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

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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 ...

2010-01-01

2

Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis  

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Alcohol consumption has been recognized as a risk factor for breast cancer. Experimental studies demonstrate that alcohol exposure promotes the progression of existing mammary tumors. However, the mechanisms underlying this effect remain unclear. In the present study, the role of vascular endothelial growth factor (VEGF) in alcohol promotion of breast cancer development was investigated using a mouse xenograft model of mammary tumors and a three-dimensional (3D) tumor/endothelial cell co-culture system. For the mouse xenograft model, mouse E0771 breast cancer cells were implanted into the mammary fat pad of C57BL6 mice. These mice were exposed to alcohol in their drinking water. For the 3D co-culture system, E0771 cells and MDA-MB231 breast cancer cells were co-cultured with SVEC4-10EE2 and human umbilical vein endothelial cells, respectively. The results demonstrated that alcohol increased tumor angiogenesis and accelerated tumor growth. Furthermore, it appeared that alcohol induced VEGF expression in breast cancer cells in vitro and in vivo. Blocking VEGF signaling by SU5416 inhibited tumor angiogenesis in the 3D tumor/endothelial cell co-culture system. Furthermore, injection of SU5416 into mice inhibited alcohol-promoted mammary tumor growth in vivo. These results indicate that alcohol may promote mammary tumor growth by stimulating VEGF-dependent angiogenesis.

LU, YANMIN; NI, FANG; XU, MEI; YANG, JINLIAN; CHEN, JI; CHEN, ZHUO; WANG, XINYI; LUO, JIA; WANG, SIYING

2014-01-01

3

Fibrinolysis in Tumor Associated Angiogenesis.  

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Angiogenesis has been shown 0 be necessary for tumor growth and metastasis but specific targets for antiangiogenic therapy in breast cancer have not been identified. Patient samples, a tissue assay of angiogenesis with a mammary vessel explant, and xenogr...

S. W. McLeskey

2003-01-01

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

1988-01-01

5

Mammary tumors  

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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.

Weller, R.E.

1988-10-01

6

Role of chemokine receptor CXCR2 expression in mammary tumor growth, angiogenesis and metastasis  

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Background: Chemokines and their receptors have long been known to regulate metastasis in various cancers. Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples. The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear. We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer. The objective of this study is to investigate the potential role of CXCR2 in the metastatic phenotype of mouse mammary tumor cells. Materials and Methods: We evaluated the functional role of CXCR2 in breast cancer by stably downregulating the expression of CXCR2 in metastatic mammary tumor cell lines Cl66 and 4T1, using short hairpin RNA (shRNA). The effects of CXCR2 downregulation on tumor growth, invasion and metastatic potential were analyzed in vitro and in vivo. Results: We demonstrated knock down of CXCR2 in Cl66 and 4T1 cells (Cl66-shCXCR2 and 4T1-shCXCR2) cells by reverse transcriptase polymerase chain reaction (RT-PCR) at the transcriptional level and by immunohistochemistry at the protein level. We did not observe a significant difference in in vitro cell proliferation between vector control and CXCR2 knock-down Cl66 or 4T1 cells. Next, we examined the invasive potential of Cl66-shCXCR2 cells by in vitro Matrigel invasion assay. We observed a significantly lower number (52 ± 5) of Cl66-shCXCR2 cells invading through Matrigel compared to control cells (Cl66-control) (182 ± 3) (P < 0.05). We analyzed the in vivo metastatic potential of Cl66-shCXCR2 using a spontaneous metastasis model by orthotopically implanting cells into the mammary fat pad of female BALB/c mice. Animals were sacrificed 12 weeks post tumor implantation and tissue samples were analyzed for metastatic nodules. CXCR2 downregulation significantly inhibited tumor cell metastasis. All the mice (n = 10) implanted with control Cl66 cells spontaneously developed lung metastasis, whereas a significantly lower number of mice (40%) implanted with Cl66-shCXCR2 cells exhibited lung metastases. Conclusions: Together, these results suggest that CXCR2 may play a critical role in breast cancer invasion and metastasis.

Nannuru, Kalyan C.; Sharma, Bhawna; Varney, Michelle L.; Singh, Rakesh K.

2011-01-01

7

Targeting CXCR2 enhances chemotherapeutic response, inhibits mammary tumor growth, angiogenesis and lung metastasis  

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Breast cancer is one of the leading causes of cancer deaths among females. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often due to therapy resistance. How breast cancer cells evade chemotherapy and the underlying mechanism remains unclear. We and others have observed that malignant cells that survive initial chemo-and radiation therapy express higher levels of CXCR2 ligands which might provide a survival benefit leading to therapy resistance. In this report, we test the hypothesis that CXCR2-dependent signaling in malignant cells might be critical for chemotherapy resistance and targeting this signaling axis may enhance the antitumor and antimetastatic activity of chemotherapeutic drugs and limit their toxicity. We used Cl66-wt, 4T1-wt, Cl66sh-CXCR2 and 4T1sh-CXCR2 cells expressing differential levels of the CXCR2 receptor to evaluate the role of targeting CXCR2 on chemotherapeutic responses. Knockdown of CXCR2 enhances paclitaxel and doxorubicin mediated toxicity at suboptimal doses. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand in paclitaxel and doxorubicin treated mammary tumor cells which were inhibited following CXCR2 knockdown. Knockdown of CXCR2 enhanced antitumor activity of paclitaxel in an in vivo mammary tumor model. We observed significant inhibition of spontaneous lung metastases in animals bearing CXCR2 knockdown tumors and treated with paclitaxel as compared to the control group. Our data suggest the novel role of CXCR2 and its ligands in maintaining chemotherapy resistance and provide evidence that targeting CXCR2-signaling in an adjuvant setting will help circumvent chemotherapy resistance.

Sharma, Bhawna; Nawandar, Dhananjay M.; Nannuru, Kalyan C.; Varney, Michelle L.; Singh, Rakesh K.

2013-01-01

8

Mammary Tumors.  

Science.gov (United States)

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 neop...

R. E. Weller

1988-01-01

9

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

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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.

Broggini-Tenzer Angela

2011-06-01

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Angiogenesis and tumor  

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Full Text Available Angiogenesis, the process of new blood vessel formation from existing ones, plays an important role in the physiologic circumstances such as embryonic development, placenta formation, and wound healing. It is also crucial to progress of pathogenic processes of a variety of disorders, including tumor growth and metastasis. In general, angiogenesis process is a multi-factorial and highly structured sequence of cellular events comprising migration, proliferation and differentiation of endothelial cells and finally vascular formation, maturation and remodeling.Thereby, angiogenesis inhibition as a helping agent to conventional therapies such as chemotherapy and radiation has attracted the scientists’ attentions studying in this field.

Kamran Mansouri

2010-12-01

11

Imaging tumor angiogenesis  

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The imaging of patients with cancer is of increasing importance. There is an increasing prevalence of tumors within a aging population and the success of cancer therapy has resulted in increased numbers of patients surviving cancer and a need to monitor the therapeutic response. Angiogenesis describes a fundamental process in the development of tumors whereby the growing malignancy appropriates its own blood supply from adjacent tissues. This process is essential for tumor growth and metastatic spread. Using a multi-disciplinary approach that builds from a basis of physiological and pathological principles to radiology and automated image analysis, the processes of angiogenesis can be visualized in vivo providing diagnostic and prognostic information for patients with cancer. This approach can also provide a more general template for the analysis of medical images.

Miles, K. A.

1999-07-01

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Inhibiting Tumor Angiogenesis in Children  

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In this trial, researchers are testing an angiogenesis inhibitor called cediranib in pediatric patients who have solid tumors (except brain tumors) or acute myeloid leukemia (AML), a type of blood cancer.

13

High-Density Gene Expression Analysis of Tumor-Associated Macrophages from Mouse Mammary Tumors  

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Clinical and experimental evidence indicates that tumor-associated macrophages (TAMs) promote malignant progression. In breast cancer, TAMs enhance tumor angiogenesis, tumor cell invasion, matrix remodeling, and immune suppression against the tumor. In this study, we examined late-stage mammary tumors from a transgenic mouse model of breast cancer. We used flow cytometry under conditions that minimized gene expression changes to isolate a rigorously defined TAM population previously shown to ...

Ojalvo, Laureen S.; King, William; Cox, Dianne; Pollard, Jeffrey W.

2009-01-01

14

Sphingolipids in tumor metastases and angiogenesis.  

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This review article summarizes data on the involvement of sphingolipids (sphingosine-1-phosphate, sphingosine-1-phosphocholine, neutral glycosphingolipids, and gangliosides) in tumor metastases and angiogenesis. PMID:16615853

Dyatlovitskaya, E V; Kandyba, A G

2006-04-01

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The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells  

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The microenvironment of the mammary gland has been shown to exert a deterministic control over cells from different normal organs during murine mammary gland regeneration in transplantation studies. When mouse mammary tumor virus (MMTV)-neu-induced tumor cells were mixed with normal mammary epithelial cells (MECs) in a dilution series and inoculated into epithelium- free mammary fat pads, they were redirected to noncarcinogenic cell fates by interaction with untransformed MECs during regenera...

Booth, Bw; Boulanger, Ca; Anderson, Lh; Smith, Gh

2011-01-01

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Mammary gland tumors in captive African hedgehogs.  

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From December 1995 to July 1999, eight mammary gland tumors were diagnosed in eight adult captive female African hedgehogs (Atelerix albiventris). The tumors presented as single or multiple subcutaneous masses along the cranial or caudal abdomen that varied in size for each hedgehog. Histologically, seven of eight (88%) mammary gland tumors were malignant. Tumors were classified as solid (4 cases), tubular (2 cases), and papillary (2 cases). Seven tumors had infiltrated into the surrounding stroma and three tumors had histologic evidence of neoplastic vascular invasion. Three hedgehogs had concurrent neoplasms. These are believed to be the first reported cases of mammary gland tumors in African hedgehogs. PMID:10813628

Raymond, J T; Gerner, M

2000-04-01

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Selective amplification of mouse mammary tumor virus in mammary tumors of GR mice.  

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DNAs extracted from the mammary tumors of GR mice were analyzed for mouse mammary tumor virus proviral sequences by the restriction enzyme-Southern blot procedure. The tumor DNAs contain more proviral copies of mouse mammary tumor virus than DNA from a nonmalignant tissue. The degree of proviral amplification is small (ca. one to five additional copies) and appears to be variable from tumor to tumor. The restriction patterns of the amplified proviral sequences suggest a clonal origin for the ...

Fanning, T. G.; Puma, J. P.; Cardiff, R. D.

1980-01-01

18

Tumor-associated antigen of spontaneous mammary tumor in rats.  

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The present study was undertaken to detect the spontaneous mammary tumor-associated antigen ( MTAA ), and to find the cross-reacting antigen in chemically-induced mammary tumor. The antisera against spontaneous mammary tumor were raised in the WAF1 rats of the same strain and tested for the detection of tumor-associated soluble antigen of mammary tumor induced by N-ethylnitrosourea (ENU) and N-butylnitrosourea ( BNU ). The MTAA was found in the extract of spontaneous mammary tumor by the double immunodiffusion test, while it was not found in the extract of normal and fetal tissues, hyperplastic mammary gland, spontaneous fibroadenoma, and chemically-induced mammary tumor. On the other hand, the MTAA was not detected in the other types of tumors induced by ENU or BNU , i.e. gastric cancer, intestinal tumor, brain tumor, kidney tumor, bladder tumor, hemangioma, rhabdomyosarcoma, or leukemia. The spontaneous MTAA could not be detected in the spontaneous mammary tumor of C3H mice or human breast cancer either. The MTAA was extracted effectively by 3 M KC1. Furthermore, the MTAA was found in the cytoplasm of continuous established mammary tumor cell line ( SpMT -1) by the immunofluorescence test. PMID:6427720

Imamura, N; Yanagihara, K; Kusunoki, Y

1984-01-01

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Imaging Key Biomarkers of Tumor Angiogenesis  

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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.

Marina V. Backer, Joseph M. Backer

2012-01-01

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New molecular mediators in tumor angiogenesis  

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Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is suf...

2007-01-01

 
 
 
 
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Mammary tumor virus proviral DNA in normal murine tissue and non-virally induced mammary tumors.  

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The Southern DNA filter transfer technique was used to study the involvement of the endogenous mouse mammary tumor virus (MMTV) in the development of mammary tumors of nonviral etiology. The presence of extra MMTV proviruses in the genomes of these non-virally induced mammary tumors would indicate an integration of the provirus of an activated endogenous MMTV. Acquisition of MMTV proviruses did not seem to be an absolute requirement for the development of hormone or carcinogenically induced m...

Michalides, R.; Wagenaar, E.; Groner, B.; Hynes, N. E.

1981-01-01

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The role of microenvironment in tumor angiogenesis  

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in tumors and in multiple myeloma. The encouraging results of pre-clinical and clinical trials in which tumors have been treated by targeting the tumor microenvironment are also di...

Ribatti, Domenico; Vacca, Angelo

2008-01-01

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Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective  

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Much progress has been made since the conceptualization of tumor angiogenesis—the induction of growth of new blood vessels by tumor—as a salient feature of clinically significant primary or metastatic cancers. From a practicing histopathologist's point of view, we appraise the application of this concept in breast cancer with particular reference to the evaluation of proangiogenic factors and the assessment of new microvessels in histopathological examination. Recently, much focus has also been centered on the active roles played by tumor-associated macrophages in relation to tumor angiogenesis. We review the literature; many data supporting this facet of tumor angiogenesis were derived from the breast cancer models. We scrutinize the large body of clinical evidence exploring the link between the tumor-associated macrophages and breast tumor angiogenesis and discuss particularly the methodology and limitations of incorporating such an assessment in histopathological examination.

Ch'ng, Ewe Seng; Jaafar, Hasnan; Tuan Sharif, Sharifah Emilia

2011-01-01

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Molecular Imaging System for Monitoring Tumor Angiogenesis  

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In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

Aytac, Esra; Burcin Unlu, Mehmet

2012-02-01

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Nanotechnology-mediated targeting of tumor angiogenesis  

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Abstract Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced...

Banerjee Deboshri; Harfouche Rania; Sengupta Shiladitya

2011-01-01

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Nanotechnology-mediated targeting of tumor angiogenesis  

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Abstract Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity ...

2010-01-01

27

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-promotion is discussed

2002-01-01

28

Tumor angiogenesis in advanced stage ovarian carcinoma.  

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Tumor angiogenesis has been found to have prognostic significance in many tumor types for predicting an increased risk of metastasis. We assessed tumor vascularity in 43 cases of advanced stage (International Federation of Gynecologists and Obstetricians stages III and IV) ovarian cancer by using the highly specific endothelial cell marker CD34. Microvessel counts and stage were associated with disease-free survival and with overall survival by Kaplan-Meier analysis. The plots show that highe...

Hollingsworth, H. C.; Kohn, E. C.; Steinberg, S. M.; Rothenberg, M. L.; Merino, M. J.

1995-01-01

29

Mapping Genetic Modifiers of Mammary Tumor Susceptibility.  

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Mutations in APC/Apc predispose both humans and mice to multiple polyps of the colon and small intestine. Min/+ mice carry a mutation at Apc and are predisposed to developing spontaneous intestinal and mammary tumors. On a C57BL/6J (B6) background, Min/+ ...

R. L. Williams A. Moser

2001-01-01

30

Heavy ion radiation-induced mammary tumors and their prevention  

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The aim of this research is to investigate whether heavy ion radiation cause mammary tumors in rats of lactation period and to find useful protectors against the incidence of the mammary tumors. This year, we have continued the irradiation experiment to study the radiation dose dependent mammary tumor formation. We totally irradiated 23-24 rats for each group (0.1, 0.25, 0.5, 1.0, 2.0 Gy) and found that the incidence of mammary tumors saturated at 0.5 Gy. Using this dose, we began the experiments to examine the protecting effect of amifostine against heavy ion radiation-induced mammary tumors. (author)

2010-06-01

31

Genetics of Mouse Mammary Tumor Virus-Induced Mammary Tumors: Linkage of Tumor Induction to the gag Gene  

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Retroviruses are believed to induce tumors by acting as insertional mutagens that activate expression of cellular protooncogenes. Indeed, almost 90% of mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/He mice show upregulation of Int protooncogenes. We have analyzed three different MMTV variants [MMTV(C3H), MMTV(HeJ), and a genetically engineered MMTV hybrid provirus (HP)] for tumorigenicity in mice from two distinct genetic backgrounds. All three viruses were tumor causing in B...

Hook, Lauren M.; Agafonova, Yelena; Ross, Susan R.; Turner, Stephanie J.; Golovkina, Tatyana V.

2000-01-01

32

Alpha basic crystallin expression in canine mammary tumors  

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The aim of this study was to evaluate prognostic and/or diagnostic factors of canine mammary tumors by immunohistochemically analyzing the expression of alpha basic crystallin (?B-c). For this, formalin-fixed, paraffin-embedded blocks of 51 naturally-occurring canine mammary tumors (11 benign and 40 malignant) were used. Tissue from eight normal canine mammary glands were served as a control. Immunohistochemically, in the control mammary tissues, a few luminal epithelial cells were ?B-c pos...

Guvenc, Tolga; Gulbahar, Mustafa Yavuz; Yarim, Murat; Kabak, Yonca Betil; Karayigit, Onder; Sozmen, Mahmut

2012-01-01

33

Notch signaling in developmental and tumor angiogenesis.  

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The discovery that Notch, a key regulator of cell fate determination, is functional in the vasculature has greatly improved our understanding of differentiation and specialization of vessels. Notch signaling has been proven to be critical for arterial specification, sprouting angiogenesis, and vessel maturation. In newly forming vascular sprouts, Notch promotes the distinction between the leading "tip" endothelial cell and the growing "stalk" cell, the endothelial cells that eventually form a new capillary. Notch signaling has also been implicated in vessel stability by regulating vascular mural cell function. More recently, macrophages carrying an activated Notch have been implicated in shaping the course of new sprout formation. Tumor vessels abide by similar principles and use Notch signaling in similar ways. An exciting discovery, made by several researchers, shows that blocking Notch function in tumor vasculature provides a means by which to suppress tumor growth. The authors discuss the developmental and physiological role of Notch in the vasculature and apply this knowledge to an overview of how Notch targeting in the tumor environment can affect tumor angiogenesis and growth. PMID:22866202

Kofler, Natalie M; Shawber, Carrie J; Kangsamaksin, Thaned; Reed, Hasina Outtz; Galatioto, Josephine; Kitajewski, Jan

2011-12-01

34

Endogenous mammary tumor viruses in mice  

International Nuclear Information System (INIS)

The hypothesis of an endogenous mammary tumor virus seems to be substantiated in this paper by: transfer of genetic information for an MTV in vitro by GR sperm cells; segregation of MTV-P and MTV-L markers in the test cross of the F1 hybrid between C3Hf, producing MTV-L, and GR, releasing MTV-P; induction of MTV antigens by BrdU in cultures of kidneys from various mouse strains; and induction of MTV-O in BALB/c mice by lethal doses of radiation. The picture that emerges is that different genetic systems control the expression of endogenous mammary tumor viruses. There are those which seem to affect only that germinal provirus with which they are genetically linked, while others have an influence on other germinal proviruses as well as somatic proviruses. Further studies on the genetic regulation of the expression of the germinal MTV proviruses are in progress

1975-01-01

35

A Nash Topology Game for Tumoral Anti-angiogenesis  

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Tumoral angiogenesis and anti-angiogenesis are modeled as a Nash game. We consider the vessel-matrix-tumor system as a porous medium from the tumor viewpoint and as an elastic structural medium from the host tissue viewpoint. We define a competition between two density functions which are intended to represent respectively activators and inhibitors of angiogenesis. The activators want to minimize the pressure drop while the inhibitors intend to minimize the elastic compliance of the matrix or...

Habbal, Abderrahmane

2004-01-01

36

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 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

2008-06-01

37

Granular-cell tumor: A rare variant of mammary tumor  

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Full Text Available Background. Granular cell tumor (GCT is a rare variant of mammary tumor beset with diagnostic dilemmas that may be resolved by using numerous, very complex, enzymohistochemical and immunohistochemical methods. Case reports. We reported three female patients 16, 21 and 65 years old, operated on for mammary tumor at the Surgical Clinic of the School of Medicine in Niš, over the period of thirty years, 1977 to 2007. During this period 14.022 mammary tumors were diagnosed, including these three cases. These tumors had benign characteristics, without associated tumors in other localizations. A typical histological feature of GCT was a granular cytoplasm in large ovoid cells, organized like nests or like a trabecular arrangement. The tumors were analyzed by sets of histochemical, enzymohistochemical, immunohistochemical methods as well as ultrastructural examination. Protein, S-100 neuron-specific enolase and vimentin expressed a diffuse and intensive immunohistochemical activity, while expression of estrogen and progesterone receptors, as well as HER-2 oncoprotein was negative. The ultrastructural analysis confirmed that the tumor cells were enriched by lysosomes and consequential disorganization of cytoplasm. Conclusion. The reported enzymo- and immunohistochemical combined methods provide a precise diagnosis and confirm the GCT's neural origin, which has been disputed for years.

Ili? Ivan

2008-01-01

38

Imaging hypoxia and angiogenesis in tumors.  

Science.gov (United States)

There is a clear need in cancer treatment for a noninvasive imaging assay that evaluates the oxygenation status and heterogeneity of hypoxia and angiogenesis in individual patients. Such an assay could be used to select alternative treatments and to monitor the effects of treatment. Of the several methods available, each imaging procedure has at least one disadvantage. The limited quantitative potential of single-photon emission CT and MR imaging always limits tracer imaging based on these detection systems. PET imaging with FMISO and Cu-ATSM is ready for coordinated multicenter trials, however, that should move aggressively forward to resolve the debate over the importance of hypoxia in limiting response to cancer therapy. Advances in radiation treatment planning, such as intensity-modulated radiotherapy, provide the ability to customize radiation delivery based on physical conformity. With incorporation of regional biologic information, such as hypoxia and proliferating vascular density in treatment planning, imaging can create a biologic profile of the tumor to direct radiation therapy. Presence of widespread hypoxia in the tumor benefits from a systemic hypoxic cell cytotoxin. Angiogenesis is also an important therapeutic target. Imaging hypoxia and angiogenesis complements the efforts in development of antiangiogenesis and hypoxia-targeted drugs. The complementary use of hypoxia and angiogenesis imaging methods should provide the impetus for development and clinical evaluation of novel drugs targeted at angiogenesis and hypoxia. Hypoxia imaging brings in information different from that of FDG-PET but it will play an important niche role in oncologic imaging in the near future. FMISO, radioiodinated azamycin arabinosides, and Cu-ATSM are all being evaluated in patients. The Cu-ATSM images show the best contrast early after injection but these images are confounded by blood flow and their mechanism of localization is one step removed from the intracellular O2 concentration. FMISO has been criticized as inadequate because of its clearance characteristics, but its uptake after 2 hours is probably the most purely reflective of regional PO2 at the time the radiopharmaceutical is used. The FMISO images show less contrast than those of Cu-ATSM because of the lipophilicity and slower clearance of FMISO but attempts to increase the rate of clearance led to tracers whose distribution is contaminated by blood flow effects. For single-photon emission CT the only option is radioiodinated azamycin arabinosides, because the technetium agents are not yet ready for clinical evaluation. Rather than develop new and improved hypoxia agents, or even quibbling about the pros and cons of alternative agents, the nuclear medicine community needs to convince the oncology community that imaging hypoxia is an important procedure that can lead to improved treatment outcome. PMID:15693655

Rajendran, Joseph G; Krohn, Kenneth A

2005-01-01

39

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

Science.gov (United States)

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

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

2014-01-01

40

Human adenovirus type 9-induced rat mammary tumors.  

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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...

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

1991-01-01

 
 
 
 
41

Correlations between nuclear and fluorescent Imaging of mammary tumors in mice  

Science.gov (United States)

Progress with new imaging technologies permits the study of biological processes both in vivo and noninvasively. Two systems, a position-sensitive gamma camera and a cooled-CCD camera have been applied in this work. A C3H strain of mouse carrying the Mouse Mammary Tumor Virus (MMTV) was imaged using 800 nm Q-tracker fluorescent dots conjugated to a peptide targeting integrin ??? C a mammary marker for angiogenesis. We subsequently imaged with the gamma camera to detect low levels of ^125I distribution, and hence, the activity of a trans-membrane protein called the sodium iodide symporter (NIS) responsible for iodine transport. Preliminary results indicate that the biodistribution of the tagged Q-tracker dots and ^125I co-localize very early in seemingly normal mammary glands of infected MMTV mice, while in larger palpable tumors the Q-dot signals are less apparent in comparison with the^125I signal.

