Zhejiang (China)

    2011-09-15

    One of the major obstacles of the clinical translation of {sup 18}F-labeled arginine-glycine-aspartic acid (RGD) peptides has been the laborious multistep radiosynthesis. In order to facilitate the application of RGD-based positron emission tomography (PET) probes in the clinical setting we investigated in this study the feasibility of using the chelation reaction between Al{sup 18}F and a macrocyclic chelator-conjugated dimeric RGD peptide as a simple one-step {sup 18}F labeling strategy for development of a PET probe for tumor angiogenesis imaging. Dimeric cyclic peptide E[c(RGDyK)]{sub 2} (RGD{sub 2}) was first conjugated with a macrocyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the resulting bioconjugate NOTA-RGD{sub 2} was then radiofluorinated via Al{sup 18}F intermediate to synthesize {sup 18}F-AlF-NOTA-RGD{sub 2}. Integrin binding affinities of the peptides were assessed by a U87MG cell-based receptor binding assay using {sup 125}I-echistatin as the radioligand. The tumor targeting efficacy and in vivo profile of {sup 18}F-AlF-NOTA-RGD{sub 2} were further evaluated in a subcutaneous U87MG glioblastoma xenograft model by microPET and biodistribution. NOTA-RGD{sub 2} was successfully {sup 18}F-fluorinated with good yield within 40 min using the Al{sup 18}F intermediate. The IC{sub 50} of {sup 19}F-AlF-NOTA-RGD{sub 2} was determined to be 46 {+-} 4.4 nM. Quantitative microPET studies demonstrated that {sup 18}F-AlF-NOTA-RGD{sub 2} showed high tumor uptake, fast clearance from the body, and good tumor to normal organ ratios. NOTA-RGD{sub 2} bioconjugate has been successfully prepared and labeled with Al{sup 18}F in one single step of radiosynthesis. The favorable in vivo performance and the short radiosynthetic route of {sup 18}F-AlF-NOTA-RGD{sub 2} warrant further optimization of the probe and the radiofluorination strategy to accelerate the clinical translation of {sup 18}F-labeled RGD peptides. (orig.)

  9. Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor.

    Science.gov (United States)

    Wyder, Lorenza; Suply, Thomas; Ricoux, Bérangère; Billy, Eric; Schnell, Christian; Baumgarten, Birgit U; Maira, Sauveur Michel; Koelbing, Claudia; Ferretti, Mireille; Kinzel, Bernd; Müller, Matthias; Seuwen, Klaus; Ludwig, Marie-Gabrielle

    2011-12-01

    The G protein-coupled receptor GPR4 is activated by acidic pH and recent evidence indicates that it is expressed in endothelial cells. In agreement with these reports, we observe a high correlation of GPR4 mRNA expression with endothelial marker genes, and we confirm expression and acidic pH dependent function of GPR4 in primary human vascular endothelial cells. GPR4-deficient mice were generated; these are viable and fertile and show no gross abnormalities. However, these animals show a significantly reduced angiogenic response to VEGF (vascular endothelial growth factor), but not to bFGF (basic fibroblast growth factor), in a growth factor implant model. Accordingly, in two different orthotopic models, tumor growth is strongly reduced in mice lacking GPR4. Histological analysis of tumors indicates reduced tumor cell proliferation as well as altered vessel morphology, length and density. Moreover, GPR4 deficiency results in reduced VEGFR2 (VEGF Receptor 2) levels in endothelial cells, accounting, at least in part, for the observed phenotype. Our data suggest that endothelial cells sense local tissue acidosis via GPR4 and that this signal is required to generate a full angiogenic response to VEGF. PMID:22045552

  10. Optimization of methods to assess mitochondrial DNA in archival paraffin-embedded tissues from mammary canine tumors Otimização dos métodos para avaliar o DNA mitocondrial obtido a partir de tumores mamários caninos incluídos em parafina

    Directory of Open Access Journals (Sweden)

    Angélica C. Bertagnolli

    2008-08-01

    Full Text Available In this study we describe the alterations used to extract and amplify mitochondrial desoxyribonucleic acid (DNA from formalin-fixed paraffin-embedded samples of canine mammary tumors. The epithelial and mesenchymal components (chondromyxoid and chondroid of each tumor, as well as the normal mammary gland tissues, were manually microdissected from 19 mixed canine mammary tumors (10 benign mixed tumors and nine carcinomas arising in mixed tumors. DNA was extracted by Invisorb® Spin Tissue Mini Kit, with protocol changes proposed by the manufacturer. A 273-bp fragment was amplified by polymerase chain reaction (PCR and submitted to automatic sequence analysis. The fragment was successfully analyzed in 100% of the samples. However, an additional lysis step, the reduction of volume in buffer solutions and PCR, a higher annealing temperature and an increase in the number of PCR cycles were required. The initial PCR products were diluted and re-amplified in six samples so that they could be successfully analyzed.A presente comunicação descreve as modificações usadas para extrair e amplificar o DNA mitocondrial obtido de amostras de tumores mamários caninos fixados em formol tamponado a 10% e incluídos em parafina. Os componentes epiteliais e mesenquimais (condromixóide e condróide, bem como a mama normal adjacente, foram microdissectados manualmente de 19 tumores mamários (10 tumores mistos benignos e nove carcinomas em tumores mistos. O DNA foi extraído utilizando-se o Invisorb® Spin Tissue Mini Kit com modificações do protocolo proposto pelo fabricante. Um fragmento de 273-pb foi amplificado por reação em cadeia da polimerase (PCR e seqüenciado em seqüenciador automático. O fragmento foi analisado em 100% das amostras, entretanto modificações como lise adicional, redução do volume das soluções de extração e PCR, aumento da temperatura de anelamento e do número de ciclos de amplificação foram necessárias. Em seis amostras os produtos iniciais de PCR foram diluídos e reamplificados para obtenção de sucesso.