Carroll, Robin; Stone, John; Blue, Eric; Bradley, Eric; Qian, Jianguo; Saha, Margaret; Welsh, Robert

2008-10-01

42

Human adenovirus type 9-induced rat mammary tumors.  

Science.gov (United States)

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 immunohistochemical techniques established that benign fibroadenomas were derived from mammary fibroblasts (collagen type I- and vimentin-positive cells) and that malignant tumors were derived from myoepithelial cells (collagen type IV-, vimentin-, and muscle-specific actin-positive cells). The fact that mammary tumors were limited to female rats suggested that female hormones are essential for tumor growth and development. In this regard, ovariectomy of Ad9-infected female rats prevented tumor development, while subsequent diethylstilbestrol (DES) treatment elicited tumor formation. In addition, Ad9-infected and castrated male rats which received DES also developed mammary tumors. Established male mammary tumors regressed when DES treatment was stopped and reappeared after DES treatment was resumed. Together, these results indicate that estrogen is required for both initiation and maintenance of Ad9-induced mammary tumors. Southern blot analysis of high-molecular-weight tumor DNA showed that mammary tumor cells contained single or multiple integrated copies of the entire Ad9 genome. RNase protection experiments established that estrogen receptor as well as Ad9 E1a and E4 mRNAs were expressed in mammary tumors, but Ad9 E3 and, surprisingly, E1b mRNAs were not expressed at detectable levels. Images

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

1991-01-01

43

NMR characteristics of rat mammary tumors  

International Nuclear Information System (INIS)

12 rats were injected intradermally with 13762A rat mammary adenocarcinoma (1 x 10/sup 6/ cells). 3 rats died before completion of the study and 2 rat had tumor regression; the first 3 were excluded from data analysis. NMR imaging with a 1.5K gauss resistive magnet at 2, 3, 4, and 5 weeks after injection demonstrated increasing tumor mass. Saturation recovery (SR), inversion recovery (IR), and spin echo (SE) pulse sequence images and T/sub 1/ calculation were done for tumor characterization. (Tumor size was too small to identify at 2 weeks.) 3 rats were sacrificed after the last 3 imaging periods for histological studies, done to distinguish solid tumor mass from necrosis. Planimetry of tumor areas showed that as tumors grew in size, the ratio of necrotic area to area of solid tumor increased (week 3 = .3 +- .11; week 4 = .45 +- .07; week 5 = .51 +- 05); simultaneous calculated T/sub 1/ values also increased (week 3 = .35 +- .15; week 4 = .45 +- .06; week 5 = .42 +- 03). Qualitative NMR image T/sub 1/ values also increased as evidenced by progression of SR and IR tumor image intensity from very bright compared to the rest of the body at week 3 to less intense than other structures at week 5. These findings indicate that change in T/sub 1/ may be secondary to the pathophysiological change in the tumor (the increasing in necrosis, associated with increased free water). Thus, the range of T/sub 1/ values obtained in tumors in this study (and in previous studies) may be due to change in tumor physiology and anatomy. Careful correlation of histological with NMR data may allow ultimate use of NMR relaxation characteristics for determination of the physiological state of tumors

1984-06-05

44

Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis  

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Full Text Available Abnormal vasculature, termed tumor vessels, is a hallmark of solid tumors. The degree of angiogenesis is associated with tumor aggressiveness and clinical outcome. Therefore, exact quantification of tumor vessels is useful to evaluate prognosis. Furthermore, selective detection of newly formed tumor vessels within cancer tissues using specific markers raises the possibility of molecular targeted therapy via the inhibition of tumor angiogenesis. Nestin, an intermediate filament protein, is reportedly expressed in repair processes, various neoplasms, and proliferating vascular endothelial cells. Nestin expression is detected in endothelial cells of embryonic capillaries, capillaries of the corpus luteum, which replenishes itself by angiogenesis, and proliferating endothelial progenitor cells, but not in mature endothelial cells. Therefore, expression of nestin is relatively limited to proliferating vascular endothelial cells and endothelial progenitor cells. Nestin expression is also reported in blood vessels within glioblastoma, prostate cancer, colorectal cancer, and pancreatic cancer, and its expression is more specific for newly formed blood vessels than other endothelial cell markers. Nestin-positive blood vessels form smaller vessels with high proliferation activity in tumors. Knockdown of nestin in vascular endothelial cells suppresses endothelial cell growth and tumor formation ability of pancreatic cancers in vivo. Using nestin to more accurately evaluate microvessel density in cancer specimens may be a novel prognostic indicator. Furthermore, nestin-targeted therapy may suppress tumor proliferation via inhibition of angiogenesis in numerous malignancies, including pancreatic cancer. In this review article, we focus on nestin as a novel angiogenesis marker and possible therapeutic target via inhibition of tumor angiogenesis.

Yoko Matsuda

2013-01-01

45

Lysosomal enzyme activation in irradiated mammary tumors  

International Nuclear Information System (INIS)

Lysosomal enzyme activity of C3H mouse mammary tumors was measured quantitatively by a histochemical method. Following whole-body doses of 3600 rad or less no changes were observed in the lysosomal enzyme activity for 12 hr after the irradiation, but very large increases in acid phosphatase and ?-naphthylamidase activity were, however, observed 24 hr after irradiation. Significant increases in enzyme activity were detected 72 hr after a dose of 300 rad and the increases of enzyme activity were dose dependent over the range 300 to 900 rad. Testosterone (80 mg/kg) injected into mice 2 hr before irradiation (850 rad) caused a significant increase of lysosomal enzyme activity over and above that of the same dose of irradiation alone. If the tumor-bearing mice were given 95 percent oxygen/5 percent carbon dioxide to breathe for 8 min before irradiation the effect of 850 rad on lysosomal acid phosphatase was increased to 160 percent/that of the irradiation given alone. Activitation of lysosomal enzymes in mammary tumors is an important primary or secondary consequence of radiation

1976-01-01

46

Heavy ion radiation-induced mammary tumors and their prevention  

International Nuclear Information System (INIS)

The aim of this research is to find useful protectors against the incidence of the mammary tumors caused by heavy ion radiation. This year, we have continued the experiments to examine the protecting effect of amifostine against heavy ion radiation-induced mammary tumors. We have also begun the experiments to examine the protecting effect of cysteamine. (author)

2011-11-01

47

Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis  

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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.

Susan R. Ross

2010-09-01

48

TUMOR ANGIOGENESIS–IMPLICATIONS IN CANCER THERAPY  

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Full Text Available Neovascularization is a crucial component of cancer cell growth and progression. Cancer cells are dependent on blood vessels for growth and metastases. Angiogenesis is finely balanced by pro- and anti-angiogenetic factors. Under normal conditions, the balance leans toward the anti-angiogenetic phenotype. Hypoxia is the major element of the angiogenetic switch, which leads to overexpression of angiogenetic factors, mostly vascular endothelial growth factor (VEGF, favoring new vessel formation. VEGF appears to be one of the key players, and therefore current anti-angiogenetic strategies are mainly aimed at targeting the VEGF pathway. A variety of approaches to targeting VEGF and its signaling system have been developed: anti-VEGF antibodies such as bevacizumab (for metastatic colorectal, breast, lung and renal cancers and small molecules like sunitinib (for renal cancers and gastrointestinal stromal tumors, sorafenib (for hepatocellular and renal cell carcinoma, pazopanib and motesanib (for metastatic breast cancer.

M. Marinca

2010-05-01

49

Classification and grading of canine malignant mammary tumors  

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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.

Abbas Tavasoly

2013-03-01

50

Induction of mammary epithelial hyperplasias and mammary tumors in transgenic mice expressing a murine mammary tumor virus/activated c-src fusion gene.  

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Activation of the c-Src tyrosine kinase has been implicated as an important step in the induction of mammary tumors in both mice and humans. To directly assess the effect of mammary gland-specific expression of activated c-Src, we established transgenic mice that carry a constitutively activated form of c-src under transcriptional control of the murine mammary tumor virus long terminal repeat. Female mice derived from several independent transgenic lines lactate poorly as a consequence of an ...

Webster, M. A.; Cardiff, R. D.; Muller, W. J.

1995-01-01

51

Quantitative of murine mammary tumor virus-related RNA in mammary tissues of low- and high-mammary-tumor-incidence mouse strains.  

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Lactating mammary glands and hormonally induced mammary tumors of BALB/c mice from three geographically separated breeding colonies were examined by molecular hybridization, using murine mammary tumor virus (MuMTV) cDNA representing the entire viral genome to determine the amount of MuMTV-related RNA expressed in these tissues. The RNA extracted from these tissues by the classical sodium dodecyl sulfate-pronase, phenol-chloroform procedure (method 1) contained barely detectable levels of MuMT...

Marcus, S. L.; Smith, S. W.; Sarkar, N. H.

1981-01-01

52

Suppression of mouse mammary tumor proviral DNA and protooncogene expression: association with nutritional regulation of mammary tumor development.  

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Chronic energy intake restriction (CEIR) reduces mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice. Fewer than 10% of C3H/Ou mice developed mammary tumors during 88 wk of study when subjected to CEIR regardless of calorie source (fat vs. carbohydrate). By contrast, 100% of mice fed ad libitum diets relatively high in fat or carbohydrate or a commercial diet developed tumors by 35-40 wk. MMTV proviral DNA transcription was shown to be activated in spleen, liver, lung, kidn...

Chen, R. F.; Good, R. A.; Engelman, R. W.; Hamada, N.; Tanaka, A.; Nonoyama, M.; Day, N. K.

1990-01-01

53

Heavy ion radiation-induced mammary tumors and their prevention  

International Nuclear Information System (INIS)

The aim of this research theme is to investigate whether heavy ion radiation cause mammary tumors in rats of lactation period and to find useful protectors against the incidence of the mammary tumors. This year, we have continued the irradiation experiment to study the radiation dose dependent mammary tumor formation. We have totaly irradiated 23-24 rats for each group (0.1, 0.25, 0.5, 1.0, 2.0 Gy). It takes at least one year to get the results. (author)

2009-06-01

54

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 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

1989-01-01

55

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)

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

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

56

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

Science.gov (United States)

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

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

2014-01-01

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Malignant mammary tumor in female dogs: environmental contaminants  

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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 insec...

2010-01-01

58

Malignant mammary tumor in female dogs: environmental contaminants  

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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 ...

2010-01-01

59

Protein Kinase C beta in the tumor microenvironment promotes mammary tumorigenesis  

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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.

GinaMSizemore

2014-04-01

60

Protein Kinase C Beta in the Tumor Microenvironment Promotes Mammary Tumorigenesis  

Science.gov (United States)

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 with diminished collagen deposition. 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.

Wallace, Julie A.; Pitarresi, Jason R.; Sharma, Nandini; Palettas, Marilly; Cuitino, Maria C.; Sizemore, Steven T.; Yu, Lianbo; Sanderlin, Allen; Rosol, Thomas J.; Mehta, Kamal D.; Sizemore, Gina M.; Ostrowski, Michael C.

2014-01-01

 
 
 
 
61

Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.  

Science.gov (United States)

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease. PMID:14517400

Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

2003-01-01

62

In vivo Bioluminescent Imaging of Mammary Tumors Using IVIS Spectrum  

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4T1 mouse mammary tumor cells can be implanted sub-cutaneously in nu/nu mice to form palpable tumors in 15 to 20 days. This xenograft tumor model system is valuable for the pre-clinical in vivo evaluation of putative antitumor compounds.

Lim, Ed; Modi, Kshitij D.; Kim, Jaebeom

2009-01-01

63

Exploring the role of CHI3L1 in “pre-metastatic” lungs of mammary tumor-bearing mice  

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Full Text Available Elevated levels of chitinase-3-like-1 (CHI3L1 are associated with poor prognosis, shorter recurrence-free intervals and low survival in breast cancer patients. Breast cancer often metastasizes to the lung. We hypothesized that molecules expressed in the “pre-metastatic” lung microenvironment could support the newly immigrant tumor cells by providing growth and angiogenic factors. Macrophages are known to play an important role in tumor growth by releasing pro-angiogenic molecules. Using mouse mammary tumor models, we have previously shown that during neoplastic progression both the mammary tumor cells and splenic macrophages from tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice. However, the role of CHI3L1 in inducing angiogenesis by macrophages at the pulmonary microenvironment to support newly arriving breast cancer cells is not yet known. In this study, we determined the expression of CHI3L1 in bronchoalveolar lavage macrophages and interstitial macrophages in regulating angiogenesis that could support the growth of newly immigrant mammary tumor cells into the lung. Here we show that in vitro treatment of pulmonary macrophages with recombinant murine CHI3L1 resulted in enhanced expression of pro-angiogenic molecules including CCL2, CXCL2 and MMP-9. We and others have previously shown that inhibition of CHI3L1 decreases the production of angiogenic molecules. In this study, we explored if in vivo administration of chitin microparticles has an effect on the expression of CHI3L1 and pro-angiogenic molecules in the lungs of mammary tumor-bearing mice. We show that treatment with chitin microparticles decreases the expression of CHI3L1 and pro-angiogenic molecules in the “metastatic” lung. These studies suggest that targeting CHI3L1 may serve as a potential therapeutic agent to inhibit angiogenesis and thus possibly tumor growth and metastasis.

VijayaIragavarapu-Charyulu

2013-12-01

64

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development  

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Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting i...

Finke, Daniela; Luther, Sanjiv A.; Acha-orbea, Hans

2003-01-01

65

Heterogeneity of estrogen binding sites in mammary tumors.  

Science.gov (United States)

This paper provides a brief summary of our recent work on the heterogeneity of estradiol binding sites in mammary tumors of the mouse and human. Mammary tumors from both species contain the classical estrogen receptor and a second site(s) which we call type II. These type II sites are found in the cytoplasmic and nuclear compartments of both tumors, and can interfere with the measurement of estrogen receptors. The function of type II sites is not known; however, an assessment of these sites in conjunction with an accurate measurement of the estrogen receptor may provide a clearer picture of the true hormone dependence of breast tumors. PMID:6871482

Clark, J H; Watson, C S; Markaverich, B M; Syne, J S; Panko, W B

1983-01-01

66

COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis  

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Tumor growth depends on nutrients and oxygen supplied by the vasculature through angiogenesis. Here, we show that the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a member of the nuclear receptor family, is a major angiogenesis regulator within the tumor microenvironment. Conditional ablation of COUP-TFII in adults severely compromised neoangiogenesis and suppressed tumor growth in xenograft mouse models. In addition, tumor growth and tumor metastasis were also imp...

Qin, Jun; Chen, Xinpu; Xie, Xin; Tsai, Ming-jer; Tsai, Sophia Y.

2010-01-01

67

Dual role of tumor necrosis factor-alpha in angiogenesis.  

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The role of tumor necrosis factor-alpha (TNF; cachectin) in angiogenesis has been controversial. In vitro TNF inhibits proliferation of endothelial cells (EC) whereas in the cornea it appears to stimulate vessel growth. The authors tested TNF in their recently developed disc angiogenesis system (DAS), designed to measure the proliferation of microvessels. The DAS, implanted subcutaneously in mice, was either fitted with a central pellet containing mouse recombinant TNF (mrTNF), or exposed to ...

Fajardo, L. F.; Kwan, H. H.; Kowalski, J.; Prionas, S. D.; Allison, A. C.

1992-01-01

68

Malignant mammary tumor in female dogs: environmental contaminants  

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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.

Bissacot Denise Z

2010-06-01

69

Prolactin effects on the dietary regulation of mouse mammary tumor virus proviral DNA expression.  

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Chronic energy-intake restriction inhibits mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice by greater than 90%. We have shown that associated with suppression of mammary tumorigenesis there is a reduction or inhibition of circulating prolactin, MMTV particles expressed, and MMTV mRNA transcription in mammary glands (and in most organs tested). To understand the concerted action of prolactin, energy-consumption level, and MMTV on inducing mammary tumors, experiments were...

1990-01-01

70

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

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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.

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

71

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

1986-01-01

72

Equine estrogen-induced mammary tumors in rats  

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Long-term hormone replacement therapy is associated with an increased risk of breast, ovarian and endometrial cancers in women. Equine estrogens are a principal component of hormone replacement therapy; however, their tumorigenic potential toward mammary tissue and reproductive organs has not been extensively explored. A pellet containing equilin was inserted under the skin of female ACI rats and the development of mammary tumors was monitored. Histological examination revealed premalignant l...

Okamoto, Yoshinori; Liu, Xiaoping; Suzuki, Naomi; Okamoto, Kanako; Kim, Hyo Jeong; Santosh Laxmi, Y. R.; Sayama, Kazutoshi; Shibutani, Shinya

2010-01-01

73

Collagen density promotes mammary tumor initiation and progression  

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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.

Knittel Justin G

2008-04-01

74

Occurrence of mammary tumors in beagls given radium-226  

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A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with {sup 226}Ra 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 {sup 226}Ra 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 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 {yields} 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.

Bruenger, F.W.; Lloyd, R.D.; Miller, S.C.; Taylor, G.N.; Angus, W.; Huth, D.A. [Univ. of Utah, Salt Lake City, UT (United States)

1994-06-01

75

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 "2"2"6Ra 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 "2"2"6Ra 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 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

1994-06-01

76

IL-1 is required for tumor invasiveness and angiogenesis  

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Here, we describe that microenvironmental IL-1? and, to a lesser extent, IL-1? are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1? knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1? KO mice. The...

2003-01-01

77

Occurrence of mammary tumors in beagles given radium-226.  

Science.gov (United States)

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 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. Results of this study are potentially useful in understanding risks of radium-induced breast cancers in humans. PMID:8184018

Bruenger, F W; Lloyd, R D; Miller, S C; Taylor, G N; Angus, W; Huth, D A

1994-06-01

78

Notch Signaling in Developmental and Tumor Angiogenesis  

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The discovery that Notch, a key regulator of cell fate determination, is functional in the vasculature has greatly improved our understanding of differentiation and specialization of vessels. Notch signaling has been proven to be critical for arterial specification, sprouting angiogenesis, and vessel maturation. In newly forming vascular sprouts, Notch promotes the distinction between the leading “tip” endothelial cell and the growing “stalk” cell, the endothelial cells that eventuall...

Kofler, Natalie M.; Shawber, Carrie J.; Kangsamaksin, Thaned; Reed, Hasina Outtz; Galatioto, Josephine; Kitajewski, Jan

2011-01-01

79

Phyllodes malignant mammary tumors:communication of three cases  

International Nuclear Information System (INIS)

Three cases of phyllode malignant mammary tumors were studied in the Anatomo-Pathology Chair of the Montevideo, Uruguay.The discussion covered epidemiology, morphologic staging and biological significance of phyllode tumor within the broader spectrum of libro-epithelial breast tumors.An overview of literature shows that histo-pathological criteria recommended by world Health Organization(WHO) are the ones which determine the behaviour of phyllode mammary tumors, wheter bening, malignant of borderline.Prognostic factors of metastases are those involved in stroma overgrowth, anaplasia high mitotic index and infiltrative edge of tumor.None of the clinical aspects,including tumor size, are significant from the viewpoint of prognosis.Efective treatment is broad extended surgical excision (adequate margins),mastectomy being reserved for large tummors that are borderline, malignant or recurrent

2003-01-01

80

Comparative expression pathway analysis of human and canine mammary tumors  

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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 represe...

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

2009-01-01

 
 
 
 
81

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

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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.

Stanis?aw Szala

2009-12-01

82

[Angiogenesis and immune suppression: yin and yang of tumor progression?].  

Science.gov (United States)

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. PMID:20009124

Szala, Stanis?aw

2009-01-01

83

Induction of mouse mammary tumor virus RNA in mammary tumors of BALB/c mice treated with urethane, x-irradiation, and hormones  

International Nuclear Information System (INIS)

The involvement of mouse mammary tumor virus (MTV) in the development of mammary tumors of nonviral etiology in BALB/c mice was studied by measuring the levels of MTV RNA, MTV DNA, and MTV proteins in spontaneously arising and hormally, chemically, and/or physically induced mammary tumors of BALB/c females. The following results were obtained: (1) spontaneous mammary tumors contained very low levels of MTV RNA; 4 x 10-6% of the cytoplasmic RNA was MTV RNA. No MTV proteins could be demonstrated by using sensitive radioimmunoassays for MTV proteins p27 and gp52. (2) Mammary tumors induced by treatments with urethane or x-irradiation alone contained higher levels of MTV RNA; these tumors contained 3- and 19-fold more MTV RNA, respectively, compared with spontaneous mammary tumors. (3) Mammary tumors induced by combined treatment with urethane and x-irradiation expressed high levels of MTV RNA in the mammary tumors; a 1,724-fold increase in MTV RNA content compared with spontaneous mammary tumors was observed. However, very low levels of MTV proteins gp52 and p27 were detected, suggesting some kind of impairment at the translation of MTV RNA. MTV RNA was also induced by this treatment in mammary glands and spleens, but not in the livers of tumor-bearing animals. (4) BALB/c females continuously exposed to prolactin contained high levels of MTV RNA and MTV proteins in stimulated mammary glands and in the hormonally induced mammary tumors. These findings suggest that MTV is not responsible for the maintenance and probably also not for the development of all murine mammary cancers

1979-01-01

84

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

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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.

VijayaIragavarapu-Charyulu

2014-02-01

85

Feasibility for inhibiting tumor metastasis with Chinese herbal medicines as angiogenesis inhibitors  

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Full Text Available Abstract: Anti-angiogenesis is one of the important ways to control tumor growth and metastasis, and searching for anti-angiogenesis herbs targeting tumor angiogenesis has become a hot topic in both basic and clinical research for tumor. Utilizing the traditional Chinese medicine theory, authors of this article discussed the feasibility and research of anti-angiogenesis effect of Chinese medicine on tumor. To develop new drugs inhibiting tumor angiogenesis from the Chinese native herbal medicine has an extremely vital significance in blocking tumor invasion and metastasis, as well as improving the patients' prognosis and their survival rates.

Huan-rong LI

2007-07-01

86

Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors  

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Id proteins bind basic helix–loop–helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus–neu mice were bred with Id1–/–Id3+/– mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mamma...

2003-01-01

87

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

Science.gov (United States)

Semaphorins are a large family of molecules involved in axonal guidance during the development of the nervous system and 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 through ?1?1integrins. SEMA7A has been shown to promote monocyte chemotaxis and induce them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in a murine model of breast cancer. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4), and that peritoneal elicited macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to those derived from normal mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecule CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2/MIP-2 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 mammary tumors. We postulate that SEMA7A in mammary carcinomas may skew monocytes into a pro-tumorigenic phenotype to support tumor growth. SEMA7A could prove to be valuable in establishing new research avenues toward unraveling important tumor-host immune interactions in breast cancer patients. PMID:24550834

Garcia-Areas, Ramon; Libreros, Stephania; Amat, Samantha; Keating, Patricia; Carrio, Roberto; Robinson, Phillip; Blieden, Clifford; Iragavarapu-Charyulu, Vijaya

2014-01-01

88

Proposed classification of the feline "complex" mammary tumors as ductal and intraductal papillary mammary tumors.  

Science.gov (United States)

When compared with the canine species, feline mammary tumors (FMTs) are much less heterogeneous, with a predominance of simple malignant neoplasm. Benign FMTs are rare, and it is unclear if complex and mixed tumors exist in the feline. In this study, we selected for immunohistochemical analyses 12 FMTs that had unusual histologic features. A group of 8 (2 benign and 6 malignant) FMTs showed a biphasic epithelial/myoepithelial population and a very regular cord-like distribution in a "Chinese lettering" pattern, within ectatic ducts. A second group (2 benign and 2 malignant) had an intraductal epithelial papillary growth pattern with a basally located monolayer of myoepithelial cells and a supporting fibrovascular stroma. The myoepithelial component always produced a standard immunohistochemical signature. All malignancies were grade I, and the subjects were all alive at 1 year postdiagnosis. On the basis of their morphology, we propose that they be classified as feline ductal adenoma/carcinoma and feline intraductal papillary adenoma/carcinoma, respectively. They overlap with their canine counterparts and lack the typical myoepithelial differentiation patterns seen in canine complex neoplasms, and therefore, the term complex should be avoided in felines. This study will add new information on FMT classification and be useful for prognostic studies. PMID:23735615

Zappulli, V; Caliari, D; Rasotto, R; Ferro, S; Castagnaro, M; Goldschmidt, M

2013-11-01

89

Comparative expression pathway analysis of human and canine mammary tumors  

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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.

Marconato Laura

2009-03-01

90

Radiation response of autochthonous mammary tumors in SHN mice  

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The radiation response of spontaneously induced autochthonous mammary tumors was studied in SHN mice, a strain developed at the National Cancer Center. Tumors were mostly adenocarcinomas and grew with an average volume-doubling time of 3.0 days. When tumors reached a size of 8 -- 10 mm in diameter, they were given a single, local irradiation with 6 MVp X-rays generated by a medical linear accelerator. With radiation doses lower than 2 krad, the tumors regrew after a temporary interruption. Surviving fractions of tumor cells in situ were estimated from the tumor regrowth times, yielding a survival curve with D/sub 0/ = 480 rad for n = 2. With 6.5 krad, tumor regression was very rapid: the volume-halving time was 1.7 days, and temporary tumor control was achieved. This rapid radiation response was not necessarily correlated with the radiosensitivity of tumor cells and is thought to be related to the structure of the mammary tumor mass. A disadvantage of this mouse strain was its high multiple tumor incidence which interfered with the observation of tumor control for adequate periods after irradiation.

Tanooka, H.; Tokuzen, R.; Tanaka, K. (National Cancer Center, Tokyo (Japan). Research Inst.)

1981-08-01

91

Radiation response of autochthonous mammary tumors in SHN mice  

International Nuclear Information System (INIS)

The radiation response of spontaneously induced autochthonous mammary tumors was studies in SHN mice, a strain developed at the National Cancer Center. Tumors were mostly adenocarcinomas and grew with an average volume-doubling time of 3.0 days. When tumors reached a size of 8 -- 10 mm in diameter, they were given a single, local irradiation with 6 MVp X-rays generated by a medical linear accelerator. With radiation doses lower than 2 krad, the tumors regrew after a temporary interruption. Surviving fractions of tumor cells in situ were estimated from the tumor regrowth times, yielding a survival curve with D"0 = 480 rad for n = 2. With 6.5 krad, tumor regression was very rapid: the volume-halving time was 1.7 days, and temporary tumor control was achieved. This rapid radiation response was not necessarily correlated with the radiosensitivity of tumor cells and is thought to be related to the structure of the mammary tumor mass. A disadvantage of this mouse strain was its high multiple tumor incidence which interfered with the observation of tumor control for adequate periods after irradiation. (author)

1981-01-01

92

ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis.  

Science.gov (United States)

Tumor suppressors with extracellular function are likely to have advantages as targets for cancer therapy, but few are known. Here, we focused on angiopoietin-like 4 (ANGPTL4), which is a secreted glycoprotein involved in lipoprotein metabolism and angiogenesis, is methylation-silenced in human cancers, but has unclear roles in cancer development and progression. We found a deletion mutation in its coiled-coil domain at its N-terminal in human gastric cancers, in addition to hypermethylation of the ANGPTL4 promoter CpG islands. Forced expression of wild-type ANGPTL4, but not ANGPTL4 with the deletion, at physiological levels markedly suppressed in vivo tumorigenicity and tumor angiogenesis, indicating that the latter caused the former. Tumor-derived ANGPTL4 suppressed in vitro vascular tube formation and proliferation of human umbilical vascular endothelial cells, partly due to suppression of ERK signaling. These showed that ANGPTL4 is a genetically and epigenetically inactivated secreted tumor suppressor that inhibits tumor angiogenesis. PMID:23686315

Okochi-Takada, E; Hattori, N; Tsukamoto, T; Miyamoto, K; Ando, T; Ito, S; Yamamura, Y; Wakabayashi, M; Nobeyama, Y; Ushijima, T

2014-04-24

93

Mouse mammary tumor virus/v-Ha-ras transgene-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome?4  

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Hybrid mice carrying oncogenic transgenes afford powerful systems for investigating loss of heterozygosity (LOH) in tumors. Here, we apply this approach to a neoplasm of key importance in human medicine: mammary carcinoma. We performed a whole genome search for LOH using the mouse mammary tumor virus/v-Ha-ras mammary carcinoma model in female (FVB/N × Mus musculus castaneus)F1 mice. Mammary tumors developed as expected, as well as a few tumors of a second type (uterine leiomyosarcoma) not pr...

Radany, Eric H.; Hong, Karen; Kesharvarzi, Sima; Lander, Eric S.; Bishop, J. Michael

1997-01-01

94

An approach to malignant mammary phyllodes tumors detection  

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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...

2009-01-01

95

Experimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors.  

Science.gov (United States)

Epidemiological and in vitro data have not provided conclusive evidence concerning the involvement of thyroid hormones (THs) on mammary carcinogenesis. We used an in vivo model to assess the relationship between THs, adipose tissue and breast cancer development. Female Sprague?Dawley rats were treated with a dose of 7,12-dimethylbenz(a)anthracene (15 mg/rat) at 55 days of age and were then divided into four experimental groups: hypothyroid rats (HypoT, 0.01% 6-N-propyl-2-thiouracil in drinking water), untreated control (EUT); hyperthyroid rats (HyperT, 0.25 mg/kg/day T4 s.c.) and vehicle-treated control rats. The latency of tumor appearance and the incidence and progression of tumors were determined. At sacrifice, blood samples were collected for hormone determinations and samples of tumor and mammary glands were obtained for immunohistological studies. HypoT rats had retarded growth and an increase in mammary fat. The latency was longer (pprolactin and progesterone were observed. However, circulating estradiol (E2) was significantly lower in HypoT and HyperT rats. Serum leptin levels were reduced in HypoT rats even though the abdominal fat mass was similar in all groups. To note, the leptin level was higher in HypoT rats that developed mammary tumors than the level in non-tumoral HypoT rats. In conclusion, hypothyroidism altered animal growth, breast morphology, body composition, leptin secretion and serum E2 enhancing apoptosis and, consequently, retarding mammary carcinogenesis in rats. PMID:23912381

López-Fontana, Constanza Matilde; Sasso, Corina Verónica; Maselli, María Eugenia; Santiano, Flavia Eliana; Semino, Silvana Noemí; Cuello Carrión, Fernando Darío; Jahn, Graciela Alma; Carón, Rubén Walter

2013-10-01

96

Identification of Radiation Specific Gene Signatures in Rat Mammary Tumors  

International Nuclear Information System (INIS)

It is well accepted that cancer arises in a multi-step fashion and that environmental exposures to physical and chemical agents are major etiological factors. Exposure to carcinogens plays a major and probably in etiological role in the initiation of this human disease. In experimental animal models, ionizing radiation induces mammary carcinomas both in vivo and in vitro, however, the cellular and molecular mechanisms of radiation induced carcinogenesis are not known. In this paper, we compare to gene expression patterns by cDNA microarray in gamma-radiation or DMBA induced rat mammary tumors and found that radiation specific gene expression signature was present in radiation induced breast cancer

2006-11-02

97

Identification of Radiation Specific Gene Signatures in Rat Mammary Tumors  

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It is well accepted that cancer arises in a multi-step fashion and that environmental exposures to physical and chemical agents are major etiological factors. Exposure to carcinogens plays a major and probably in etiological role in the initiation of this human disease. In experimental animal models, ionizing radiation induces mammary carcinomas both in vivo and in vitro, however, the cellular and molecular mechanisms of radiation induced carcinogenesis are not known. In this paper, we compare to gene expression patterns by cDNA microarray in gamma-radiation or DMBA induced rat mammary tumors and found that radiation specific gene expression signature was present in radiation induced breast cancer.

Lee, Yoon-Jin; Lee, Hae-June; Kang, Chang-Mo; Bae, Sang-Woo; Jang, Ja-June; Lee, Seung-Sook; Lee, Yun-Sil [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Jang, Ja-June [Seoul National Univ., Seoul (Korea, Republic of)

2006-07-01

98

Murine mammary tumor cells with a claudin-low genotype  

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Full Text Available Abstract Background Molecular classification of human breast cancers has identified at least 5 distinct tumor subtypes; luminal A, luminal B, Her2-enriched, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of luminal differentiation markers and claudins 3, 4 and 7 and high levels of mesenchymal markers. Claudin-low tumors have a reported prevalence of 7-14% and these tumors have a poor prognosis. Results In this study we report the characterization of several cell lines established from mammary tumors that develop in MTB-IGFIR transgenic mice. Two lines, RM11A and RJ348 present with histological features and gene expression patterns that resemble claudin-low breast tumors. Specifically, RM11A and RJ348 cells express high levels of the mesenchymal genes Zeb1, Zeb2, Twist1 and Twist2 and very low levels of E-cadherin and claudins 3, 4 and 7. The RM11A and RJ348 cells are also highly tumorigenic when re-introduced into the mammary fat pad of mice. Conclusions Mammary tumor cells established from MTB-IGFIR transgenic mice can be used as in vitro and in vivo model systems to further our understanding of the poorly characterized, claudin-low, breast cancer subtype.

Siwicky Megan D

2011-08-01

99

Cancer stem cells and tumor angiogenesis  

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Cancer stem cells (CSCs) have been identified in several human solid and hematological tumors. They are able to initiate tumor formation and metastasis and express specific cell surface markers. CSC tend to be more resistant to chemotherapeutic agents and radiation therapy than more mature cell types from the same tissue because of increased expression of antiapoptotic proteins. In this context, the development of agents that eliminate or control CSC may be an effective strategy for cancer pr...

2012-01-01

100

Inhibition of tumor angiogenesis by oral etoposide  

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The chemotherapeutic agent etoposide is a topoisomerase II inhibitor widely used for cancer therapy. Low-dose oral etoposide, administered at close regular intervals, has potent anti-tumor activity in patients who are refractory to intravenous etoposide; however, the mechanism remains unclear. Since endothelial cells may be more sensitive than tumor cells to chemotherapy agents, we determined the effects of etoposide alone and in combination with oral cyclooxygenase-2 inhibitors and peroxisom...

Panigrahy, Dipak; Kaipainen, Arja; Butterfield, Catherine E.; Chaponis, Deviney M.; Laforme, Andrea M.; Folkman, Judah; Kieran, Mark W.

2010-01-01

 
 
 
 
101

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

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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...

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

1997-01-01

102

Inhibition of tumor angiogenesis by globotriaosylceramide immunotargeting  

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Current antiangiogenic immunotherapeutic strategies mainly focus on the blockade of circulating cytokines or receptors that are overexpressed by endothelial cells. We proposed globotriaosylceramide (Gb3) as a viable alternative target for antiangiogenic therapies. In this setting, we developed an anti-Gb3 antibody and validated its therapeutic efficacy in metastatic tumor models.

Birkle?, Ste?phane; Desselle, Ariane; Chaumette, Tanguy; Gaugler, Marie-he?le?ne; Cochonneau, Denis; Fleurence, Julien; Dubois, Nolwenn; Hulin, Philippe; Aubry, Jacques; Paris, Franc?ois

2013-01-01

103

Estrogen receptors in canine mammary tumors.  

Science.gov (United States)

The presence of estrogen receptor in 67 canine mammary lesions was correlated with pathological features of the disease. All tissue specimens were analyzed for estrogen receptor content by a sucrose gradient ultracentrifugation method previously used in analyzing human breast cancer cytosols. Pathological features of the tissues were assessed by a veterinary pathologist without knowledge of results of estrogen receptor analysis. Sixty-two (92.5%) of the tissue samples analyzed were classified as epithelial neoplastic lesions, and 38 of these (61.3%), including 24 adenocarcinomas, were estrogen receptor for positive (i.e., estrogen receptor concentration equal to or greater than 10 fmol/mg cytosol protein). All five of the nonepithelial neoplastic lesions were estrogen receptor negative. Canine and human breast cancers share common histological types and have similar biological behavior. If a significant percentage of canine mammary cancer is also estrogen dependent, the dog may be a useful model for hormonal studies and for the development of models of endocrine therapy for human breast cancer. PMID:7074608

MacEwen, E G; Patnaik, A K; Harvey, H J; Panko, W B

1982-06-01

104

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

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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 ...

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

1981-01-01

105

Mouse Mammary Tumor Virus Proviral Sequences Congenital to C3H/Sm Mice Are Differentially Hypomethylated in Chemically Induced, Virus-Induced, and Spontaneous Mammary Tumors  

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C3H/Sm mice have lost the exogenous milk-borne mouse mammary tumor virus (MMTV) characteristic of the C3H strain and have a very low (1.5%) incidence of spontaneous mammary tumors, yet they are highly susceptible to mammary carcinogenesis by either chemical carcinogens or infection with the milk-borne virus. We have analyzed the MMTV proviral DNA content of normal tissues and of spontaneous, virus-induced, and chemically induced mammary tumors by restriction endonuclease digestion and Souther...

1982-01-01

106

Tumor Angiogenesis and Vascular Patterning: A Mathematical Model  

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Understanding tumor induced angiogenesis is a challenging problem with important consequences for diagnosis and treatment of cancer. Recently, strong evidences suggest the dual role of endothelial cells on the migrating tips and on the proliferating body of blood vessels, in consonance with further events behind lumen formation and vascular patterning. In this paper we present a multi-scale phase-field model that combines the benefits of continuum physics description and the capability of tra...

Travasso, Rui D. M.; Corvera Poire?, Eugenia; Castro, Mario; Rodrguez-manzaneque, Juan Carlos; Herna?ndez-machado, A.

2011-01-01

107

Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types.  

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The p75 and p110 isoforms of the CUX1 homeodomain protein are overexpressed in breast tumors and cancer cell lines. To assess and compare the ability of these short CUX1 isoforms in driving mammary tumor development, we used site-specific transgenesis into the Hprt locus to generate transgenic mice expressing p75 or p110 CUX1 under the control of the mouse mammary tumor virus-long terminal repeat. We report that mammary tumors developed after a long latency period, and although various histopathologies were observed, the proportion of adenosquamous carcinomas was significantly higher in p75 CUX1 than in p110 CUX1 transgenic mice. Metastasis to the lung was observed in three p75 CUX1 transgenic mice. Comparisons between tumors and adjacent normal mammary glands revealed that transgenes were overexpressed in most but not all tumors, yet in all cases tested, CUX1 DNA binding was increased, suggesting that both higher expression and changes in post-translational modifications can contribute to stimulate transgene activity. Interestingly, higher expression of erbB2 mRNA was seen in most tumors, not only solid carcinomas but also adenosquamous carcinomas, whereas higher expression of various Wnt genes and activation of the beta-catenin pathway was observed primarily in adenosquamous carcinomas. Activation of erbB2 expression appeared to represent a cooperating event that occurred independently of CUX1. In contrast, chromatin immunoprecipitation, short hairpin RNA-mediated knockdown, and reporter assays established that CUX1 is involved in the transcriptional regulation of several Wnt genes. Together, these results support the notion that oncogenic activity of CUX1 can facilitate the establishment of a Wnt/beta-catenin autocrine loop. PMID:19738070

Cadieux, Chantal; Kedinger, Valérie; Yao, Lu; Vadnais, Charles; Drossos, Maria; Paquet, Marilène; Nepveu, Alain

2009-09-15

108

In-vivo NIR autofluorescence imaging of rat mammary tumors  

Science.gov (United States)

We investigate in vivo detection of mammary tumors in a rat model using autofluorescence imaging in the red and far-red spectral regions. The objective was to explore this method for non-invasive detection of malignant tumors and correlation between autofluorescence properties of tumors and their pathologic status. Eighteen tumor-bearing rats, bearing eight benign and seventeen malignant tumors were imaged. Autofluorescence images were acquired using spectral windows centered at 700-nm, 750-nm and 800-nm under laser excitation at 632.8-nm and 670- nm. Intensity in the autofluorescence images of malignant tumors under 670-nm excitation was higher than that of the adjacent normal tissue. whereas intensity of benign tumors was lower compared to normal tissue.

Fournier, Laure S.; Lucidi, Vincenzo; Berejnoi, Kirill; Miller, Theodore; Demos, Stavros G.; Brasch, Robert C.

2006-07-01

109

Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth  

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Full Text Available Abstract Background Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD tumors grow only in the presence of progestins, whereas hormone independent (HI variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI HD cells can induce HD tumor growth. Methods Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p Conclusions Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.

Lanari Claudia

2010-06-01

110

Matrix metalloproteinases and their inhibitors in canine mammary tumors  

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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.

Bradaschia Alice

2011-07-01

111

Type-2 pericytes participate in normal and tumoral angiogenesis.  

Science.gov (United States)

Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identification of the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. We examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double-transgenic Nestin-GFP/NG2-DsRed mice, we identified two pericyte subsets. We found that Nestin-GFP(-)/NG2-DsRed(+) (type-1) and Nestin-GFP(+)/NG2-DsRed(+) (type-2) pericytes attach to the walls of small and large blood vessels in vivo; in vitro, type-2, but not type-1, pericytes spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 pericytes were recruited during its angiogenesis. As inhibition of angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses. PMID:24788248

Birbrair, Alexander; Zhang, Tan; Wang, Zhong-Min; Messi, Maria Laura; Olson, John D; Mintz, Akiva; Delbono, Osvaldo

2014-07-01

112

A hypothesis to relate salivary tumors with mammary and prostate neoplasias  

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Salivary, mammary and prostate glands are sex hormone-dependent organs sharing common aspects in structure, hormonal responsiveness and tumor histopathology. Salivary tumors (especially the malignant types) are not as frequent as mammary and prostate neoplasias. Hence, prognosis of some salivary tumors is not always efficient. Here, we review the oncology of salivary gland and its putative relation to breast/prostate tumors.

Actis, Adriana B.

2005-01-01

113

Effect of Hedyotis Diffusa Willd extract on tumor angiogenesis.  

Science.gov (United States)

Inhibition of tumor angiogenesis has become an attractive target of anticancer chemotherapy. However, drug resistance and cytotoxicity against non-tumor associated endothelial cells limit the long-term use and the therapeutic effectiveness of angiogenesis inhibitors, thus increasing the necessity for the development of multi-target agents with minimal side effects. Traditional Chinese medicine (TCM) formulas, which have relatively fewer side effects and have been used clinically to treat various types of diseases, including cancer, for thousands of years, are considered to be multi-component and multi-target agents exerting their therapeutic function in a more holistic way. Hedyotis Diffusa Willd (EEHDW) has long been used as an important component in several TCM formulas to treat various types of cancer. Although recently we reported that EEHDW promotes cancer cell apoptosis via activation of the mitochondrial-dependent pathway, the precise mechanism of its tumoricidalactivity still remains to be clarified. In the present study, we investigated the angiogenic effects of the ethanol extract of EEHDW. Cell cycle analysis was perfomed using flow cytometry. Cell viability was analyzed using MTT assay. We found that EEHDW inhibited angiogenesis in vivo in chick embryo chorioallantoic membrane (CAM). In addition, we observed that EEHDW dose- and time-dependently inhibited the prolife-ration of human umbilical vein endothelial cells (HUVEC) by blocking the cell cycle G1 to S progression. Moreover, EEHDW inhibited the migration and tube formation of HUVECs. Furthermore, EEHDW treatment down-regulated the mRNA and protein expression levels of VEGF-A in HT-29 human colon carcinoma cells and HUVECs. Our findings suggest that inhibiting tumor angiogenesis is one of the mechanisms by which EEHDW is involved in cancer therapy. PMID:21887465

Lin, Jiumao; Wei, Lihui; Xu, Wei; Hong, Zhenfeng; Liu, Xianxiang; Peng, Jun

2011-01-01

114

Dll4-Notch signaling as a therapeutic target in tumor angiogenesis  

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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.

Kuhnert Frank

2011-09-01

115

Caveolin-1 expression is elevated in claudin-low mammary tumor cells  

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Full Text Available Abstract Background Caveolin-1 is a scaffolding protein found in plasma membrane invaginations known as caveolae. Caveolin-1 can regulate a number of intracellular processes such as signal transduction, cholesterol metabolism and vesicular transport. With respect to breast cancer caveolin-1 has been observed in both tumor cells and stromal cells surrounding tumors however most of the recent research has focused on how the loss of caveolin-1 in the stromal cells surrounding the tumor alters the tumor microenvironment. Methods Caveolin-1 expression was evaluated in (1 mammary tumors induced by the transgenic overexpression of the type I insulin-like growth factor receptor (IGF-IR, (2 mammary tumors that became independent of IGF-IR signalling and acquired a claudin-low genotype, (3 two murine mammary epithelial tumor cell lines and (4 two murine mammary claudin-low tumor cell lines. Results We found that mammary tumors induced by IGF-IR overexpression expressed low levels of caveolin-1 while mammary tumors that became independent of IGF-IR signalling expressed considerably higher levels of caveolin-1. Interestingly, pockets of caveolin-1 positive cells could be observed in some of the IGF-IR-induced mammary tumors and these caveolin-1 positive cells were associated with tumor cells that expressed basal cytokeratins (cytokeratins 5 and 14. This caveolin-1 expression pattern was maintained in the murine mammary tumor cell lines in that the epithelial mammary tumor cell lines expressed little or no caveolin-1 while the claudin-low cell lines expressed caveolin-1. Conclusions Our model indicates that mammary tumor cells with epithelial characteristics lack caveolin-1 while mesenchymal tumor cells express caveolin-1 suggesting that caveolin-1 may serve as a marker of mammary tumor cells with mesenchymal characteristics such as claudin-low breast tumors.

Thompson Devan E

2012-02-01

116

Preferential Binding of Mouse Mammary Tumor Virus to B Lymphocytes  

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Mouse mammary tumor virus (MMTV) has been shown to preferentially infect B lymphocytes in vivo. We have used recombinant envelope-coated fluospheres and highly purified MMTV particles to study the distribution of the viral receptors on fresh mouse lymphocytes. A preferential dose-dependent binding to B lymphocytes was observed which could be competed with neutralizing antibodies. In contrast, T-lymphocyte binding remained at background levels. These results strongly suggest a higher density o...

Baribaud, Fre?de?ric; Vessaz Shaw, Annelyse; Scarpellino, Leo; Diggelmann, Heidi; Acha-orbea, Hans

1999-01-01

117

Reduced Levels of ATF-2 Predispose Mice to Mammary Tumors† ?  

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Transcription factor ATF-2 is a nuclear target of stress-activated protein kinases, such as p38, which are activated by various extracellular stresses, including UV light. Here, we show that ATF-2 plays a critical role in hypoxia- and high-cell-density-induced apoptosis and the development of mammary tumors. Compared to wild-type cells, Atf-2?/? mouse embryonic fibroblasts (MEFs) were more resistant to hypoxia- and anisomycin-induced apoptosis but remained equally susceptible to other str...

2007-01-01

118

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

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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, ...

Raa, Anette; Stansberg, Christine; Steen, Vidar Martin; Bjerkvig, Rolf; Reed, Rolf K.; Stuhr, Linda Elin Birkhaug

2007-01-01

119

Host genetic background effect on the frequency of mouse mammary tumor virus-induced rearrangements of the int-1 and int-2 loci in mouse mammary tumors.  

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The frequency with which int-1 and int-2 are rearranged in mouse mammary tumors by mouse mammary tumor virus (MMTV)-induced insertional mutagenesis is a consequence of the host genetic background. In 75% of C3H mammary tumors, int-1 is rearranged by MMTV insertion, whereas only 30% of BALB/cfC3H tumors contain a virus-induced rearrangement of int-1. This difference is significant (P less than 0.005) and could not be accounted for by the potentially additive effect of the genetically transmitt...

Marchetti, A.; Robbins, J.; Campbell, G.; Buttitta, F.; Squartini, F.; Bistocchi, M.; Callahan, R.

1991-01-01

120

RIII/Sa Mice with a High Incidence of Mammary Tumors Express Two Exogenous Strains and One Potential Endogenous Strain of Mouse Mammary Tumor Virus  

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The inbred mouse strain RIII has long been known for shedding large amounts of mouse mammary tumor virus (MMTV) particles in milk and for the development of hormone-dependent early mammary tumors at a very high incidence (>90%). We have established one RIII subline (RIII/Sa) that shows a pattern of virus expression and tumor incidence similar to that in RIII mice. In the present study, we analyzed the milk and mammary tumors of RIII/Sa mice for virus characterization by reverse transcriptase ...