  11. Presence of lung metastases in bitches affected by malignant mammary neoplasms in Medellin (Colombia) / Presencia de tumores mamarios malignos con metástasis a pulmón en perras en Medellín (Colombia)

    Scientific Electronic Library Online (English)

    Brigitte, Gómez J; María, Ramírez R; Juan, Maldonado E.

    2983-29-01

    Full Text Available Objetivo. Definir la presencia de metástasis pulmonar en perras con tumores mamarios. Materiales y métodos. En una muestra de 30 perras atendidas en el Hospital Veterinario de la Universidad de Antioquia (Medellín, Colombia) con diagnóstico de tumores mamarios, al momento de la consulta, fueron regi [...] strados las variables clínicas y el grado de compromiso de las glándulas mamarias y de los nódulos linfáticos. Imágenes radiográficas latero-laterales y ventro-dorsales del tórax fueron tomadas para la identificación de hallazgos radiográficos compatibles con metástasis pulmonar. Biopsias mamarias afectadas fueron sometidas a estudio histopatológico y clasificación del tipo de tumor. Los datos fueron analizados mediante estadística descriptiva. Resultados. La edad promedio (± error estándar) al diagnóstico clínico fue 10.87 ± 2.65 años de edad. La raza más frecuentemente afectada fue la French poodle (46.6%) seguida de perros cruzados (13.3%) y Schnauzer (10%). El carcinoma fue el tumor más hallado (81%) seguido del adenoma (8.1%) y otros tipos de tumor (10.8%). Las glándulas mamarias más afectadas fueron las inguinales derecha (70%) e izquierda (66.6%). Cinco de las 30 pacientes (16.6%), presentaron metástasis a pulmón. Entre estas, 4 de 5 (80%) tenían carcinoma complejo. Conclusiones. El carcinoma complejo fue la neoplasia más frecuente y es el tipo más relacionado con metástasis pulmonar. Abstract in english Objective. To define the presence of lung metastasis in bitches with malignant mammary neoplasms. Materials and methods. Thirty female dogs that were attended at Veterinary Hospital (University of Antioquia, Medellin, Colombia) were selected for the study. At consultation clinical variables and grad [...] e of mammary and inguinal lymph node compromise were registered. Latero-lateral and ventral-dorsal radiographic images of thorax were done for identification of radiographic lesions suggestive of lung metastasis. At surgery biopsies of affected mammary glands were taken for histopathological study and classification of tumors. Data were analyzed by descriptive statistics. Results. The average (± standard error) age at clinical diagnosis was 10.87±2.65 year old. French poodle (46.6%) cross-breed (13.3%) and Schnauzer (10%) were the breeds most frequently affected by mammary tumors. The most frequent tumor found was carcinoma (81%), followed by adenoma (8.1%), and other types (10.8%). The most frequently affected mammary glands by tumors were the right and the left inguinal glands (70% and 66.6%, respectively). Five out of 30 bitches (16.6%) had lung metastasis according to radiographic examination. From this group of dogs, 4 out of 5 neoplasms (80%) were diagnosed as complex carcinoma by histopathology diagnosis. Conclusions. We provide evidence suggesting that complex carcinoma is the most frequent mammary tumor in bitches in our city and it is highly related to lung metastasis.

  12. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Hua; Yang, Ying-Hua [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Binmadi, Nada O. [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Oral Basic and Clinical Sciences, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Proia, Patrizia [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Sports Science (DISMOT), University of Palermo, Via Eleonora Duse 2 90146, Palermo (Italy); Basile, John R., E-mail: jbasile@umaryland.edu [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Greenebaum Cancer Center, 22S. Greene Street, Baltimore, MD 21201 (United States)

    2012-08-15

    Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: Black-Right-Pointing-Pointer Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. Black-Right-Pointing-Pointer Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. Black-Right-Pointing-Pointer These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. Black-Right-Pointing-Pointer Anti-SEMA4D blocking antibody inhibits Plexin-B1 activation. Black-Right-Pointing-Pointer SEMA4D is a valid anti-angiogenic target in the treatment of OSCC.

  13. Interstitial laser irradiation of metastatic mammary tumors in combination with intratumoral injection of immunoadjuvant

    Science.gov (United States)

    Joshi, Chet; Jose, Jessnie; Figueroa, Daniel; Goddard, Jessica; Li, Xiaosong; Liu, Hong; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2012-03-01

    Laser immunotherapy (LIT) was developed to treat metastatic cancers using a combination of laser irradiation and immunological stimulation. The original design of LIT employs a non-invasive, selective laser photothermal interaction, using an in situ light-absorbing dye. However, this non-invasive treatment mode faces challenges in treating deep, large tumors. Furthermore, it has difficulties in the cases of highly pigmented skin overlying target tumors. To overcome these limitations, interstitial laser immunotherapy (ILIT) was proposed. In ILIT, a cylindrical, side-fire fiber diffuser is placed inside the target tumor</