Sarkar, Nurul H.; Golovkina, Tatyana; Uz-zaman, Taher

2004-01-01

 
 
 
 
121

Synthesis of specific nanoparticles for targeting tumor angiogenesis using electron-beam irradiation  

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Angiogenesis plays a critical role in both growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) is an endogenous mediator of tumor angiogenesis. Blocking associations of the VEGF with its corresponding receptors (KDR) have become critical for anti-tumor therapy. Acyclo-peptide (CBO- P11), derived from VEGF, able to inhibit the interaction between the growth factor and its receptor, was synthesized in our laboratory to provide a target for angiogenesis. We have prepared b...

Deshayes, Ste?phanie; Maurizot, Victor; Clochard, Marie-claude; Berthelot, Thomas; Baudin, Ce?cile; Deleris, Ge?rard

2010-01-01

122

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

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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...

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

1989-01-01

123

Morphological and immunohistochemical assays of surgically removed mammary gland tumors in bitches  

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In this study an estimation of the malignancy of mammary gland tumors was carried out based upon clinical examination, macroscopic and pathohistological characteristics of neoplasms and expression of cytokeratins. In the study 60 bitches of different ages, race and reproductive status with clinically evident signs of mammary gland tumor were included. After clinical examination the mammary gland tumors were excided, after which tissue samples were taken for subsequent pathohistological and im...

Magaš Vladimir; Jovi? S.; Neši? V.; Baceti? D.; Aleksi?-Kova?evi? Sanja

2007-01-01

124

A Novel Mechanism of Resistance to Mouse Mammary Tumor Virus Infection  

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Exogenous mouse mammary tumor virus (MMTV) is carried from the gut of suckling pups to the mammary glands by lymphocytes and induces mammary gland tumors. MMTV-induced tumor incidence in inbred mice of different strains ranges from 0 to as high as 100%. For example, mice of the C3H/HeN strain are highly susceptible, whereas mice of the I/LnJ strain are highly resistant. Of the different factors that together determine the susceptibility of mice to development of MMTV-induced mammary tumors, g...

Golovkina, Tatyana V.

2000-01-01

125

A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.  

Science.gov (United States)

Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation. PMID:23871637

Masiero, Massimo; Simões, Filipa Costa; Han, Hee Dong; Snell, Cameron; Peterkin, Tessa; Bridges, Esther; Mangala, Lingegowda S; Wu, Sherry Yen-Yao; Pradeep, Sunila; Li, Demin; Han, Cheng; Dalton, Heather; Lopez-Berestein, Gabriel; Tuynman, Jurriaan B; Mortensen, Neil; Li, Ji-Liang; Patient, Roger; Sood, Anil K; Banham, Alison H; Harris, Adrian L; Buffa, Francesca M

2013-08-12

126

Folic acid supplementation promotes mammary tumor progression in a rat model.  

Science.gov (United States)

Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification. PMID:24465421

Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In

2014-01-01

127

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

Science.gov (United States)

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.

RISMANCHI, SANAZ; YADEGAR, ORLY; MUHAMMADNEJAD, SAMAD; AMANPOUR, SAEID; TAGHIZADEH-JAHED, MASOUD; MUHAMMADNEJAD, AHAD

2014-01-01

128

BST-2/tetherin is overexpressed in mammary gland and tumor tissues in MMTV-induced mammary cancer  

Science.gov (United States)

BST-2 restricts MMTV replication, but once infection has established, MMTV modulates BST-2 levels. MMTV-directed BST-2 modulation is tissue-specific and dependent on infection and neoplastic transformation status of cells. In the lymphoid compartment of infected mice, BST-2 expression is first upregulated and then significantly downregulated regardless of absence or presence of mammary tumors. However, in mammary gland tissues, upregulation of BST-2 expression is dependent on the presence of mammary tumors and tumor tissues themselves have high BST-2 levels. Elevated BST-2 expression in these tissues is not attributable to IFN since levels of IFN? and IFN? negatively correlate with BST-2. Importantly, soluble factors released by tumor cells suppress IFN? and IFN? but induce BST-2. These data suggest that overexpression of BST-2 in carcinoma tissues could not be attributed to IFNs but to a yet to be determined factor that upregulates BST-2 once oncogenesis is initiated.

Jones, Philip H.; Mahauad-Fernandez, Wadie D.; Madison, M. Nia; Okeoma, Chioma M.

2014-01-01

129

Single and Fractionated Irradiation of Mammary Tumor of Rat  

International Nuclear Information System (INIS)

The therapeutic effect of mammary breast cancer of rat (Sprague Dawley) was estimated by single and 5 fractionated irradiation of Co60 X-ray. Response rates over 50% were 20, 43, 67, 80% respectively by single dose irradiation of 800, 1,200, 1,600, 2,000rad, and 20, 38, 57, 88% by 5 fractionated irradiation of 1,400, 2,100, 2,800, 3,500rad. 50% tumor control dose (TCD50) were 1,282rad, 2 312rad respectively with single and fractionated irradiation

1984-12-01

130

Different regulation of physiological and tumor angiogenesis in zebrafish by protein kinase D1 (PKD1).  

Science.gov (United States)

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 angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis. PMID:23874489

Hollenbach, Marcus; Stoll, Sandra Jasmin; Jörgens, Kristina; Seufferlein, Thomas; Kroll, Jens

2013-01-01

131

Growth hormone mRNA in mammary gland tumors of dogs and cats.  

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We have shown recently that in the dog progestin administration results in mammary production of immunoreactive growth hormone (GH). At present we demonstrate the expression of the gene encoding GH in the mammary gland of dogs and cats using reverse-transcriptase PCR. GH mRNA was found in the great majority of normal mammary tissues as well as benign and malignant mammary tumors of the dog and was associated with the presence of immunoreactive GH in cryostat sections. The mammary PCR product ...

Mol, J. A.; Garderen, E.; Selman, P. J.; Wolfswinkel, J.; Rijinberk, A.; Rutteman, G. R.

1995-01-01

132

Localization of mammary tumors in vivo with /sup 131/I-labeled Fab fragments of antibodies against mouse mammary epithelial (MME) antigens. [Mice  

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The Fab fragments of antibodies against cell-type-specific surface antigens of mouse mammary epithelial cells (MME-antigens) were used to localize mammary tumors successfully. The radioiodine-labeled anti-MME (Fab) was injected into mice carrying simulated mammary metastases, and after 24 hours the amount of label per gram of excised tissue was several times greater in the tumor than in liver, brain, lung, or muscle. With a high-purity germanium camera, mammary tumors were clearly located by the /sup 131/I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of /sup 131/I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of /sup 131/I-anti-MME (Fab) was observed in nonmammary tumors nor in mammary tumors when labeled nonspecific Fab was used.

Wilbanks, T. (Children' s Hospital, Oakland, CA); Peterson, J.A.; Miller, S.; Kaufman, L.; Ortendahl, D.; Ceriani, R.L.

1981-10-15

133

Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells  

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Dendritic cells (DCs)—immunomodulatory cells that initiate adaptive immune responses—have recently been shown to exert proangiogenic effects when infiltrating the tumor microenvironment. As tumors that escape immune surveillance inhibit DC maturation, we explored whether maturation status determines their ability to promote angiogenesis and whether angiogenesis depends on the presence of DCs. Using mouse xenograft models of human tumors, we show that fast-growing “angiogenic” tumors a...

2010-01-01

134

Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.  

Science.gov (United States)

Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a(+/+) fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer. PMID:23708660

Foley, C J; Fanjul-Fernández, M; Bohm, A; Nguyen, N; Agarwal, A; Austin, K; Koukos, G; Covic, L; López-Otín, C; Kuliopulos, A

2014-04-24

135

Role of pesticides in the induction of tumor angiogenesis.  

Science.gov (United States)

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

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

2013-01-01

136

Angiogenesis-independent tumor growth mediated by stem-like cancer cells.  

Science.gov (United States)

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors. PMID:17056721

Sakariassen, Per Ø; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit Bølge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; Øyan, Anne M; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G; Terzis, A Jorge A; Bjerkvig, Rolf; Enger, Per Øyvind

2006-10-31

137

Angiogenesis-independent tumor growth mediated by stem-like cancer cells  

Science.gov (United States)

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Sakariassen, Per ?.; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit B?lge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; ?yan, Anne M.; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G.; Terzis, A. Jorge A.; Bjerkvig, Rolf; Enger, Per ?yvind

2006-01-01

138

Lectin functionalized quantum dots for recognition of mammary tumors  

Science.gov (United States)

In this study we use CdS/Cd(OH)2 quantum dots functionalized with concanavalin-A (Con-A) lectin, specific to glucose/mannose residues, to investigate cell alterations regarding carbohydrate profile in human mammary tissues diagnosed as fibroadenoma (benign tumor). These particles were functionalized with glutaraldehyde and Con-A and 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 unspecific labeling of the tissues with glutaraldehyde 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 and their use in diagnostics.

Santos, Beate S.; de Farias, Patricia M. A.; de Menezes, Frederico D.; de C. Ferreira, Ricardo; Júnior, Severino A.; Figueiredo, Regina C. B. Q.; Beltrão, Eduardo I. C.

2006-03-01

139

Reduction of tumor angiogenesis induced by desmopressin in a breast cancer model.  

Science.gov (United States)

Desmopressin (DDAVP), a synthetic peptide analog of vasopressin, is a safe antidiuretic and hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor. It is known that DDAVP can inhibit progression of residual metastatic cells and also improves chemotherapy effects in preclinical breast cancer models. Here, we explored the effects of DDAVP on tumor angiogenesis using the aggressive F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of the compound (2 ?g/kg) markedly decreased vascularization of growing subcutaneous tumors, as well as inhibited the early angiogenic response around intradermal inoculation sites. In vitro studies confirmed the presence of vasopressin V2 receptors on F3II cells and a modest antiproliferative activity of DDAVP. Interestingly, conditioned media from F3II monolayers exposed to low doses of DDAVP (100 nM) significantly increased angiostatin formation in the presence of purified plasminogen. Such increase was associated with an enhancement of tumor-secreted urokinase-type plasminogen activator, suggesting the proteolytic conversion of plasminogen to angiostatin in vitro. Similar results were observed with the MCF-7 human breast carcinoma, a cell line known to express the vasopressin V2 receptor. No direct effects of DDAVP (100 nM–1 ?M) were found on capillary-like tube formation by human microvascular cells HMVEC. Our studies showed that DDAVP induces anti-angiogenic effects that may be associated with the generation of angiostatin by tumor cells. Further preclinical studies with DDAVP and other vasopressin analogs are warranted to determine their potential in cancer management. PMID:24122393

Ripoll, Giselle V; Garona, Juan; Pifano, Marina; Farina, Hernan G; Gomez, Daniel E; Alonso, Daniel F

2013-11-01

140

Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors  

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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 {sup 3}H-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.

Hubbard, N.E.

1987-01-01

 
 
 
 
141

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

1987-01-01

142

Angiogenic responses elicited from chorioallantoic membrane vessels by neoplastic, preneoplastic, and normal mammary tissues from GR mice.  

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Neoplastic tumors are able to elicit the ingrowth of new capillaries, a process known as angiogenesis. The chorioallantoic membrane (CAM) of chicken embryos was used in an assay for this response, and normal mammary glands and various mammary growths from GR mice, including plaques, hyperplasic alveolar nodules, and hormone-dependent and hormone-independent tumors were tested. Fifteen percent of the male mammary glands tested were positive, as were 28% of the resting female mammary glands. Fi...

Strum, J. M.

1983-01-01

143

Low-calorie diet prevents the development of mammary tumors in C3H mice and reduces circulating prolactin level, murine mammary tumor virus expression, and proliferation of mammary alveolar cells  

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The effect of carlorie intake on the development of spontaneous mammary tumors in virgin C3H mice was studied. Only about 10% of the mice fed a low-calorie diet [10 kcal/day (1 kcal = 4.184 kJ)] since weaning developed mammary tumors, compared to about 60% of those mice that were reared on high-calorie diets (16 kcal/day or lab chow ad lib). In order to understand the mechanism by which a low-calorie diet decreases the occurrence of mammary tumors in mice, we compared the sex cycle, the amoun...

1982-01-01

144

In-vitro investigation on the role of pancreatic stellate cells and tumor cells in angiogenesis  

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Background: Angiogenesis represents a multistep process involving proliferation, migration and tube formation of endothelial cells. In most tumors including pancreatic carcinoma, angiogenesis plays a pivotal role in the cancer progression. Pancreatic stellate cells (PSCs) are the main source of extracellular matrix providing a microenvironment which is advantageous for pancreatic cancer growth and survival. Until now the role of PSCs in angiogenesis is unclear. This study investigated the rol...

Zhang, Zhigong

2012-01-01

145

Mammary tumor suppression by transforming growth factor beta 1 transgene expression.  

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In cell culture, type alpha transforming growth factor (TGF-alpha) stimulates epithelial cell growth, whereas TGF-beta 1 overrides this stimulatory effect and is growth inhibitory. Transgenic mice that overexpress TGF-alpha under control of the mouse mammary tumor virus (MMTV) promoter/enhancer exhibit mammary ductal hyperplasia and stochastic development of mammary carcinomas, a process that can be accelerated by administration of the chemical carcinogen 7,12-dimethylbenz[a]anthracene. MMTV-...

Pierce, D. F.; Gorska, A. E.; Chytil, A.; Meise, K. S.; Page, D. L.; Coffey, R. J.; Moses, H. L.

1995-01-01

146

A Spectrum of Monoclonal Antibodies Reactive with Human Mammary Tumor Cells  

Science.gov (United States)

Splenic lymphocytes of mice, immunized with membrane-enriched fractions of metastatic human mammary carcinoma tissues, were fused with the NS-1 non-immunoglobulin-secreting murine myeloma cell line. This resulted in the generation of hybridoma cultures secreting immunoglobulins reactive in solid-phase radioimmunoassays with extracts of metastatic mammary carcinoma cells from involved livers, but not with extracts of apparently normal human liver. As a result of further screening of immunoglobulin reactivities and double cloning of cultures, 11 monoclonal antibodies were chosen that demonstrated reactivities with human mammary tumor cells and not with apparently normal human tissues. These monoclonal antibodies could be placed into at least five major groups on the basis of their differential binding to the surface of various live human mammary tumor cells in culture, to extracts of mammary tumor tissues, or to tissue sections of mammary tumor cells studied by the immunoperoxidase technique. Whereas a spectrum of reactivities to mammary tumors was observed with the 11 monoclonal antibodies, no reactivity was observed to apparently normal cells of the following human tissues: breast, lymph node, lung, skin, testis, kidney, thymus, bone marrow, spleen, uterus, thyroid, intestine, liver, bladder, tonsils, stomach, prostate, and salivary gland. Several of the antibodies also demonstrated a ``pancarcinoma'' reactivity, showing binding to selected non-breast carcinomas. None of the monoclonal antibodies showed binding to purified ferritin or carcinoembryonic antigen. Monoclonal antibodies of all five major groups, however, demonstrated binding to human metastatic mammary carcinoma cells both in axillary lymph nodes and at distal sites.

Colcher, D.; Horan Hand, P.; Nuti, M.; Schlom, J.

1981-05-01

147

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

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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 de...

Wright Mollie H; Robles Ana I; Herschkowitz Jason I; Hollingshead Melinda G; Anver Miriam R; Perou Charles M; Varticovski Lyuba

2008-01-01

148

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

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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 pr...

Podsypanina Katrina; Li Yi; Varmus Harold E

2004-01-01

149

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 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)

2005-03-01

150

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

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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.

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

151

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

2013-07-12

152

Mammary tumor inhibition by IP6: a review.  

Science.gov (United States)

While most studies of diet and breast cancer are focused on the role of fat, very few have addressed the effect of fiber. Emerging epidemiological data, and careful review of previous studies point to a negative correlation of breast cancer with high fiber cereal diets. Inositol hexaphosphate (IP6) is abundant in cereals and legumes, particularly in the bran part of mature seeds. Experimental studies using 7,12-dimethylbenz [alpha]anthracene (DMBA) and N-methylnitrosourea (NMU) in rats and mice in vivo, as well as human cell lines in vitro demonstrate a reproducible and striking anti-cancer action of IP6. It therefore appears that IP6 is one of the components, if not the most active ingredient, of high fiber cereal diet responsible for cancer inhibition. Could eating high fiber diet afford the same protection as IP6? Thus, we investigated whether dietary fiber containing high IP6 shows a dose-response inhibition of DMBA-induced rat mammary carcinogenesis, and if pure IP6 is more active as a cancer preventive agent, compared to that in diet. Our data show that supplemental dietary fiber in the form of bran exhibited a modest, statistically nonsignificant inhibitory effect. In contrast, animals given IP6 in drink showed significant reduction in tumor number, incidence and multiplicity. Therefore, pure IP6 is definitively more effective than a high fiber diet in preventing experimental mammary tumors. Thus, for cancer prevention, prophylactic intake of IP6 may be not only more effective, but also more practical than gorging on large quantities of fiber. PMID:10625937

Shamsuddin, A M; Vucenik, I

1999-01-01

153

Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and ERK signaling pathways  

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Thymoquinone, a component derived from the medial plant Nigella sativa, has been used for medical purposes for more than two thousands of years. Recent studies reported that thymoquinone exhibited inhibitory effects on cell proliferation of many cancer cell lines and hormone-refractory prostate cancer by suppressing androgen receptor and E2F-1. Whether thymoquinone inhibits angiogenesis, the critical step of tumor growth and metastasis, is still unknown. In this study, we found that thymoquin...

Yi, Tingfang; Cho, Sung-gook; Yi, Zhengfang; Pang, Xiufeng; Rodriguez, Melissa; Wang, Ying; Sethi, Gautam; Aggarwal, Bharat B.; Liu, Mingyao

2008-01-01

154

Human Tumor Cells Induce Angiogenesis through Positive Feedback between CD147 and Insulin-Like Growth Factor-I  

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Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). In this study, we made a three-dimensional (3D) tumor angiogenesis model using a co-culture system of human hepatocellular carcinoma cells SMMC-7721 and humanumbilical vein en...

Chen, Yanke; Gou, Xingchun; Ke, Xia; Cui, Hongyong; Chen, Zhinan

2012-01-01

155

Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice.  

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Little is known about chromatin mechanisms that regulate tumor-initiating cells that are proposed to be responsible for tumor recurrence and relapse. We have previously shown that Pygopus 2 (Pygo2), a chromatin effector and context-dependent Wnt signaling coactivator, regulates mammary gland development by expanding epithelial stem/progenitor cells. However, the role of Pygo2 in mammary tumorigenesis in vivo remains to be addressed. In this study, we show that epithelia-specific ablation of Pygo2 in MMTV-Wnt1 transgenic mice results in delayed mammary ductal elongation, but the hyperbranching phenotype, aberrant accumulation of stem/progenitor-like cells, and canonical Wnt signaling output are largely unaffected. Chronic loss of Pygo2 significantly delays mammary tumor onset in MMTV-Wnt1 females, whereas acute deletion of Pygo2 in MMTV-Wnt1 tumor cells leads to a significant decrease in their tumor-initiating capability upon transplantation. Finally, we provide evidence supporting a role for Pygo2 in modulating the lineage potential of MMTV-Wnt1 tumor initiating cells. Collectively, our results suggest that Pygo2 acts at a step downstream of mammary stem cell accumulation to facilitate transformation, and that it regulates the tumor initiating capacity and lineage preference of the already transformed mammary cells, in MMTV-Wnt1 mice. These findings offer valuable insights into our understanding of the molecular basis of heterogeneity within breast tumors. PMID:23334328

Watanabe, K; Fallahi, M; Dai, X

2014-01-30

156

Tumor growth and angiogenesis is impaired in CIB1 knockout mice  

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Full Text Available Abstract Background Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process more precisely on a molecular level. Previously we found that CIB1, a 22 kDa regulatory protein, plays a critical role in endothelial cell function, angiogenic growth factor-mediated cellular functions, PAK1 activation, MMP-2 expression, and in vivo ischemia-induced angiogenesis. Since pathological angiogenesis is highly dependent on many of these same processes, we hypothesized that CIB1 may also regulate tumor-induced angiogenesis. Methods To test this hypothesis, we allografted either murine B16 melanoma or Lewis lung carcinoma cells into WT and CIB1-KO mice, and monitored tumor growth, morphology, histology, and intra-tumoral microvessel density. Results Allografted melanoma tumors that developed in CIB1-KO mice were smaller in volume, had a distinct necrotic appearance, and had significantly less intra-tumoral microvessel density. Similarly, allografted Lewis lung carcinoma tumors in CIB1-KO mice were smaller in volume and mass, and appeared to have decreased perfusion. Intra-tumoral hemorrhage, necrosis, and perivascular fibrosis were also increased in tumors that developed in CIB1-KO mice. Conclusions These findings suggest that, in addition to its other functions, CIB1 plays a critical role in facilitating tumor growth and tumor-induced angiogenesis.

Zayed Mohamed A

2010-08-01

157

A 'tête-à tête' between cancer stem cells and endothelial progenitor cells in tumor angiogenesis.  

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Accumulating evidence suggests the involvement of stem cells in tumor angiogenesis. Two major types of stem cells frequently discussed in this regard are bone marrow-derived endothelial progenitor cells (EPCs) and tumor-derived cancer stem cells (CSCs). The present review discusses the possibility of a close association between these two cell types that drives the tumor towards metastasis. An exploration of this plausible relationship between EPCs and CSCs is imperative to completely unveil the mechanisms of tumor angiogenesis and develop CSC- and/or EPC-targeted anti-tumor therapies. PMID:23979912

Kaur, S; Bajwa, P

2014-02-01

158

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

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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.

Steen Vidar M

2007-01-01

159

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

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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 an...

2010-01-01

160

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

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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...

Djokovic, Dusan

2011-01-01

 
 
 
 
161

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

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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...

Ischenko, Ivan

2007-01-01

162

Novel EphB4 Monoclonal Antibodies Modulate Angiogenesis and Inhibit Tumor Growth  

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EphB4 receptor tyrosine kinase and its cognate ligand EphrinB2 regulate induction and maturation of newly forming vessels. Inhibition of their interaction arrests angiogenesis, vessel maturation, and pericyte recruitment. In addition, EphB4 is expressed in the vast majority of epithelial cancers and provides a survival advantage to most. Here, we describe two anti-EphB4 monoclonal antibodies that inhibit tumor angiogenesis and tumor growth by two distinct pathways. MAb131 binds to fibronectin...

Krasnoperov, Valery; Kumar, S. Ram; Ley, Eric; Li, Xiuqing; Scehnet, Jeffrey; Liu, Ren; Zozulya, Sergey; Gill, Parkash S.

2010-01-01

163

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

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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.

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

2008-01-01

164

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras  

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Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperat...

Podsypanina, Katrina; Politi, Katerina; Beverly, Levi J.; Varmus, Harold E.

2008-01-01

165

An Immunohistochemical Study on the Expression of Sex Steroid Receptors in Canine Mammary Tumors  

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Steroid hormones are found to play a major role in the genesis and progression of mammary tumors. The aim of this study was to immunohistochemically detect the presence of estrogen receptor alpha (ER?), estrogen receptor beta (ER?), and progesterone receptor (PR) and also to study the association between these markers in 29 cases of benign (11) and malignant (18) canine mammary tumors. ER? immunostaining was noticed in only one case of carcinosarcoma specifically in the nuclei of epithelia...

Leena Rajathy Port Louis; Khub Chandra Varshney; Madhavan Gopalakrishnan Nair

2012-01-01

166

Study on mammary gland tumors in rats born of parents irradiated before mating  

Energy Technology Data Exchange (ETDEWEB)

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.

Strel' tsova, V.N.; Pavlenko-Mikhajlov, Yu.N.; Oshchepkov, A.B.

1982-01-01

167

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

1982-01-01

168

Expression of the int-1 and int-2 loci in endogenous mouse mammary tumor virus-induced mammary tumorigenesis in the C3Hf mouse.  

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The int-1 locus appears to be involved in over 80% of C3H exogenous mouse mammary tumor virus (MMTV)-induced mouse mammary tumors, and the int-2 locus appears to be involved in approximately 10% of these tumors. Analysis of 46 C3Hf mammary tumors resulting from endogenous, rather than exogenous, MMTV infection revealed that only 41% expressed int-1 RNA, while 2% expressed int-2 RNA. Our results suggest that in addition to the int-1 and int-2 loci, other loci may be involved in endogenous-MMTV...

Etkind, P. R.

1989-01-01

169

The fibrinolytic system and matrix metalloproteinases in angiogenesis and tumor progression.  

Science.gov (United States)

Angiogenesis is the formation of new microvessels from existing vasculature. It is a crucial component of normal embryogenic development and of some physiological processes in adulthood. Pathological conditions such as tumor growth and metastasis, which involve tissue remodeling and inflammation, are usually associated with vascular leakage and subsequent angiogenesis. Tumor angiogenesis often augments tumor survival, progression, and metastasis, thus enhancing the malignant characteristics of the disease. Proteolytic degradation of the extracellular matrix that surrounds both the capillary sprouts and the migrating tumor cells is an essential part of tumor angiogenesis and tumor growth. In particular, proteases of the fibrinolytic system and the matrix metalloproteinase family play a role in these processes. In addition to proangiogenic effects, proteases also can negatively regulate angiogenesis. Protein fragments that result from proteolytic degradation of extracellular matrix components and other proteins can exhibit potent antiangiogenic properties. A thorough understanding of tumor-associated proteolytic processes is required to identify specific targets that are suitable for protease-based tumor therapy. PMID:15034799

Engelse, Marten A; Hanemaaijer, Roeland; Koolwijk, Pieter; van Hinsbergh, Victor W

2004-02-01

170

Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression.  

Science.gov (United States)

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 glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor ?-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID:23928381

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

2013-10-01

171

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

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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...

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

172

Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis  

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Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissu...

Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge; Melero-martin, Juan M.; Lin, Ruei-zeng; Klagsbrun, Michael; Dudley, Andrew C.

2012-01-01

173

Experimental studies on mammary tumors in rats. Role of dietary fat component in radiation-induced mammary carcinogenesis, and response of mammary tumors to experimental radiotherapy  

Energy Technology Data Exchange (ETDEWEB)

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 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.

Tanimoto, Masanori (Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology)

1989-02-01

174

A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis.  

Science.gov (United States)

The incidence of most solid tumors is remarkably reduced in individuals with Down syndrome. Using mouse models of Down syndrome, we have previously shown that this decrease in tumor incidence is due, in part, to suppression of tumor angiogenesis as a consequence of attenuated calcineurin signaling in endothelial cells. Our prior studies utilized xenografted tumors in a transgenic mouse model with three copies of the Down syndrome critical region-1 (Dscr1) gene, a chromosome 21-encoded endogenous calcineurin inhibitor. These data indicate that upregulated Dscr1 contributes to broad cancer protection by suppressing tumor angiogenesis through inhibiting the calcineurin pathway in the vascular endothelium. However, it still remains to be confirmed whether a single extra copy of Dscr1 is also sufficient to suppress tumor angiogenesis in slow growing spontaneous tumors that more accurately recapitulate molecular features of human malignancies. In this study, utilizing LSL-Kras(G12D) mice, an inducible and autochthonous model of human lung adenocarcinoma, on a Dscr1 transgenic mouse background, we show that a single extra transgenic copy of Dscr1 provides a survival advantage in these mice developing spontaneous lung tumors driven by oncogenic Kras(G12D) without affecting either initiation or progression of spontaneous lung tumors. Furthermore, we show that Dscr1 trisomy significantly reduces microvessel density in lung tumors and thus limits the growth of lung tumors through decreased proliferation and increased apoptosis of lung tumor cells. These data provide evidence that a single extra copy of Dscr1 is sufficient to suppress tumor angiogenesis during spontaneous lung tumorigenesis and further support our hypothesis that suppression of tumor angiogenesis by an additional copy of Dscr1 contributes to the reduced cancer incidence in individuals with Down syndrome and the calcineurin pathway in the tumor vasculature is a potential target for cancer treatment. PMID:24051307

Shin, Jimin; Lee, Jang Choon; Baek, Kwan-Hyuck

2014-01-01

175

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

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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.

Li Yi

2004-06-01

176

Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens  

Science.gov (United States)

Mouse mammary tumor viruses express a superantigen essential for their life cycle. It has been proposed that viral superantigens (vSags) require processing by prohormone convertases (PCs) for activity. We now observe, using a panel of mutant forms of potential PC cleavage sites and in vitro cleavage assays, that only the CS1 (position 68 to 71) and CS2 (position 169 to 172) sites are utilized by furin and PC5. Other members of the convertase family that are expressed in lymphocytes are not endowed with this activity. Furthermore, mutant forms of two different viral superantigens, vSag7 and vSag9, which completely abrogated in vitro processing by convertases, were efficient in functional presentation to responsive T-cell hybridomas. This effect was observed in both endogenous presentation and paracrine transfer of the vSag. Processing by convertases thus appears not to be essential for vSag function. Finally, we have identified the purified endosomal protease cathepsin L as another protease that is able to cleave convertase mutant vSag in vitro, yielding fragments similar to those detected in vivo, thus suggesting that proteases other than convertases are involved in the activation of vSags.

Denis, Francois; Shoukry, Naglaa H.; Delcourt, Marc; Thibodeau, Jacques; Labrecque, Nathalie; McGrath, Helen; Munzer, J. Scott; Seidah, Nabil G.; Sekaly, Rafick-Pierre

2000-01-01

177

A putative int domain for mouse mammary tumor virus on mouse chromosome 7 is a 5' extension of int-2.  

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We extended the physical map of the mouse int-2 locus by demonstrating that the site of insertion for mouse mammary tumor virus DNA in plaque-type mammary tumors of GR mice is directly linked to int-2. An additional example of proviral integration is described in which a provirus in a presumed enhancer-insertion mode 15 kilobases upstream of the int-2 promoters is capable of activating expression of the gene at levels typical of other virally induced mammary tumors.

Peters, G.; Brookes, S.; Placzek, M.; Schuermann, M.; Michalides, R.; Dickson, C.

1989-01-01

178

Morphological and immunohistochemical characterization of spontaneous mammary gland tumors in the guinea pig (Cavia porcellus).  

Science.gov (United States)

Ten spontaneous mammary gland tumors affecting guinea pigs (GP) were analyzed histologically and immunohistochemically. Histologically, 3 were benign (2 simple adenomas and 1 benign mixed tumor) and 7 were malignant (1 simple solid carcinoma and 6 simple tubulopapillary carcinomas). Immunohistochemical data revealed the glandular immunoprofile of all the tumors and suggested their ductal origin on the basis of cytokeratin 20 expression. Interestingly, cytokeratin 7 was detected in basal/myoepithelial cells. Further, all tumors were positive for type alpha estrogen and progesterone receptors, suggesting a role for steroid hormones in the development of these neoplasias in GP. This article describes the morphological and immunohistochemical features of the normal mammary gland and spontaneous mammary gland tumors in GP. PMID:20106793

Suárez-Bonnet, A; Martín de Las Mulas, J; Millán, M Y; Herráez, P; Rodríguez, F; Espinosa de los Monteros, A

2010-03-01

179

Localization of mammary tumors in vivo with "1"3"1I-labeled Fab fragments of antibodies against mouse mammary epithelial (MME) antigens  

International Nuclear Information System (INIS)

The Fab fragments of antibodies against cell-type-specific surface antigens of mouse mammary epithelial cells (MME-antigens) were used to localize mammary tumors successfully. The radioiodine-labeled anti-MME (Fab) was injected into mice carrying simulated mammary metastases, and after 24 hours the amount of label per gram of excised tissue was several times greater in the tumor than in liver, brain, lung, or muscle. Kidney showed considerable accumulation of label but this appeared to be nonspecific. Kinetic studies revealed a rapid elimination of labeled Fab in the urine with only 1% of the injected dose remaining in the entire blood pool after 24 hours. Wit a high-purity germanium camera, mammary tumors were clearly located ty the "1"3"1I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of "1"3"1I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of "1"3"1I-anti-MME (Fab) was observed in nonmammary tumors nor in mammary tumors when labeled nonspecific Fab was used. An analogous system using an antihuman mammary epithelial antiserum is being developed for localization of breast metastases in humans

1981-01-01

180

Localization of mammary tumors in vivo with /sup 131/I-labeled Fab fragments of antibodies against mouse mammary epithelial (MME) antigens  

Energy Technology Data Exchange (ETDEWEB)

The Fab fragments of antibodies against cell-type-specific surface antigens of mouse mammary epithelial cells (MME-antigens) were used to localize mammary tumors successfully. The radioiodine-labeled anti-MME (Fab) was injected into mice carrying simulated mammary metastases, and after 24 hours the amount of label per gram of excised tissue was several times greater in the tumor than in liver, brain, lung, or muscle. Kidney showed considerable accumulation of label but this appeared to be nonspecific. Kinetic studies revealed a rapid elimination of labeled Fab in the urine with only 1% of the injected dose remaining in the entire blood pool after 24 hours. Wit a high-purity germanium camera, mammary tumors were clearly located ty the /sup 131/I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of /sup 131/I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of /sup 131/I-anti-MME (Fab) was observed in nonmammary tumors nor in mammary tumors when labeled nonspecific Fab was used. An analogous system using an antihuman mammary epithelial antiserum is being developed for localization of breast metastases in humans.

Wilbanks, T.; Peterson, J.A.; Miller, S.; Kaufman, L.; Ortendahl, D.; Ceriani, R.L.

1981-01-01

 
 
 
 
181

mTOR Inhibition Abrogates Insulin-Mediated Mammary Tumor Progression in Type 2 Diabetes  

Science.gov (United States)

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological and genetic mTOR ablation suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2- driven mammary tumor cells (Met-1 and MCNeuA cells, respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia and thus, mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.

Fierz, Yvonne; Novosyadlyy, Ruslan; Vijayakumar, Archana; Yakar, Shoshana; LeRoith, Derek

2014-01-01

182

Angiogenesis-independent tumor growth mediated by stem-like cancer cells  

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In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually trans...

2006-01-01

183

Inhibition of Tumor Growth and Angiogenesis by Soluble EphB41  

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EphB receptors and their ephrinB ligands play a key role in the formation of a regular vascular system. Recent studies have also shown the involvement of Eph/ephrin interactions in malignant tumor progression and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4)-expressing A375 melanoma cells to study the effect of dominant negatively acting sEphB4 on tumor growth and angiogenesis. Soluble EphB4-expressing A375 tumors grown subcutaneously in nude mice show dramatically reduced ...

Martiny-baron, Georg; Korff, Thomas; Schaffner, Florence; Esser, Norbert; Eggstein, Stefan; Marme?, Dieter; Augustin, Hellmut G.

2004-01-01

184

Coexpression of exogenous and endogenous mouse mammary tumor virus RNA in vivo results in viral recombination and broadens the virus host range.  

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Mouse mammary tumor virus is a replication-competent B-type murine retrovirus responsible for mammary gland tumorigenesis in some strains of laboratory mice. Mouse mammary tumor virus is transmitted horizontally through the milk (exogenous or milk-borne virus) to susceptible offspring or vertically through the germ line (endogenous provirus). Exogenously acquired and some endogenous mouse mammary tumor viruses are expressed at high levels in lactating mammary glands. We show here that there i...

1994-01-01

185

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

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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...

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

1999-01-01

186

Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma.  

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Tumor angiogenesis is essential for tumor growth and metastasis, and intratumoral microvessel density correlates with prognosis in breast carcinoma. Yet, how intratumoral microvessel density correlates with tumor cell and intratumoral endothelial cell proliferation remains incompletely understood. To this end, we stained 57 formalin-fixed, paraffin-embedded breast carcinomas with antibody MIB1 to determine tumor cell Ki67 labeling index and with anti-CD34 to observe microvessels. We correlate...

1994-01-01

187

Transgenic IGF-IR overexpression induces mammary tumors with basal-like characteristics, whereas IGF-IR-independent mammary tumors express a claudin-low gene signature  

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Molecular profiling has allowed a more precise classification of human cancers. With respect to breast cancer, this approach has been used to identify five subtypes; luminal A, luminal B, HER2-enriched, basal-like and claudin-low. In addition, this approach can be used to determine the type of tumor represented by particular cell lines or transgenic animal models. Therefore, this approach was utilized to classify the mammary tumors that develop in MTB-IGFIR transgenic mice. It was determined ...

Franks, S. E.; Campbell, C. I.; Barnett, E. F.; Siwicky, M. D.; Livingstone, J.; Cory, S.; Moorehead, R. A.

2012-01-01

188

Critical Role of Aberrant Angiogenesis in the Development of Tumor Hypoxia and Associated Radioresistance  

Directory of Open Access Journals (Sweden)

Full Text Available Newly formed microvessels in most solid tumors show an abnormal morphology and thus do not fulfil the metabolic demands of the growing tumor mass. Due to the chaotic and heterogeneous tumor microcirculation, a hostile tumor microenvironment develops, that is characterized inter alia by local hypoxia, which in turn can stimulate the HIF-system. The latter can lead to tumor progression and may be involved in hypoxia-mediated radioresistance of tumor cells. Herein, cellular and molecular mechanisms in tumor angiogenesis are discussed that, among others, might impact hypoxia-related radioresistance.

Gabriele Multhoff

2014-04-01

189

An approach to malignant mammary phyllodes tumors detection  

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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.

Ili? Ivan

2009-01-01

190

The neonatal Fc receptor is not required for mucosal infection by mouse mammary tumor virus.  

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The milk-borne mouse mammary tumor virus (MMTV) infects newborn mice via the intestine. Infection is initially restricted to Peyer's patches and later spreads to the epithelial cells of the mammary gland. The receptor that mediates uptake and transport of MMTV across the intestinal barrier has not yet been identified, The neonatal Fc receptor (nFcR), which is expressed by enterocytes during the first two weeks of life, is downregulated at weaning, and its disappearance correlates with the ons...

Velin, D.; Acha-orbea, H.; Kraehenbuhl, J. P.

1996-01-01

191

Paradoxical antiproliferative effect by a murine mammary tumor-derived epithelial cell line  

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Abstract Background Despite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis. In this study, we isolated and characterized murine mammary tumor-derived epithelial and myofibroblast cell lines, and investigated the in vitro and in vivo effect of cel...

2007-01-01

192

Sequential imaging of indium-111-labeled monoclonal antibody in human mammary tumors hosted in nude mice  

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Using a bifunctional chelating agent, indium-111 was attached to a monoclonal antibody 10-3D2, specific for a 126-kilodalton phosphoglycoprotein antigen associated with human mammary carcinoma, and was then used to localize and visualize human mammary tumors hosted in nude mice. Simultaneous tumor concentration of In-111-10-3D2 was eight times greater than that of control I-125-MOPC-21. Uptake of F(ab')/sub 2/ and Fab of 10-3D2 was also compared. The scintigrams demonstrated that intact antibody provided the best images. Control In-111-labeled MOPC-21 and plasma did not show specific localization in the tumor. Uptake of In-111-labeled 10-3D2 was also compared in two lines of human mammary tumors, BT-20 and HS-578T. Imaging with 10-3D2 was better for BT-20 than for HS-578T.

Khaw, B.A.; Strauss, H.W.; Cahill, S.L.; Soule, H.R.; Edgington, T.; Cooney, J.

1984-05-01

193

Sequential imaging of indium-111-labeled monoclonal antibody in human mammary tumors hosted in nude mice  

International Nuclear Information System (INIS)

Using a bifunctional chelating agent, indium-111 was attached to a monoclonal antibody 10-3D2, specific for a 126-kilodalton phosphoglycoprotein antigen associated with human mammary carcinoma, and was then used to localize and visualize human mammary tumors hosted in nude mice. Simultaneous tumor concentration of In-111-10-3D2 was eight times greater than that of control I-125-MOPC-21. Uptake of F(ab')2 and Fab of 10-3D2 was also compared. The scintigrams demonstrated that intact antibody provided the best images. Control In-111-labeled MOPC-21 and plasma did not show specific localization in the tumor. Uptake of In-111-labeled 10-3D2 was also compared in two lines of human mammary tumors, BT-20 and HS-578T. Imaging with 10-3D2 was better for BT-20 than for HS-578T

1984-01-01

194

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

Science.gov (United States)

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

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

2014-01-01

195

Survey radiography and computerized tomography imaging of the thorax in female dogs with mammary tumors  

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Full Text Available Abstract Background Accurate early diagnosis of lung metastases is important for establishing therapeutic measures. Therefore, the present study aimed to compare survey thoracic radiographs and computerized tomography (CT scans to specifically identify lung metastases in female dogs with mammary tumors. Methods Twenty-one female dogs, weighing 3 to 34 kg and aged from 5 years to 14 years and 10 months, with mammary tumors were studied. In all dogs before the imaging examinations, fine-needle aspiration cytology of the mammary tumors was performed to confirm the diagnosis. Three-view thoracic radiographs were accomplished: right lateral, left lateral and ventrodorsal views. Sequential transverse images of the thorax were acquired on a spiral Scanner, before and after intravenous bolus injection of nonionic iodine contrast. Soft-tissue and lung windows were applied. All the mammary tumors were surgically removed and examined histologically. Results The correlation between the cytological and histological results regarding presence of malignancy was observed in only 17 cases. In radiographic examinations, no dog displayed signs of lung metastases or thorax chest lesions. CT detected lung metastasis in two cases, while small areas of lung atelectasis located peripherally were found in 28.57% of the dogs. Conclusion In this study population, spiral CT showed higher sensitivity than chest radiographies to detect lung metastasis; this indicates that CT should be performed on all female dogs with malignant mammary tumors.

Giordano Tatiana

2010-03-01

196

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

DEFF Research Database (Denmark)

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

Gordon, Ryan R; Hunter, Kent W

2008-01-01

197

Tumors and Tumor-like Lesions in the Mammary Gland of 24 Pet Rabbits: A Histomorphological and Immunohistochemical Characterization.  

Science.gov (United States)

The aim of this retrospective study (2004-2011) was to examine mammary tumors and tumor-like lesions in 24 pet rabbits by histopathology and immunohistochemistry. Rabbits were aged 2 to 8 years. Seventeen were female and 7 female-spayed. Diagnosed tumor-like lesions were lobular hyperplasia (2 rabbits) and multiple cysts (10 rabbits). Tumors included cystadenoma (7 tumors; 3 rabbits), intraductal papilloma (2 tumors; 1 rabbit), intraductal papillary carcinoma (1 tumor), adenocarcinoma (14 tumors; 13 rabbits), adenosquamous carcinoma (2 tumors; 2 rabbits), and matrix-producing carcinoma (1 tumor). The most frequently diagnosed lesion was invasive carcinoma (n = 17). Ten rabbits had several lesions. Immunohistochemistry for calponin and p63 showed that the diagnosed tumor-like lesions, benign tumors, and noninvasive carcinoma had a peripheral myoepithelial layer that was lacking in the invasive carcinomas. In 13 of 14 (93%) of the invasive carcinomas, however, there were variable numbers of calponin- and/or p63-immunopositive cells ranging from 0.1% to 40% with morphological features of either retained nonneoplastic myoepithelial cells or neoplastic epithelial cells with a myoepithelial differentiation. Tumor recurrence was reported in the rabbit with the matrix-producing carcinoma and in 3 rabbits with mammary adenocarcinomas displaying ?20 mitotic figures in 10 high-power fields and high numbers of neoplastic cells with a myoepithelial differentiation (19%-39%). The rabbit with the matrix-producing mammary carcinoma developed cutaneous metastases confirmed by histopathology. This study shows that different types of mammary tumor-like lesions and tumors can occur in pet rabbits. PMID:23892377

Schöniger, S; Horn, L-C; Schoon, H-A

2014-05-01

198

Pristimerin, a Triterpenoid, Inhibits Tumor Angiogenesis by Targeting VEGFR2 Activation  

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Full Text Available Pristimerin is a triterpenoid isolated from Celastrus and Maytenus spp. that has been shown to possess a variety of biological activities, including anti-cancer activity. However, little is known about pristimerin’s effects on tumor angiogenesis. In this study, we examined the function and the mechanism of this compound in tumor angiogenesis using multiple angiogenesis assays. We found that pristimerin significantly reduced both the volume and weight of solid tumors and decreased angiogenesis in a xenograft mouse tumor model in vivo. Pristimerin significantly inhibited the neovascularization of chicken chorioallantoic membrane (CAM in vivo and abrogated vascular endothelial growth factor (VEGF-induced microvessel sprouting in an ex vivo rat aortic ring assay. Furthermore, pristimerin inhibited the VEGF-induced proliferation, migration and capillary-like structure formation of human umbilical vascular endothelial cells (HUVECs in a concentration-dependent manner. Mechanistic studies revealed that pristimerin suppressed the VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1 and the activity of AKT, ERK1/2, mTOR, and ribosomal protein S6 kinase. Taken together, our results provide evidence for the first time that pristimerin potently suppresses angiogenesis by targeting VEGFR2 activation. These results provide a novel mechanism of action for pristimerin which may be important in the treatment of cancer.

Luyong Zhang

2012-06-01

199

Nucleolar Trafficking of the Mouse Mammary Tumor Virus Gag Protein Induced by Interaction with Ribosomal Protein L9  

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The mouse mammary tumor virus (MMTV) Gag protein directs the assembly in the cytoplasm of immature viral capsids, which subsequently bud from the plasma membranes of infected cells. MMTV Gag localizes to discrete cytoplasmic foci in mouse mammary epithelial cells, consistent with the formation of cytosolic capsids. Unexpectedly, we also observed an accumulation of Gag in the nucleoli of infected cells derived from mammary gland tumors. To detect Gag-interacting proteins that might influence i...

Beyer, Andrea R.; Bann, Darrin V.; Rice, Breanna; Pultz, Ingrid S.; Kane, Melissa; Goff, Stephen P.; Golovkina, Tatyana V.; Parent, Leslie J.

2013-01-01

200

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

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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 va...

Tsui, Paulus; Rubenstein, Marvin; Guinan, Patrick

2005-01-01

 
 
 
 
201

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

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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,...

Arrieta Oscar; Michel Ortega Rosa; Ángeles-Sánchez Julián; Villarreal-Garza Cynthia; Avilés-Salas Alejandro; Chanona-Vilchis José G; Aréchaga-Ocampo Elena; Luévano-González Arturo; Jiménez Miguel; Aguilar José

2009-01-01

202

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)

2013-02-19

203

A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors.  

Science.gov (United States)

Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity. PMID:24317954

Mira, Emilia; Carmona-Rodríguez, Lorena; Tardáguila, Manuel; Azcoitia, Iñigo; González-Martín, Alicia; Almonacid, Luis; Casas, Josefina; Fabriás, Gemma; Mañes, Santos

2013-12-01

204

A Compendium of the Mouse Mammary Tumor Biologist: From the Initial Observations in the House Mouse to the Development of Genetically Engineered Mice  

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For over a century, mouse mammary tumor biology and the associated mouse mammary tumor virus (MMTV) have served as the foundation for experimental cancer research, in general, and, in particular, experimental breast cancer research. Spontaneous mouse mammary tumors were the basis for studies of the natural history of neoplasia, oncogenic viruses, host responses, endocrinology and neoplastic progression. However, lacking formal proof of a human mammary tumor virus, the preeminence of the mouse...

Cardiff, Robert D.; Kenney, Nicholas

2011-01-01

205

Influence of selenium on the growth of N-nitrosomethylurea-induced mammary tumor cells in culture  

Energy Technology Data Exchange (ETDEWEB)

Selenium is an essential dietary trace element which has anticancer properties. Among its effects in rats, selenium has been shown to inhibit the development of carcinogen-induced mammary tumors by interfering with the post-initiation, promotion phase of carcinogenesis. We studied the effects of selenium on the growth of rat mammary tumor cells in primary culture. The objective was to determine whether selenium had any direct influence on cell growth which might explain its influence on tumor development. Rat mammary tumors were induced by N-nitrosomethylurea. The addition of low concentrations of sodium selenite, less than 1.0 ..mu..g/ml, stimulated tumor cell proliferation. Protein synthesis and the production of type IV collagen increased within the first hour of exposure, prior to any measurable increase in DNA synthesis. Concentrations of selenite greater than 1.0 ..mu..g/ml inhibited cell proliferation, the synthesis of protein, and the replication of DNA in a dose-related manner. These studies demonstrated that selenium has the potential to influence the post-initiation phase of rat mammary tumorigenesis by directly altering the growth of tumor cells, possibly through the regulation of protein synthesis.

Lewko, W.M.; McConnell, K.P.

1985-10-01

206

Hypoxia-regulated overexpression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth.  

Science.gov (United States)

VEGFs are found at high levels in hypoxic tumors. As major components directing pathologic neovascularization, they regulate stromal reactions. Consequently, novel strategies targeting and inhibiting VEGF overproduction upon hypoxia offer considerable potential for modern anticancer therapies controlling rather than destroying tumor angiogenesis. Here, we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia-responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: Tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on control of angiogenesis. A concomitant increase of intratumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel-controlled normalization and the design of adjuvants for combined cancer therapies. PMID:24170768

Collet, Guillaume; Lamerant-Fayel, Nathalie; Tertil, Magdalena; El Hafny-Rahbi, Bouchra; Stepniewski, Jacek; Guichard, Alan; Foucault-Collet, Alexandra; Klimkiewicz, Krzysztof; Petoud, Stéphane; Matejuk, Agata; Grillon, Catherine; Jozkowicz, Alicja; Dulak, Jozef; Kieda, Claudine

2014-01-01

207

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

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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.

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

2004-01-28

208

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

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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 � (PDGFR�) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFR�, 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.

Baker, Ann-Marie; Bird, Demelza

2013-01-01

209

Combination of angiogenesis inhibitors increases the anti-tumor efficacy of photodynamic therapy in a human bladder tumor xenograft model  

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Photodynamic therapy (PDT) is a standard treatment for various malignant and non-malignant conditions. Though therapeutic responses are encouraging, recurrences have been noted, as one of the limitations of PDT is treatment-induced hypoxia that triggers angiogenesis. The present study evaluates the use of angiogenic inhibitors Avastin, that targets vascular endothelial growth factor (VEGF) and Erbitux that targets epidermal growth factor receptor (EGFR) with PDT in an in vivo bladder carcinoma xenograft. Tumor bearing mice were assigned to 6 different categories: control, PDT only, Avastin + Erbitux, PDT + Avastin, PDT + Erbitux and PDT + Avastin and Erbitux. Treated and control tumors were monitored for recurrence for up to 90 days. VEGF and EGFR expression was detected in the tumor tissue. Migratory assay was performed to establish the inhibitory effect of the angiogenesis agents. Using confocal laser endomicroscopy, the tumor microvasculature was assessed. Tumors treated with the combination therapy of PDT + inhibitors showed significantly greater response compared to control and PDT only treated group. Combination therapy treated tumors also showed the most post-treatment damage with reduced tumor vasculature. These results demonstrate that the combination of PDT with inhibitors that target different angiogenesis pathways can improve tumor control.

Bhuvaneswari, Ramaswamy; Gan, Yik Yuen; Thong, Patricia S. P.; Chin, William Wei L.; Soo, Khee Chee; Olivo, Malini

2009-06-01

210

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

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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

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

2013-12-01

211

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

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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.

Li Zhong-Lian

2010-10-01

212

The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth  

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Abstract Background Increased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions.

Bellou Sofia; Karali Evdoxia; Bagli Eleni; Al-Maharik Nawaf; Morbidelli Lucia; Ziche Marina; Adlercreutz Herman; Murphy Carol; Fotsis Theodore

2012-01-01

213

Critical Role of Dendritic Cells in Mouse Mammary Tumor Virus In Vivo Infection?  

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Mouse mammary tumor virus (MMTV) is a milk-transmitted betaretrovirus that causes mammary tumors in mice. Although mammary epithelial cells are the ultimate targets of MMTV, the virus utilizes components of the host immune system to establish infection. Previous studies indicated that dendritic cells play a role in MMTV infection. Here we show that dendritic cells are the first cells to be infected by MMTV in vivo and that they are capable of producing infectious virus that can be transmitted to other cell types. Moreover, upon contact with the virus, dendritic cells became more mature and migrated in response to the chemokine macrophage inflammatory protein 3?. Finally, we demonstrate that targeted ablation of dendritic cells in vivo dramatically attenuated MMTV infection. These data indicate that MMTV infection of dendritic cells is critical to initial propagation of the virus in vivo.

Courreges, Maria Cecilia; Burzyn, Dalia; Nepomnaschy, Irene; Piazzon, Isabel; Ross, Susan R.

2007-01-01

214

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

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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)

2008-01-01

215

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

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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.

Marshall Aaron M

2012-01-01

216

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

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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

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

217

Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model1  

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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, CD3...

Akhtar, Nasim; Padilla, Marcia L.; Dickerson, Erin B.; Steinberg, Howard; Breen, Matthew; Auerbach, Robert; Helfand, Stuart C.

2004-01-01

218

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

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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...

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

219

Wnt1 is epistatic to Id2 in inducing mammary hyperplasia, ductal side-branching, and tumors in the mouse  

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Full Text Available Abstract Background During pregnancy, the mammary glands from Id2 mutant animals are deficient in lobulo-alveolar development. This failure of development is believed to be due to a proliferation defect. Methods We have asked whether functional Id2 expression is necessary for Wnt induced mammary hyperplasia, side branching, and cancer, by generating mice expressing a Wnt1 transgene in an Id2 mutant background. Results We show in this work that forced expression of Wnt1 in the mammary gland is capable of overcoming the block to proliferation caused by the absence of Id2. We also show that Wnt1 expression is able to cause mammary tumors in an Id2 mutant background. Conclusions We conclude that functional Id2 expression is not required for Wnt1 to induce mammary hyperplasia and mammary tumors.

Yokota Yoshifumi

2004-12-01

220

Dietary lipids and calorie restriction affect mammary tumor incidence and gene expression in mouse mammary tumor virus/v-Ha-ras transgenic mice.  

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We have studied the effects of food restriction (FR) and substitution of fish oil (FO; omega 3) for corn oil (CO; omega 6) on breast tumor incidence and survival in mouse mammary tumor virus/v-Ha-ras transgenic (Onco) mice. The diets were as follows: group 1, 5% (wt/wt) CO fed ad libitum (AL); group 2, 5% CO, restricted calories (40% fewer calories than AL; FR); group 3, 20% CO fed AL; and group 4, 20% FO fed AL. After 3 years, 40% of FR Onco (group 2) mice were alive, whereas there were no s...

Fernandes, G.; Chandrasekar, B.; Troyer, D. A.; Venkatraman, J. T.; Good, R. A.

1995-01-01

 
 
 
 
221

Ets2 Regulation of ErbB2-Induced Mammary Tumors.  

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Ets2 is a transcription factor that has been implicated in growth factor signaling and is essential for embryonic development. Reduced Ets2 activity restricts the appearance of transgenic mammary tumors caused by either Polyoma middle T antigen (PyMT) or ...

J. Tynan F. Wen

2005-01-01

222

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

Science.gov (United States)

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. PMID:12677695

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

2003-03-01

223

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

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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.

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

2003-01-01

224

Molecular chaperones in mammary cancer growth and breast tumor therapy  

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Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and prog...

Calderwood, Stuart K.; Gong, Jianlin

2012-01-01

225

Synthesis of specific nanoparticles for targeting tumor angiogenesis using electron-beam irradiation  

International Nuclear Information System (INIS)

Angiogenesis plays a critical role in both growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) is an endogenous mediator of tumor angiogenesis. Blocking associations of the VEGF with its corresponding receptors (KDR) have become critical for anti-tumor therapy. A cyclo-peptide (CBO-P11), derived from VEGF, able to inhibit the interaction between the growth factor and its receptor, was synthesized in our laboratory to provide a target for angiogenesis. We have prepared biocompatible poly(vinylidene fluoride) (PVDF) nanoparticles in order to obtain long blood circulating systems. Electron-beam (EB) irradiation was used to activate the PVDF nanoparticles. From electron paramagnetic resonance (EPR) measurements, we studied the radical stability in order to optimize the radio-grafting of acrylic acid (AA). Further functionalization of PVDF-g-PAA nanoparticles with the cyclo-peptide via a spacer arm was also possible by performing coupling reactions. High resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) and MALDI mass spectrometry allowed us to follow each chemical step of this peptide immobilization. We designed a new nanodevice suggesting a great potential for targeting angiogenesis. 7727-21-1

2010-03-01

226

Mouse mammary tumor virus (MMTV)-like DNA sequences in the breast tumors of father, mother, and daughter  

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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 b...

Etkind Polly R; Fr, Stewart Alexandre; Wiernik Peter H

2008-01-01

227

Hyperspectral imaging system to discern malignant and benign canine mammary tumors  

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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.

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

2013-05-01

228

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

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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 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

2004-02-01

229

{sup 18}F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis  

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Brain tumors are highly angiogenesis dependent. The cell adhesion receptor integrin {alpha}{sub v}{beta}{sub 3} is overexpressed in glioma and activated endothelial cells and plays an important role in brain tumor growth, spread and angiogenesis. Suitably labeled {alpha}{sub v}{beta}{sub 3}-integrin antagonists may therefore be useful for imaging brain tumor associated angiogenesis. Cyclic RGD peptide c(RGDyK) was labeled with {sup 18}F via N-succinimidyl-4-[{sup 18}F]fluorobenzoate through the side-chain {epsilon}-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-[{sup 18}F]fluorobenzoyl-RGD ([{sup 18}F]FB-RGD) was produced in less than 2 h with 20-25% decay-corrected yields and specific activity of 230 GBq/{mu}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 [{sup 18}F]FB-RGD in the presence of excess amount of c(RGDyK) revealed receptor specific activity accumulation. Hence, N-4-[{sup 18}F]fluorobenzoyl labeled cyclic RGD peptide [{sup 18}F]FB-RGD is a potential tracer for imaging {alpha}{sub v}{beta}{sub 3}-integrin positive tumors in brain and other anatomic locations.

Chen Xiaoyuan; Park, Ryan; Shahinian, Anthony H.; Tohme, Michel; Khankaldyyan, Vazgen; Bozorgzadeh, Mohammed H.; Bading, James R.; Moats, Rex; Laug, Walter E.; Conti, Peter S. E-mail: pconti@usc.edu

2004-02-01

230

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

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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.

Günzburg Walter H

2007-10-01

231

Cell line established starting with a mouse mammary tumor. Effect of the addition of hormones  

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From 7th international conference on mammary tumors; SaintPierre-de- Chartreuse, France (12 Jun 1972). The PS-MT cell line was defined (18th passage); isolated from a pool of mammary tumors of the PS strain of mice, it remained dormant for 6 months and then grew out very slowly. Subcultures were possible only after 19 months. The morphology is epithelial. After storage in liquid nitrogen in a medium containing 5% DMSO, the viability was approximately 80%. It was not possible to disclose the presence of mycoplasmas. With the standard insulincontaining medium, a few C-type particles were observed by electron-microscopic examination. The addition of hydrocortisone or prolactin, or both hormones together, increases slightly the production of C-type particles. If the secretory stimulating activity of hydrocortisone is maintained for one week before the addition of prolactin for another week, a large amount of A and B particles are found, mixed with C-type particles. They are present in large number in the pellets obtained from the tissue culture media. Five mammary tumors within 6 months were obtained in BALB/c females. Thus, the production of A- and B-type particles is hormone-dependent and requires the same sequence of hormones as the production of casein by mammary glands in organ cultures. (auth)

Mouriquand, J.

1972-12-31

232

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

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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.

Dutra A.P.

2004-01-01

233

Expression of Ets-1, Ang-2 and maspin in ovarian cancer and their role in tumor angiogenesis  

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Abstract Background Various angiogenic regulators are involved in angiogenesis cascade. Transcription factor Ets-1 plays important role in angiogenesis, remodeling of extracellular matrix, and tumor metastasis. Ets-1 target genes involved in various stages of new blood vessel formation include angiopoietin, matrix metalloproteinases (MMPs) and the protease inhibitor maspin. Methods We used immunohistochemistry (IHC) to detect the expression of Ets-1, angiopoieti...

2011-01-01

234

Measuring tumor cycling hypoxia and angiogenesis using a side-firing fiber optic probe.  

Science.gov (United States)

Hypoxia and angiogenesis can significantly influence the efficacy of cancer therapy and the behavior of surviving tumor cells. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo to enable advances in drug development and optimization. This paper reports the use of frequency-domain photon migration with a side-firing probe to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human head/neck tumors administered with carbogen gas, cycling hypoxic gas or just room air. Significant increase (with carbogen gas breathing) or decrease (with hypoxic gas breathing) in tumor oxygenation was observed. The trend in tumor oxygenation during forced cycling hypoxia (CH) followed that of the blood oxygenation measured with a pulse oximeter. Natural CH was also observed in rats under room air. The studies demonstrated the potential of the technology for longitudinal monitoring of tumor CH during tumor growth or in response to therapy. (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). PMID:23242854

Yu, Bing; Shah, Amy; Wang, Bingqing; Rajaram, Narasimhan; Wang, Quanli; Ramanujam, Nirmala; Palmer, Gregory M; Dewhirst, Mark W

2014-07-01

235

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

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...

2009-01-01

236

Long-time behavior of an angiogenesis model with flux at the tumor boundary  

CERN Multimedia

This paper deals with a nonlinear system of partial differential equations modeling a simplified tumor-induced angiogenesis taking into account only the interplay between tumor angiogenic factors and endothelial cells. Considered model assumes a nonlinear flux at the tumor boundary and a nonlinear chemotactic response. It is proved that the choice of some key parameters influences the long-time behaviour of the system. More precisely, we show the convergence of solutions to different semi-trivial stationary states for different range of parameters.

Cieslak, Tomasz

2012-01-01

237

Major histocompatibility complex class II I-E-independent transmission of C3H mouse mammary tumor virus.  

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C57BL/6 mice are resistant to C3H mouse mammary tumor virus (MMTV)-induced mammary tumorigenesis and lack major histocompatibility complex class II I-E molecules that are essential for presentation of C3H superantigen to T cells. T cells are needed for transmission of milk-borne MMTV from the gut to the mammary gland. In this report, we show that infectious C3H MMTV is produced by C57BL/6 mice that nurse on C3H mothers but that virus production in the mammary gland is delayed compared with th...

1996-01-01

238

Comparative characteristics of mammary glands cancer in humans and animals  

Directory of Open Access Journals (Sweden)

Full Text Available

 

This review is devoted to a comparative analysis of receptor status, immunity, angiogenesis, metastatic mammal glands cancer expression profiling in humans and animals. Angiogenesis has been assessed by quantitative and immunohistochemical characteristics by means of evaluation of microvascular density (MVD using Claudin-5 (CLDN-5 as a marker of vascular endothelium in tumors of mammary glands in dogs.

Vorobyova ?.V.

2012-09-01

239

ROSA26 mice carry a modifier of Min-induced mammary and intestinal tumor development.  

Science.gov (United States)

B6.129S7-Gtrosa26 (B6.R26) mice carry a LacZ-neoR insertion on Chromosome (Chr) 6, made by promoter trapping with 129 ES cells. Female C57BL/6J ApcMin/+ (B6Min/+) mice are highly susceptible to intestinal tumors and to the induction of mammary tumors after treatment with ethylnitrosourea (ENU). However, B6.R26/+ Min/+ females develop fewer mammary and intestinal tumors after ENU treatment than do B6 Min/+ mice. B6.R26/+ mice from two independently derived congenic lines show this modifier effect. Each of these congenic lines carries approximately 20 cM of 129-derived DNA flanking the insertion, raising the possibility that the resistance is due to a linked modifier locus. To further map the modifier locus, we have generated several lines of mice carrying different regions of the congenic interval. We have found that resistance to mammary and intestinal tumors in ENU-treated Min/+ mice maps to a minimum 4-cM interval that includes the ROSA26 LacZ-neoR insertion. Therefore, the resistance to tumor development is due to either the ROSA26 insertion or a very tightly linked modifier locus. PMID:11130972

Kohlhepp, R L; Hegge, L F; Nett, J E; Moser, A R

2000-12-01

240

Tumoral and angiogenesis factors in hepatocellular carcinoma after locoregional therapy.  

Science.gov (United States)

Locoregional therapy (LRT) is used as a bridge to orthotopic liver transplant (OLT) for hepatocellular carcinoma (HCC) patients. Liver explants in OLT patients with HCC were studied regarding both tumor stage, histology, and immunohistochemical staining for cytokeratin (CK)7, CK19, P53, Ki-67, and vascular endothelial growth factor (VEGF). Patients receiving no LRT (control) (n=30) were compared with LRT treatment groups with conventional transarterial chemoembolization (cTACE) (n=25) or drug-eluting bead transarterial chemoembolization (DEB TACE) (n=17). Tumor stage and histology were similar between treatment and control groups. The mean percent necrosis was significantly higher for treatment groups versus the control group (p<0.0001 for both groups versus control) and was significantly higher in the cTACE group versus the DEB TACE group. Only the DEB TACE group showed peritumoral CK19 positivity, and tumors were all CK19-negative. Using a threshold of 50% of tumoral cells, tumoral VEGF was significantly different between groups, with the control group having the highest degree of positivity; however, peritumoral VEGF was not significantly different between the groups. The Ki-67 proliferation fraction was higher in the treated groups with a statistically significant difference between the DEB-treated group and those without treatment (p=0.02). There were no statistically significant differences in tumoral or peritumoral CK7 or p53. Percent necrosis and percent Ki-67 positivity were higher with LRT, with a significant difference between groups for percent necrosis, confirming that LRT causes necrosis and suggesting that treatment leads to increased proliferation and decreased tumoral VEGF. PMID:22088254

Farris, Alton B; Dursun, Nevra; Dhanasekaran, Renumathy; Coban, Ipek; McIntosh, Emily B; Adsay, N Volkan; Kim, Hyun S

2012-01-15

 
 
 
 
241

Study of clinical value and influencing factors of 1H-MR spectroscopy in mammary tumors  

International Nuclear Information System (INIS)

Objective: To investigate the diagnostic value of 1H magnetic resonance spectroscopy (1H-MRS) in mammary tumors and to discuss the technique factors which influence the detection rate. Methods: The 1H-MRS features of 47 mammary tumors, of which 24 malignant tumors and 23 benign tumors confirmed by pathology were analyzed. All of the tumors were detected before Gd-DTPA enhancement. Results: Eleven of 24 malignant tumors showed increased choline resonance peak at 3.24 ppm while 4 of 23 benign ones at 3.24 ppm. The positive value were 45.8% and 17.4% respectively. The sensitivity and specificity were 45.8% and 82.6% respectively by using 1H-MRS to discriminate benign from malignant tumors. The main factors influencing the detection rate were low suppressed lipid, low suppressed water and low single-noise rate. Conclusion: Choline is not special features of malignant tumors. Choline can be obtained despite the nature of tumor if they grow rapidly. The low sensitivity of choline to be detected mainly dues to technique factors. (authors)

2006-03-01

242

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 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

2007-03-01

243

Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: cytological and histopathological assessment  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Backgroud Extramedullary hematopoiesis (EMH is defined as the presence of hematopoietic stem cells such as erythroid and myeloid lineage plus megakaryocytes in extramedullary sites like liver, spleen and lymph nodes and is usually associated with either bone marrow or hematological disorders. Mammary EMH is a rare condition either in human and veterinary medicine and can be associated with benign mixed mammary tumors, similarly to that described in this case. Case presentation Hematopoietic stem cells were found in a benign mixed mammary tumor of a 7-year-old female mongrel dog that presents a nodule in the left inguinal mammary gland. The patient did not have any hematological abnormalities. Cytological evaluation demonstrated two distinct cell populations, composed of either epithelial or mesenchymal cells, sometimes associated with a fibrillar acidophilic matrix, apart from megakaryocytes, osteoclasts, metarubricytes, prorubricytes, rubricytes, rubriblasts, promyelocytes, myeloblasts. Histological examination confirmed the presence of an active hematopoietic bone marrow within the bone tissue of a benign mammary mixed tumor. Conclusions EMH is a rare condition described in veterinary medicine that can be associated with mammary mixed tumors. It's detection can be associated with several neoplastic and non-neoplastic mammary lesions, i.e. osteosarcomas, mixed tumors and bone metaplasia.

Leão João

2010-09-01

244

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.)

2008-09-01

245

Heat sensitivity and membrane properties of metastasizing and non-metastasizing rat mammary tumors  

Energy Technology Data Exchange (ETDEWEB)

Paired lines of metastasizing and non-metastasizing transplantable rat mammary tumors were studied for their sensitivity to hyperthermia. The metastasizing TMT-081 and SMT-2A tumors were markedly more sensitive to heat injury as measured by tumor growth delay than were their non-metastatic counterparts MT-100 and MT-W9B. The metastasizing MT-081 tumor was also significantly more sensitive than the SMT-2A tumor. The differences in heat sensitivity were not the result of difference in intra-tumor temperatures attained during water bath heating. A more likely explanation for the variable response obtained with these tumors after heat treatment may be the inherent difference in stability and composition of their cellular membranes, particularly the plasma membrane.

Yatvin, M.B.; Vorpahl, J.W.; Elson, C.E.; Ghosh, S.K.; Kim, U.

1987-06-01

246

Suppression of KFkB by Tetrathiomolybdate Inhibits Tumor Angiogenesis and Enhances Apoptosis in Human Breast Cancers.  

Science.gov (United States)

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is essential for sustained growth of solid tumors. Numerous studies have shown that copper is required to modulate several pro-angiogenic factors. However, the specific effects of...

Q. Pan

2003-01-01

247

Suppression of NFkB by Tetrathiomolybdate Inhibits Tumor Angiogenesis and Enhances Apoptosis in Human Breast Cancer.  

Science.gov (United States)

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is essential for sustained growth of solid tumors. Numerous studies have shown that copper is required to modulate several pro-angiogenic factors. However, the specific effects of...

Q. Pan

2004-01-01

248

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

DEFF Research Database (Denmark)

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.

Willmann, Jürgen K; Cheng, Zhen

2008-01-01

249

Suppression of NFkB by Tetrathiomolybdate Inhibits Tumor Angiogenesis and Enhances Apoptosis in Human Breast Cancers.  

Science.gov (United States)

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is essential for sustained growth of solid tumors. Numerous studies have shown that copper is required to modulate several pro-angiogenic factors. However, the specific effects of...

Q. Pan

2005-01-01

250

A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis.  

Science.gov (United States)

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16INK4a. PMID:23948297

Kollmann, Karoline; Heller, Gerwin; Schneckenleithner, Christine; Warsch, Wolfgang; Scheicher, Ruth; Ott, Rene G; Schäfer, Markus; Fajmann, Sabine; Schlederer, Michaela; Schiefer, Ana-Iris; Reichart, Ursula; Mayerhofer, Matthias; Hoeller, Christoph; Zöchbauer-Müller, Sabine; Kerjaschki, Dontscho; Bock, Christoph; Kenner, Lukas; Hoefler, Gerald; Freissmuth, Michael; Green, Anthony R; Moriggl, Richard; Busslinger, Meinrad; Malumbres, Marcos; Sexl, Veronika

2013-08-12

251

Active Immunotherapy Induces Antibody Responses that Target Tumor Angiogenesis  

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The inhibition of vascular endothelial growth factor (VEGF) signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that anti-angiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-C...

Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Neuberg, Donna; Mihm, Martin; Hodi, F. Stephen; Dranoff, Glenn

2010-01-01

252

Influence of age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine mammary tumor virus titer.  

Science.gov (United States)

C3H/HeN female mice with low murine mammary tumor virus titer (MTV-) were fed diets containing a targeted concentration of 640 ppb diethylstilbestrol [(DES) CAS: 56-53-1; 4,4'-(1,2-diethyl-1,2-ethenediyl)bis-phenol]. Mice were started on DES at 3, 5, 7, or 9 weeks of age. Some continued on the diet throughout the rest of their life-spans, whereas others were killed as soon as they had been fed DES for 2, 4, 6, 8, 10, or 12 weeks. Controls were also examined throughout the study. Among mice killed early, the only observation significantly influenced by age at the start of DES treatment was the presence or absence of corpora lutea (CL). DES did not prevent CL from appearing in mice started on DES at 7 or 9 weeks of age, but it did prevent their appearance in about 25% of the mice started at 5 weeks and in up to 75% of the mice started at 3 weeks of age. In the life-span-exposure groups, CL either disappeared or were never formed in 88% or more of the mice, regardless of age at the start of treatment. Neoplastic or presumptive preneoplastic lesions apparently influenced by DES in the life-span-treatment groups included ovarian tubular adenomas; granulosa cell tumors and luteomas; pituitary cystoid degeneration, hyperplasia, and adenomas; uterine adenocarcinomas and cervical adenosis; mesotheliomas; and mammary hyperplastic alveolar nodules (HANs) and adenocarcinomas. Luteoma and granulosa cell tumor incidences were reduced by DES, regardless of age at the start of treatment. Influence of age at the start of treatment was minimal or not apparent for mesotheliomas, uterine adenocarcinomas, or pituitary adenomas; however, pituitary cystoid degeneration and hyperplasia and cervical adenosis occurred in higher frequency and/or with shorter duration of DES exposure the earlier that treatment was started. A delay in the start of DES treatment was associated with a remarkable delay in HAN and mammary adenocarcinoma development. This was especially apparent in young mice (3-7 wk old) in which a 2-week delay in treatment resulted in a 20-week delay in HAN or tumor onset. Age at the start of treatment was a major factor in susceptibility of C3H/HeN-MTV- female mice to DES-induced mammary tumorigenesis. PMID:3020299

Greenman, D L; Highman, B; Chen, J J; Schieferstein, G J; Norvell, M J

1986-10-01

253

[VEGFRs in neoplastic angiogenesis and prospects for therapy of brain tumors].  

Science.gov (United States)

Glioblastoma (GBM) is the most common type of primary brain cancer that characterized by poor prognosis due to the rapid progression, active angiogenesis, enhanced tumor cell invasion and the emergence of resistance toward conventional therapy. In this connection, nowadays, new approaches for selective inhibition of crucial steps in tumor progression are actively developing. The key feature of tumor growth and development is angiogenesis. VEGF and its receptor VEGFR2 play the pivotal role in regulation of tumor vessel formation. Therefore, VEGFR2, as the main receptor of VEGF's pro-angiogenic signal transducer, is a promising molecular target for anti-angiogenic therapy. There is evidence that inhibitors of VEGF and VEGFR2 reduce endothelial cell proliferation, migration and survival that lead to regression of vessel density and decrease vascular permeability, thereby slowing tumor growth. Currently, a number of VEGFR2 inhibitors are under clinical trials (ramucirumab, cediranib) and several were approved (sunitinib, sorafenib). Despite the promising results of preclinical studies, the efficacy of antiangiogenic drugs in the clinical practice is significantly lower, mainly, due to rapid adaptation of malignant cells that consists of alternative pro-angiogenic pathways activation, recruitment of endothelial progenitor cells from bone marrow and increasing of the invasive growth. Given the diversity of pro-angiogenic mechanisms, enhancement of the efficacy of tumor therapy could be achieved by specific inhibition of VEGFR2 functions that will be supplemented by other antiangiogenic drugs (anti-VEGF,-PIGF,-HIF1alpha). In addition, multitargeting therapy should focus on the combined inhibition of angiogenesis, invasion, metastasis, proliferation and survival of tumor cells. PMID:24640739

Korchagina, A A; Shein, S A; Gurina, O I; Chekhonin, V P

2013-01-01

254

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

Science.gov (United States)

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

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

2013-07-01

255

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

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...

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

256

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

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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...

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

2007-01-01

257

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine  

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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 (VEG...

Chao Liu; Xiao-Wan Li; Li-Min Cui; Liang-Chang Li; Li-Yan Chen; Xue-Wu Zhang

2011-01-01

258

Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis and ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells and provide access to the systemic circulation. In addition to well established growth factors and inflammatory mediators that promote capillary sprouting and endothelial cell growth and migration, an emerging body of evidence supports a previously unrecognized function for axon guidance molecules in ...

Basile, John R.; Castilho, Rogerio M.; Williams, Vanessa P.; Gutkind, J. Silvio

2006-01-01

259

Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen  

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A dominant gene carried in certain inbred mouse strains confers susceptibility to tumors induced by polyoma virus. This gene, designated Pyvs, was defined in crosses between the highly susceptible C3H/BiDa strain and the highly resistant but H-2k-identical C57BR/cdJ strain. The resistance of C57BR/cdJ mice is overcome by irradiation, indicating an immunological basis. In F1 x C57BR/cdJ backcross mice, tumor susceptibility cosegregates with Mtv-7, a mouse mammary tumor provirus carried by the ...

1995-01-01

260

Quantitative and qualitative analysis of Ag-NOR in benign and malignant canine mammary gland tumors  

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In this retrospective study, quantitative and qualitative analyses of argyrophil nucleolar organizer regions (AgNORs) in 54 malignant and 18 benign canine mammary gland tumors were made. Statistical analysis showed a significant difference in the mean number of AgNORs per cell between benign and malignant tumors (p<0.01). There was no significant difference in the mean number of AgNORs per cell between complex carcinomas, simple carcinomas and carcinomas in mixed tumors (p>0.05), as wel...

Jelesijevi? Tomislav; Jovanovi? Milijana; Kneževi? Milijana A.; Aleksi?-Kova?evi? Sanja

2003-01-01

 
 
 
 
261

A concise review of magnetic resonance molecular imaging of tumor angiogenesis by targeting integrin ?v?3 with magnetic probes  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Yajie Liu, Yi Yang, Chunfu Zhang School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Abstract: Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification of tumor angiogenesis is important for early diagnosis of cancers as well as post therapy assessment of antiangiogenic drugs. The cell adhesion molecule integrin ?v?3 is a specific marker...

Liu Y; Yang Y; Zhang C

2013-01-01

262

Impact of obesity on development and progression of mammary tumors in preclinical models of breast cancer.  

Science.gov (United States)

Overweight and/or obesity are known risk factors for postmenopausal breast cancer. More recently increased body weight has also been associated with poor prognosis for premenopausal breast cancer. This relationship has primarily been identified through epidemiological studies. Additional information from in vitro studies has also been produced in attempts to delineate mechanisms of action for the association of obesity and body weight and breast cancer. This approach has identified potential growth factors such as insulin, leptin, estrogen and IGF-I which are reported to be modulated by body weight changes. However, in vitro studies are limited in scope and frequently use non-physiological concentrations of growth factors, while long follow-up is needed for human studies. Preclinical animal models provide an intermediary approach to investigate the impact of body weight and potential growth factors on mammary/breast tumor development and progression. Here results of a number of studies addressing this issue are presented. In the majority of the studies either genetically-obese or diet-induced obese rodent models have been used to investigate spontaneous, transgenic and carcinogen-induced mammary tumor development. To study tumor progression the major focus has been allograft studies in mice with either genetic or dietary-induced obesity. In general, obesity has been demonstrated to shorten mammary tumor latency and to impact tumor pathology. However, in rodents with defects in leptin and other growth factors the impact of obesity is not as straightforward. Future studies using more physiologically relevant obesity models and clearly distinguishing diet composition from body weight effects will be important in continuing to understand the factors associated with body weight's impact on mammary/breast cancer development and progression. PMID:24122258

Cleary, Margot P

2013-12-01

263

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

Science.gov (United States)

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 stimuli, such as interleukin-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. PMID:24421272

Machado, Camila Maria Longo; Andrade, Luciana Nogueira Sousa; Teixeira, Verônica Rodrigues; Costa, Fabrício Falconi; Melo, Camila Morais; dos Santos, Sofia Nascimento; Nonogaki, Suely; Liu, Fu-Tong; Bernardes, Emerson Soares; Camargo, Anamaria Aranha; Chammas, Roger

2014-04-01

264

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

Science.gov (United States)

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 stimuli, such as interleukin-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.

Machado, Camila Maria Longo; Andrade, Luciana Nogueira Sousa; Teixeira, Veronica Rodrigues; Costa, Fabricio Falconi; Melo, Camila Morais; dos Santos, Sofia Nascimento; Nonogaki, Suely; Liu, Fu-Tong; Bernardes, Emerson Soares; Camargo, Anamaria Aranha; Chammas, Roger

2014-01-01

265

Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression.  

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The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor-resistant tumors, suggesting that this may represent a novel treatment for some cancers. PMID:22476930

Zhou, Hua; Binmadi, Nada O; Yang, Ying-Hua; Proia, Patrizia; Basile, John R

2012-09-01

266

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

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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.

Li Fan

2010-04-01

267

Murine mammary tumor cells with a claudin-low genotype  

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Abstract Background Molecular classification of human breast cancers has identified at least 5 distinct tumor subtypes; luminal A, luminal B, Her2-enriched, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of luminal differentiation markers and claudins 3, 4 and 7 and high levels of mesenchymal markers. Claudin-low tumors have a reported prevalence of 7-14% and these tumors have a poor prognosis. Results<...

Campbell Craig I; Thompson Devan E; Siwicky Megan D; Moorehead Roger A

2011-01-01

268

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.  

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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...

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

1983-01-01

269

In-vivo NIR autofluorescence of rat mammary tumors discriminates pathological malignancy  

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Benign and malignant mammary tumors were induced in rats using a potent carcinogen, N-ethyl-N-nitrosurea (ENU). Induced tumors were examined under near-infrared (NIR) fluorescence imaging (excitation wavelength 670 to 730 nm, detection wavelength 750 and 800 nm) to search for a difference in the photophysical properties of the tumors reflecting their pathologic status. Three benign and eight malignant tumors were examined optically and pathologically. The non-enhanced optical images showed a significantly lower (P<0.05) spontaneous fluorescent signal in the benign tumors than in their malignant counterparts. The precise chemical origin for the observed differences in tumor autofluorescence remains undetermined. It can be hypothesized that the reported high concentration of porphyrins, NIR-fluorescing compounds, in the malignant lesions, could account for the observed increased autofluorescence.

Fournier, Laure S.; Lucidi, Vincenzo; Rosenau, Werner; Demos, Stavros G.; Brasch, Robert C.

2003-10-01

270

Detection and cloning of human DNA sequences related to the mouse mammary tumor virus genome.  

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Sequences related to the mouse mammary tumor virus (MMTV) genome have been detected in fragments of restricted human cellular DNA. These results were obtained by using recombinant DNA containing the MMTV proviral genome and lowering the stringency of blot-hybridization conditions. The MMTV genome also reacts with unique families of fragments in restricted cellular DNA from other mammalian species but not with salmon sperm DNA. A clone that reacted with labeled MMTV proviral DNA was selected f...

Callahan, R.; Drohan, W.; Tronick, S.; Schlom, J.

1982-01-01

271

Passive Immunization with Neutralizing Antibodies Interrupts the Mouse Mammary Tumor Virus Life Cycle  

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Mouse mammary tumor virus (MMTV) infects the host via mucosal surfaces and exploits the host immune system for systemic spread and chronic infection. We have tested a neutralizing rat monoclonal antibody specific for the retroviral envelope glycoprotein gp52 for its efficiency in preventing acute and chronic mucosal and systemic infection. The antibody completely inhibits the superantigen response and chronic viral infection following systemic or nasal infection. Surprisingly however, the ant...

Mpandi, M.; Otten, L. A.; Lavanchy, C.; Acha-orbea, H.; Finke, D.

2003-01-01

272

Preactivation of B Lymphocytes Does Not Enhance Mouse Mammary Tumor Virus Infection  

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We investigated whether mouse mammary tumor virus (MMTV) favors preactivated or naive B cells as targets for efficient infection. We have demonstrated previously that MMTV activates B cells upon infection. Here, we show that polyclonal activation of B cells leads instead to lower infection levels and attenuated superantigen-specific T-cell responses in vivo. This indicates that naive small resting B cells are the major targets of MMTV infection and that the activation induced by MMTV is suffi...

Finke, Daniela; Mortezavi, Laure; Acha-orbea, Hans

1998-01-01

273

In vivo effects of a recombinant vaccinia virus expressing a mouse mammary tumor virus superantigen.  

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Early after infection, the mouse mammary tumor virus (MMTV) expresses a superantigen (SAg) at the surface of B lymphocytes. Interaction with the T-cell receptor Vbeta domain induces a polyclonal proliferative response of the SAg-reactive T cells. Stimulated T cells become anergic and are deleted from the T-cell repertoire. We have used a recombinant vaccinia virus encoding the MMTV(GR) SAg to dissect the effects of the retroviral SAg during an unrelated viral infection. Subcutaneous infection...

Krummenacher, C.; Diggelmann, H.; Acha-orbea, H.

1996-01-01

274

Identification of the Receptor Binding Domain of the Mouse Mammary Tumor Virus Envelope Protein  

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Mouse mammary tumor virus (MMTV) is a betaretrovirus that infects rodent cells and uses mouse transferrin receptor 1 for cell entry. To characterize the interaction of MMTV with its receptor, we aligned the MMTV envelope surface (SU) protein with that of Friend murine leukemia virus (F-MLV) and identified a putative receptor-binding domain (RBD) that included a receptor binding sequence (RBS) of five amino acids and a heparin-binding domain (HBD). Mutation of the HBD reduced virus infectivity...

Zhang, Yuanming; Rassa, John C.; Deobaldia, Maria Elena; Albritton, Lorraine M.; Ross, Susan R.

2003-01-01

275

The manner in which calories are restricted impacts mammary tumor cancer prevention  

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Although treatments for breast cancer have improved and long-term survival after diagnosis is now common, prevention of the disease is the ultimate goal. Weight loss or weight maintenance is one approach that has been recommended to reduce the risk of breast cancer, particularly for peri/postmenopausal women. This approach is supported by decades of data indicating that calorie restriction prevents spontaneous and chemically induced mammary tumor development in rodents. In most cases, calorie...

Cleary, Margot P.; Grossmann, Michael E.

2011-01-01

276

Control of metastatic mammary tumors by laser immunotherapy through local treatment  

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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.

Chen, Wei R.; Nordquist, Robert E.

1998-08-01

277

Anti-Gb3 Monoclonal Antibody Inhibits Angiogenesis and Tumor Development  

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Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition.

Gaugler, Marie-Helene; Cochonneau, Denis; Fleurence, Julien; Dubois, Nolwenn; Hulin, Philippe; Aubry, Jacques; Birkle, Stephane; Paris, Francois

2012-01-01

278

Wogonin inhibits LPS-induced tumor angiogenesis via suppressing PI3K/Akt/NF-?B signaling.  

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Wogonin has been shown to have anti-angiogenesis and anti-tumor effects. However, whether wogonin inhibits LPS-induced tumor angiogenesis is not well known. In this study, we investigated the effect of wogonin on inhibiting LPS-induced tumor angiogenesis and further probed the underlying mechanisms. ELISA results revealed that wogonin could suppress LPS-induced VEGF secretion from tumor cells. Transwell assay, tube formation assay, rat aortic ring assay and CAM model were used to evaluate the effect of wogonin on angiogenesis induced by MCF-7 cell (treated with LPS) in vitro and in vivo. The inhibitory effect of wogonin on angiogenesis in LPS-treated MCF-7 cells was then confirmed by the above in vitro and in vivo assays. The study of the molecular mechanism showed that wogonin could suppress PI3K/Akt signaling activation. Moreover, wogonin inhibited nuclear translocation of NF-?B and its binding to DNA. The result of real-time PCR and luciferase reporter assay suggested that VEGF expression was down-regulated by wogonin primarily at the transcriptional level. IGF-1 and p65 expression plasmid were used to activate PI3K/Akt and NF-?B pathways, and to observe the effect of wogonin on the simualtion of PI3K/Akt/NF-?B signaling. Taken together, the result suggested that wogonin was a potent inhibitor of tumor angiogenesis and provided a new insight into the mechanisms of wogonin against cancer. PMID:24858369

Zhao, Kai; Song, Xiuming; Huang, Yujie; Yao, Jing; Zhou, Mi; Li, Zhiyu; You, Qidong; Guo, Qinglong; Lu, Na

2014-08-15

279

Imaging angiogenesis  

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Angiogenesis of tumors has gained tremendous attention in the research community over the last years. Novel anit-angiogenic treatment protocols are currently in various phases of clinical testing. Thus, the major challenge for Radiological diagnostics is to develop imaging methods which reliably measure the angiogenic tumor burden as well as tumor response to anti-angiogenic treatment in vivo. This article intends to provide a brief overview of imaging strategies for angiogenesis and anti-angiogenic treatment. (orig.)

2001-02-01

280

Paradoxical antiproliferative effect by a murine mammary tumor-derived epithelial cell line  

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Full Text Available Abstract Background Despite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis. In this study, we isolated and characterized murine mammary tumor-derived epithelial and myofibroblast cell lines, and investigated the in vitro and in vivo effect of cellular soluble factors produced by the epithelial cell line on tumor cells. Methods Morphology, immunophenotype, cytogenetics, invasiveness, and tumorigenicity of epithelial (LM-234ep and myofibroblast (LM-234mf cell lines isolated from two murine mammary adenocarcinomas with common ancestor were studied. The in vitro effects of LM-234ep conditioned medium on proliferation, cell cycle distribution, and expression of cell cycle proteins, were investigated in LM-234mf cells, mouse melanoma cells (B16-F10, and human cervical adenocarcinoma cells (HeLa. The in vivo anti-tumor activity of LM-234ep conditioned media was evaluated in subcutaneous tumors formed in nude mice by B16-F10 and HeLa cells. Results LM-234ep cells were found to be cytokeratin positive and hipertriploid, whereas LM-234mf cells were ?-smooth muscle actin positive and hypohexaploid. Chromosome aberrations were found in both cases. Only LM-234mf revealed to be invasive in vitro and to secrete active MMP-2, though neither of the cell types were able to produce progressing tumors. LM-234ep-derived factors were able to inhibit the in vitro growth of LM-234mf, B16-F10, and HeLa cells, inducing cell cycle arrest in G0/G1 phase. The administration of LM-234ep conditioned medium inhibited the growth of B16-F10 and HeLa tumors in nude mice. Conclusion Our data suggest the existence of epithelial cell variants with tumor suppressive properties within mammary tumors. To our knowledge, this is the first report showing antiproliferative and antineoplastic activities induced by tumor-derived epithelial cells.

Scharovsky O Graciela

2007-10-01

 
 
 
 
281

The response of mouse mammary tumor to microwave heating at 2.45 GHz  

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We have conducted experiments quantitating the effects of microwave heating on the regrowth time of mammary tumors implanted on the flank of C3H mice. To minimize the size and shape dependence of the microwave heating, we immersed the tumors in tissue equivalent bolus and treated them with parallel opposed transverse electromagnetic applicators. The animals were not anesthetized during microwave irradiation. Two types of bolus were used: a semisolid gel and a temperature-controlled solution of isotonic saline and alcohol. During tumor irradiation in the gel, temperatures were monitored adjacent to, but not inside of, the tumors. During irradiation in the liquid bolus, tumor temperatures were monitored for one out of each six animals per data point. Data from tumors treated in the semisolid bolus yielded lower regrowth slopes and higher intercepts than those heated by water baths. Both findings can be interpreted as indicating thermal nonuniformity of the microwave-heated tumors. Plots of thermal sensitivity versus temperature are parallel to, but displaced from, those determined with water bath heating, suggesting that at least some small part of the tumor treated with microwaves was about 1°C lower than the target temperature. Tumors which were heated in the liquid bolus yielded regrowth curves consistent with homogeneous heating. A plot of thermal sensitivity versus temperature suggests that all parts of the tumors were at or slightly above target temperature. Regrowth time of the probed tumors was significantly greater than that of tumors in which no probe was present during microwave irradiation.

Robinson, J. Eugene; Cheung, Augustine Y.; Harrison, George H.; Samaras, George

282

Ovarian serous carcinoma: relationship of p53 and bcl-2 with tumor angiogenesis and VEGF expression.  

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The aim of the study was to assess the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in ovarian serous carcinoma and to examine their relation with apoptosis.Paraffin-embedded specimens of 41 cases of ovarian serous carcinomas were evaluated by immunohistochemistry for VEGF, p53, and bcl-2 expression. MVD was assessed with CD31 staining. We investigated the association of tumor angiogenesis (MVD and VEGF) with clinicopathologic factors, p53 overexpression, and bcl-2 expression.There was a significant correlation between high MVD and suboptimal debulking and advanced stage disease. A significant negative correlation was expressed between bcl-2 and VEGF expression. In univariate analysis, only stage had a significant impact on disease-free survival.The results of this study suggest that higher degree of angiogenesis is associated with suboptimal debulking and advanced-stage disease. Expression of VEGF had negative association with VEGF expression. PMID:21979585

Crasta, Julian A; Mishra, Suniti; Vallikad, Elizabeth

2011-11-01

283

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

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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.

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

1997-05-01

284

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

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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

Saito, Teruyoshi; Tamura, Dai; Asano, Ryuji

2014-04-01

285

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

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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

Shaojin You

2010-03-01

286

Luteolin supplementation modulates mammary tumor growth in C3H mice fed diet with high- and low-fat content.  

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In this study we investigated the effects of luteolin supplementation (0.05% w/w) on mammary tumor growth in C3H mice, a strain of mouse mammary tumor virus negative, fed either high-fat (45% fat of energy) or low-fat diet (15% fat of energy). Animals (n = 12/group) were allocated into 4 experimental groups (low-fat diet, low-fat diet + luteolin supplementation, high-fat diet, high-fat diet + luteolin supplementation). Experimental diet were fed for 13 wk and 7,12-dimethylbenz[a]anthracene was administered once a week for 6 wk starting at Week 1 to induce mammary tumors. Study results showed that animals on low-fat diet supplemented with luteolin exhibited longer tumor latency and lower tumor weights and sizes compared to the other groups. Animals fed high-fat diet showed increased serum IGF-1 levels and the elevated mammary tissue expression of Ki-67, IRS-1, pp38, Cdk4, and Cdk6. Luteolin inhibited IRS-1, Cdk4, and Cdk6 expression in high-fat fed animals. The expression of pp38, cyclinD1, and Bcl-xL was suppressed by luteolin supplementation both in the low-fat and high-fat diet groups. These results suggest that excess energy supply increases the risk of mammary tumor formation and luteolin suppresses tumor formation regardless of dietary fat content through its cell cycle regulatory and proapoptotic activity. PMID:24074002

Song, Min-Ji; Lee, Eun-Ju; Yang, Young; Sung, Mi-Kyung

2014-01-01

287

Reduced energy intake and moderate exercise reduce mammary tumor incidence in virgin female BALB/c mice treated with 7,12-dimethylbenz(a)anthracene  

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The concurrent effects of diet (standard AIN-76A, restricted AIN-76A and high-fat diet) and moderate rotating-drum treadmill exercise on the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in virgin female BALB/cMed mice free of murine mammary tumor virus are evaluated. Analyses show that, although energy intake was related to mammary tumor incidence, neither body weight nor dietary fat predicted tumor incidence.

Lane, Helen W.; Teer, Patricia; Keith, Robert E.; White, Marguerite T.; Strahan, Susan

1991-01-01

288

Oldhamianoside II, a new triterpenoid saponin, prevents tumor growth via inducing cell apoptosis and inhibiting angiogenesis.  

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Oldhamianoside II is a new triterpenoid saponin that was isolated from the roots of Gypsophila oldhamiana. The present study aims to investigate the potential inhibitory activity of oldhamianoside II on tumor growth using an S180 tumor implantation mouse model. Oldhamianoside II at doses of 5.0 and 10.0 mg/kg was given with intraperitoneal injection for 10 days following subcutaneous inoculation of S180 tumor cells in anterior flank of mice. The tumor growth, the cell apoptosis, the microvessel density (MVD) in S180 tumors, the tumor cell viability, the tubular formation in vitro, and migration of tumor cells were examined. The expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and cyclooxygenase-2 (COX-2) was determined to analyze the associated mechanisms. The results showed that oldhamianoside II potently inhibited tumor cell viability in vitro. In addition, oldhamianoside II delayed tumor growth in anterior flank, induced S180 cell apoptosis, and reduced the MVD. Oldhamianoside II was also demonstrated to decrease the number of tubular structure and vessel formation in HUVEC cultures and chick embryo chorioallantoic membrane (CAM) model, respectively. Further study indicated that oldhamianoside II reduced the expression of VEGF, bFGF, and COX-2 in tumor sections. Moreover, oldhamianoside II inhibited the activity of migration and penetration to Matrigel of SGC7901 tumor cells in scratch wound and transwell chamber. In conclusion, our work defines oldhamianoside II, a new triterpenoid saponin, as a novel compound that can effectively inhibit S180 tumor growth, induce tumor cell apoptosis, prevent tumor angiogenesis, and inhibit cancer cell migration, suggesting that oldhamianoside II is a potential drug candidate for the treatment of cancer and for the prevention of metastasis. PMID:23924857

Wang, Feng-Ling; Sun, Jing-Yong; Wang, Yan; Mu, Yan-Ling; Liang, Yu-Ji; Chong, Zhao-Zhong; Qin, San-Hai; Yao, Qing-Qiang

2013-01-01

289

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

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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.

Tsui Paulus

2005-01-01

290

Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.  

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The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70%...

Coughlin, C. M.; Salhany, K. E.; Wysocka, M.; Aruga, E.; Kurzawa, H.; Chang, A. E.; Hunter, C. A.; Fox, J. C.; Trinchieri, G.; Lee, W. M.

1998-01-01

291

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

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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 ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, ?-catenin, GSK3?, CK1? and Axin1) and have a functional ?-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand–independent mechanisms.

van Wolferen, Monique E.; Rao, Nagesha A. S.; Grizelj, Juraj; Vince, Silvijo; Hellmen, Eva; Mol, Jan A.

2014-01-01

292

Adipocyte-derived endotrophin promotes malignant tumor progression  

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Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6?3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation t...

Park, Jiyoung; Scherer, Philipp E.

2012-01-01

293

Resveratrol derivative-rich melinjo (Gnetum gnemon L.) seed extract suppresses multiple angiogenesis-related endothelial cell functions and tumor angiogenesis.  

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Angiogenesis is a promising target for cancer prevention and treatment. This study aimed to determine the antiangiogenic effects of melinjo (Gnetum gnemon L.) seed extract and its resveratrol derivative components, such as gnetin C (GC), gnetin L (GL), gnemonoside A (GMA), gnemonoside C (GMC), and gnemonoside D (GMD). An ethanol extract of melinjo seeds (EEMS) and the two gnetins markedly inhibited the proliferation and tube formation of human umbilical vein endothelial cells (HUVEC) stimulated with vascular endothelial growth factor and basic fibroblast growth factor. The inhibitory effects of GC and GL were much stronger than those of resveratrol. GMC and GMD inhibited only proliferation, whereas GMA had almost no effect on the two endothelial cell functions. The EEMS and GC also reduced the cell viability of tube-forming HUVEC, with accompanying ERK1/2 inactivation, and suppressed the migration of HUVEC. Furthermore, dietary intake of EEMS significantly inhibited tumor angiogenesis in a mouse dorsal air sac assay. In conclusion, we found that the EEMS and its resveratrol derivatives, particularly GC, suppress multiple angiogenesis-related endothelial cell functions and/or tumor angiogenesis, indicating that the melinjo seeds and the natural resveratrol derivatives may be useful for cancer prevention and treatment. PMID:21936049

Kunimasa, Kazuhiro; Ohta, Toshiro; Tani, Hiroko; Kato, Eishin; Eguchi, Ryoji; Kaji, Kazuhiko; Ikeda, Katsumi; Mori, Hideki; Mori, Mari; Tatefuji, Tomoki; Yamori, Yukio

2011-11-01

294

Identification of a stable molecular signature in mammary tumor endothelial cells that persists in vitro.  

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Long-term, in vitro propagation of tumor-specific endothelial cells (TEC) allows for functional studies and genome-wide expression profiling of clonally derived, well-characterized subpopulations. Using a genetically engineered mouse model of mammary adenocarcinoma, we have optimized an isolation procedure and defined growth conditions for long-term propagation of mammary TEC. The isolated TEC maintain their endothelial specification and phenotype in culture. Furthermore, gene expression profiling of multiple TEC subpopulations revealed striking, persistent overexpression of several candidate genes including Irx2 and Zfp503 (transcription factors), Alcam and Cd133 (cell surface markers), Ccl4 and neurotensin (Nts) (angiocrine factors), and Gpr182 and Cnr2 (G protein-coupled receptors). Taken together, we have developed an effective method for isolating and culture-expanding mammary TEC, and uncovered several new TEC-selective genes whose overexpression persists even after long-term in vitro culture. These results suggest that the tumor microenvironment may induce changes in vascular endothelium in vivo that are stably transmittable in vitro. PMID:24257808

Xiao, Lin; Harrell, J Chuck; Perou, Charles M; Dudley, Andrew C

2014-07-01

295

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

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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.

Kim Jong-Hyuk

2010-05-01

296

Estradiol 16 alpha-hydroxylation in the mouse correlates with mammary tumor incidence and presence of murine mammary tumor virus: a possible model for the hormonal etiology of breast cancer in humans.  

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In this report, we describe our findings on the relationship between estradiol 16 alpha-hydroxylation and mammary tumor incidence. A close correlation between the two has been demonstrated with 16-hydroxylation being elevated in strains with a high incidence of tumors, such as RIII and C3H, and low in strains with a low incidence of cancer, such as C57BL. The extent of reaction is highly reproducible and unaffected by age or presence of overt mammary tumors. Studies on the inheritance of estr...

Bradlow, H. L.; Hershcopf, R. J.; Martucci, C. P.; Fishman, J.

1985-01-01

297

C3H/HeN mammary tumor-bearing mice develop type-specific neutralizing antibodies and group-specific precipitating antibodies for the mouse mammary tumor virus.  

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The development of mouse mammary tumor virus (MMTV)-neutralizing antibodies in various strains of mice was measured by their ability to neutralize the focus-forming capacity of a Kirsten sarcoma virus (C3H MMTV) pseudotype containing the MMTV envelope glycoprotein gp52. C3H/HeN, but not GR/N and RIII, mammary tumor-bearing mice were found to develop neutralizing antibodies to this pseudotype. In addition, non-tumor-bearing C3H/HeN, GR/N, RIII, NIH Swiss, C57BL/6, and BALB/c mice and 13 feral ...

1980-01-01

298

Prevalence and distribution of murine mammary tumor virus antigen detectable by immunocytochemistry in spontaneous breast tumors of wild mice.  

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Mouse mammary tumor virus (MuMTV) antigens were detected by immunoperoxidase cytochemistry in spontaneous breast tumors of wild mice from two widely separated areas of southern California. Eleven of 25 (44%) tumors from Lake Casitas (LC) mice and 4 of 5 tumors from Bouquet Canyon mice were positive. Included among the tumors lacking detectable MuMTV antigen were well-differentiated type A and type B carcinomas as well as tumors with an atypical pattern. In the antigen-positive tumors the distribution of staining was patchy and extremely variable in extent (less than 1-70% stained cells). The intensity and extent of staining were generally greater in breast tumors from hybrids of LC wild mice and C5LBL/10Sn or AKR inbred mice. A good correlation was found in the same tumors between immunoperoxidase staining, detection of MuMTV gp52 antigen by radioimmunoassay, and detection of type B particles by electron microscopy. All of the breast tumors in LC mice were positive for type C virus particles. PMID:6245303

Gardner, M B; Lund, J K; Cardiff, R D

1980-05-01

299

Effect of dietary astaxanthin at different stages of mammary tumor initiation in BALB/c mice.  

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The effects of astaxanthin on tumor growth, cardiac function and immune response in mice were studied. Female BALB/c mice were fed a control diet (diet C) for 8 weeks, 0.005% astaxathin for 8 weeks (diet A), or diet C for weeks 1-5 followed by diet A thereafter (diet CA). Mice were injected with a mammary tumor cell line on day 7 and tumor growth was measured daily. Mice fed diet A had extended tumor latency and lower tumor volume (p<0.05). Interestingly, those fed diet CA showed the fastest tumor growth. Astaxanthin feeding elevated plasma astaxanthin concentrations; there was no difference in plasma astaxanthin between mice fed CA and those fed A. Mice fed diet A, but not CA, had a higher (p<0.05) natural killer cell subpopulation and plasma interferon-gamma concentration compared to those fed diet C. Astaxanthin delayed tumor growth and modulated immune response, but only when astaxanthin was given before tumor initiation. This suggests that an adequate blood astaxanthin status is needed to protect against tumor initiation; conversely, astaxanthin supplementation after tumor initiation may be contraindicated. PMID:20651366

Nakao, Ruriko; Nelson, O Lynne; Park, Jean Soon; Mathison, Bridget D; Thompson, Pam A; Chew, Boon P

2010-06-01

300

Effects of ionizing irradiation on the estradiol and progesterone receptors in rat mammary tumors  

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The determination of estradiol and progesterone receptor concentrations in mammary tumors is useful in predicting the hormone responsiveness. As this assay is carried out on tumor tissue which may have been subjected to radiotherapy, the possibility of an ionizing irradiation affecting the steroid receptor levels in neoplastic tissue should be taken into account. The steroid receptor concentrations are examined in dimethylbenz(a)anthracene-induced tumors os Sprague-Dawley rats. The estradiol and the progesterone receptor titers become reduced significantly after treatment with 20 Gray while an application with 7 Gray does not affect the titer values. After treatment of the tumor with 20 Gray, the steroid receptor concentrations decrease progressively, reaching a maximal reduction 20 to 30 days after exposure. As radiation treatment affects the receptor concentrations, this should be kept in mind when interpreting the steroid receptor concentrations

1981-01-01

 
 
 
 
301

Mammary tumor development in MMTV-c-myc/MMTV-v-Ha-ras transgenic mice is unaffected by osteopontin deficiency.  

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Transgenic mice expressing c-myc and v-Ha-ras specifically in the mammary gland under the control of the mammary specific promoter MMTV develop unifocal mammary tumors with a half time of about 46 days, and these tumors express high levels of osteopontin mRNA and protein. In order to evaluate the requirement for osteopontin expression by these tumors, we have crossed transgenic mice expressing these two oncogenes with mice with a targeted disruption of the osteopontin gene. Littermates expressing both myc and ras, and with either wild-type or disrupted OPN alleles were evaluated for tumor incidence and growth rate. Both of these parameters were found to be unaffected by a lack of osteopontin in the whole animal. Ras and myc expression level, measured at the level of mRNA, was not different in tumors of the two genotypes. Macrophage accumulation, while extremely variable among different tumors, did not correlate with the OPN status of the animals. Expression of the related gene BSP was not detected in any of the tumors, and was similar in bones of wildtype and OPN -/- mice. Similarly, the vitronectin gene was expressed at very low levels in tumors of either genotype. These results indicate that despite its high level of expression, OPN is either not required for mammary primary tumor formation and growth in this system, or can be replaced by molecules other than BSP and vitronectin in mice that totally lack osteopontin. PMID:11079161

Feng, F; Rittling, S R

2000-09-01

302

FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma.  

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The transcription factor forkhead box D3 (FOXD3) plays a crucial role in the development of neural crest cells. However, the function and underlying mechanisms of FOXD3 in the progression of neuroblastoma (NB), an embryonal tumor that is derived from the neural crest, still remain largely unknown. Here, we report that FOXD3 is an important oncosuppressor of NB tumorigenicity and aggressiveness. We found that FOXD3 was down-regulated in NB tissues and cell lines. Patients with high FOXD3 expression have greater survival probability. Over-expression or knockdown of FOXD3 responsively altered both the protein and mRNA levels of N-myc downstream regulated 1 (NDRG1) and its downstream genes, vascular endothelial growth factor and matrix metalloproteinase 9, in cultured NB cell lines SH-SY5Y and SK-N-SH. Luciferase reporter and chromatin immunoprecipitation assays indicated that FOXD3 directly targeted the binding site within NDRG1 promoter to facilitate its transcription. Ectopic expression of FOXD3 suppressed the growth, invasion, metastasis and angiogenesis of SH-SY5Y and SK-N-SH cells in vitro and in vivo. Conversely, knockdown of FOXD3 promoted the growth, migration, invasion and angiogenesis of NB cells. In addition, rescue experiments in FOXD3 over-expressed or silenced NB cells showed that restoration of NDRG1 expression prevented the tumor cells from FOXD3-mediated changes in these biological features. Our results indicate that FOXD3 exhibits tumor suppressive activity that affects the growth, aggressiveness and angiogenesis of NB through transcriptional regulation of NDRG1. PMID:24269992

Li, Dan; Mei, Hong; Qi, Meng; Yang, Dehua; Zhao, Xiang; Xiang, Xuan; Pu, Jiarui; Huang, Kai; Zheng, Liduan; Tong, Qiangsong

2013-11-01

303

Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.  

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Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels o...

Yoshida, S.; Ono, M.; Shono, T.; Izumi, H.; Ishibashi, T.; Suzuki, H.; Kuwano, M.

1997-01-01

304

Development of Hyperplasias, Preneoplasias, and Mammary Tumors in MMTV-c-erbB-2 and MMTV-TGF? Transgenic Rats  

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Human cDNAs corresponding to two epidermal growth factor-related products that are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for transforming growth factor ? (TGF?), have been cloned downstream of the mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into the pronucleus of fertilized oocytes of Sprague-Dawley rats to produce transgenic offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue from virgin transgenic...

Davies, Barry R.; Platt-higgins, Angela M.; Schmidt, Gunter; Rudland, Philip S.

1999-01-01

305

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

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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...

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

306

Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.  

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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...

Forni, Guido; Cavallo, Federica

2001-01-01

307

Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer.  

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The antiangiogenic agent bevacizumab has been approved for the treatment of non-small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor-mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC. PMID:21896639

Aftab, Blake T; Dobromilskaya, Irina; Liu, Jun O; Rudin, Charles M

2011-11-01

308

The ROSA26 LacZ-neo(R) insertion confers resistance to mammary tumors in Apc(Min/+) mice.  

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B6.129S7-Gtrosa26 (ROSA26) mice carry a LacZ-neo(R) insertion on Chromosome (Chr) 6, made by promoter trapping with AB1 129 ES cells. Female C57BL/6J Apc(Min/+) (B6 Min/+) mice are very susceptible to the induction of mammary tumors after treatment with ethylnitrosourea (ENU). However, ENU-treated B6 mice carrying both Apc(Min) and ROSA26 are resistant to mammary tumor formation. Thus, ROSA26 mice carry a modifier of Min-induced mammary tumor susceptibility. We have previously mapped the modifier to a 4-cM interval of 129-derived DNA that also contains the ROSA26 insertion. Here we report additional evidence for the effect of the ROSA26 insertion on mammary tumor formation. To test the hypothesis that the resistance was due to a linked modifier locus, we utilized two approaches. We have derived and tested two lines of mice that are congenic for 129-derived DNA within the minimal modifier interval and show that they are as susceptible to mammary tumors as are B6 mice. Additionally, we analyzed a backcross population segregating for the insertion and show that mice carrying the insertion are more resistant to mammary tumor development than are mice not carrying the insertion. Thus, the resistance is not due to a 129-derived modifier allele, but must be due to the ROSA26 insertion. In addition, the effect of the ROSA26 insertion can be detected in a backcross population segregating for other mammary modifiers. PMID:11471054

Kohlhepp, R L; Hegge, L F; Moser, A R

2001-08-01

309

[The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis].  

Science.gov (United States)

Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs) are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN). MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs) and endothelial cells (ECs). MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT). MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM.  PMID:23001203

Fink, Krzysztof; Boraty?ski, Janusz

2012-01-01

310

 The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis  

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Full Text Available Extracellular matrix metalloproteinases (MMPs are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN. MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs and endothelial cells (ECs. MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT. MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM. 

Krzysztof Fink

2012-09-01

311

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

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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 demonstrated that Boc-group is an effective prosthetic one to prevent deiodination in vivo and meliorate tumor imaging for small peptide.

2005-10-17

312

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

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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 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.

2009-01-01

313

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

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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-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.

Zhang Dong [Department of Radiology, XinQiao Hospital, Third Military Medical University, ChongQing 400037 (China); Feng Xiaoyuan [Department of Radiology, Hua Shan Hospital, Medical Center of FuDan University, ShangHai 200040 (China); Henning, Tobias D. [UCSF, Department of Radiology, Contrast Media Laboratory, 185 Berry Street, San Francisco, CA 94107 (United States); Wen Li [Department of Radiology, XinQiao Hospital, Third Military Medical University, ChongQing 400037 (China); Lu Weiyue; Pan Hong [Department of Pharmaceutical Targeting, Institute of Pharmacy, Medical Center of FuDan University, ShangHai 200032 (China); Wu Xing [Department of Neurosurgery, Hua Shan Hospital, Medical Center of FuDan University, ShangHai 200040 (China); Zou Liguang [Department of Radiology, XinQiao Hospital, Third Military Medical University, ChongQing 400037 (China)], E-mail: cqzdwl@yahoo.com.cn

2009-04-15

314

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-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.

2009-04-01

315

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

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Full Text Available 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 benign and malignant surface epithelial ovarian tumors. METHODS: We examined 42 cases of surface epithelial ovarian tumors and divided them in two groups (14 malignant and 28 benign tumors. Both study groups were compared for smooth muscle and endothelial cells in tumor vessels using monoclonal antibodies against smooth muscle actin (SMA and CD34 (endothelial cell marker respectively. MVD, SMA expression index and CD34 intensity index was calculated in both groups. RESULTS: The malignant surface epithelial ovarian tumors showed higher MVD (34.48±12.87 as compared to benign ovarian tumors (16.49±6.17 (p<0.001. Also, the blood vessels of malignant tumor showed significantly poor SMA expression and intense CD34 expression compared with vessels of benign tumors. CONCLUSION: The present study shows higher MVD, greater endothelial cell expression and poor muscle coat in tumor vessels of malignant ovarian surface epithelial tumors. These results indicate higher tumor angiogenesis with thinner vessels, which facilitates tumor spread. [J Interdiscipl Histopathol 2013; 1(3.000: 145-152

Shelly Sehgal

2013-06-01

316

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

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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.

Avilés-Salas Alejandro

2009-08-01

317

Rat differences in mammary tumor induction with estrogen and neutron radiation  

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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

1978-01-01

318

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

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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.

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

1982-11-01

319

TGF-? autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.  

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Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-? (TGF-?) cytokines. In early-stage breast cancers, TGF-? exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-? promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-? are not fully understood. The present study validates the role of TGF-? signaling in cancer progression and explores mediators of pro-oncogenic TGF-? activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-? receptors decreased both basal and TGF-?-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-? stimulation of cell motility and invasion. TGF-? disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-?. Blockade of Raf-MEK signaling enhanced TGF-? induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-? rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-? stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-? receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-? signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-?-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-? signaling. PMID:22614218

Daroqui, María Cecilia; Vazquez, Paula; Bal de Kier Joffé, Elisa; Bakin, Andrei V; Puricelli, Lydia I

2012-08-01

320

A concise review of magnetic resonance molecular imaging of tumor angiogenesis by targeting integrin ?v?3 with magnetic probes  

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Full Text Available Yajie Liu, Yi Yang, Chunfu Zhang School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Abstract: Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification of tumor angiogenesis is important for early diagnosis of cancers as well as post therapy assessment of antiangiogenic drugs. The cell adhesion molecule integrin ?v?3 is a specific marker of angiogenesis, which is highly expressed on activated and proliferating endothelial cells, but generally not on quiescent endothelial cells. Therefore, in recent years, many different approaches have been developed for imaging ?v?3 expression, for the detection and characterization of tumor angiogenesis. The present review provides an overview of the current status of magnetic resonance molecular imaging of integrin ?v?3, including the new development of high sensitive contrast agents and strategies for improving the specificity of targeting probes and the biological effects of imaging probes on avB3 positive cells. Keywords: integrin ?v?3, molecular imaging, MRI, paramagnetic liposome, superparamagnetic iron oxide particles, tumor angiogenesis

Liu Y

2013-03-01

 
 
 
 
321

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

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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.

Samuelson Emma

2012-08-01

322

Time dependence of response of transplanted mouse mammary tumors to single or split radiation doses  

International Nuclear Information System (INIS)

The effect of single and different split radiation doses with varying rates and time intervals was invetigated in an experimental system in vivo using second generation isotransplants of two mouse mammary carcinomas. The changes in the growth delay time (GDT) and tumor control rate (TCR) were analyzed, and explained by a dose dependence of the repair of sublethal radiation damage, reoxygeneration and cellular repopulation in the tumors. A direct relationship was found between the size of the first of two dose fractions and the time interval between two exposures at which treatment with split doses is most effective in delaying or preventing tumor growth. Multiple exposures to unequal dose fractions are more effective than to equal fractions with the same total dose

1983-01-01

323

Direct measurement of reoxygenation in malignant mammary tumors after a single large dose of irradiation  

International Nuclear Information System (INIS)

Measurements of the tissue O_2 partial pressure distribution in C3H mouse mammary adenocarcinomas were performed just before and 72 - 74 hrs. after X- irradiation using O_2 microelectrodes of the gold in glass type. The results obtained before irradiation were similar to those usually obtained previously in fast growing murine tumors during advanced growth stages. After exposure to a single dose of 60 Gy, the distribution curve significantly changed. This change was particularly evident in the very low pO_2 range which is of crucial importance for the efficacy of radiotherapy. Due to this improvement of the tumor tissue oxygenation the number of radioresistant cells can be drastically reduced in the post- irradiation period at the time of maximum reoxygenation. Judiciously chosen fractionated treatment regimens, thus, should maintain tumor cells in optimum radiosensitivity states

1984-01-01

324

Direct measurement of reoxygenation in malignant mammary tumors after a single large dose of irradiation  

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Measurements of the tissue O/sub 2/ partial pressure distribution in C3H mouse mammary adenocarcinomas were performed just before and 72 - 74 hrs. after X- irradiation using O/sub 2/ microelectrodes of the gold in glass type. The results obtained before irradiation were similar to those usually obtained previously in fast growing murine tumors during advanced growth stages. After exposure to a single dose of 60 Gy, the distribution curve significantly changed. This change was particularly evident in the very low pO/sub 2/ range which is of crucial importance for the efficacy of radiotherapy. Due to this improvement of the tumor tissue oxygenation the number of radioresistant cells can be drastically reduced in the post- irradiation period at the time of maximum reoxygenation. Judiciously chosen fractionated treatment regimens, thus, should maintain tumor cells in optimum radiosensitivity states.

Vaupel, P.; Frinak, S.; O' Hara, M.

1984-01-01

325

Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor.  

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Ursolic acid (UA) is a pentacyclic triterpene naturally occurring in many plant foods. In the present study, we investigated anti-cancer activity of UA in vivo in Ehrlich ascites carcinoma (EAC) tumor. 15 × 10(6) EAC cells were implanted intraperitoneally (i.p., ascitic tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received UA i.p. at 25, 50 and 100mg/kg bw for 14 d in ascitic and 100mg/kg bw in solid tumor for 30 d. On day 15, blood samples were collected for hematological assessment of hemoglobin (Hb%), RBCs, WBCs and PCV. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF, iNOS, CD31, caspase-3 and Bax were also performed. UA significantly inhibited tumor growth, cell viability, in both ascites and solid tumor model in vivo (p<0.001). The anti-angiogenic effects were accompanied with decreased VEGF, iNOS, TNF-? and increased IL-12 levels. UA at 100mg/kg bw dose significantly increased SOD and CAT activity (p<0.01). GSH and TBARS were increased as compared to control group (p<0.001). Furthermore, UA increased total RBCs, WBCs as well as Hb% significantly (p<0.05) compared to cyclophosphamide (CP). Histopathological examination of tumor cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. Decreased peritoneal angiogenesis showed the anti-angiogenic potential. UA downregulated VEGF & iNOS expression whereas bax and caspase-3 expressions were upregulated suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3 and downregulation of VEGF. The present study sheds light on the potent antitumor property of the UA and can be extended further to develop therapeutic protocols for treatment of cancer. PMID:24051192

Saraswati, Sarita; Agrawal, S S; Alhaider, Abdulqader A

2013-11-25

326

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

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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

Mahasiripanth T

2012-08-01

327

mMaspin: the mouse homolog of a human tumor suppressor gene inhibits mammary tumor invasion and motility.  

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BACKGROUND: The human maspin gene encodes a protein in the serine proteinase inhibitor (serpin) family with tumor-suppressing functions in cell culture and in nude mice. In order to examine the role of maspin in an intact mammal, we cloned and sequenced the cDNA of mouse maspin. The recombinant protein was produced and its activity in cell culture was assessed. MATERIALS AND METHODS: Mouse maspin (mMaspin) was cloned by screening a mouse mammary gland cDNA library with the human maspin cDNA p...

1997-01-01

328

Demethylation and expression of murine mammary tumor proviruses in mouse thymoma cell lines.  

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Murine mammary tumor virus (MMTV) expression is analyzed in a T-lymphoid cell line (T1M1) sensitive to the killing effect of glucocorticoids and in two of its variants, one resistant (T1M1r) and one supersensitive (T1M1ss) to glucocorticoid-induced lymphocytolysis. In the T1M1 line, MMTV is expressed and induced approximately 10-fold by short treatment with dexamethasone. Southern blot analyses of restriction enzyme digests of DNA from T1M1 cells reveal three proviruses similar to those of no...

1983-01-01

329

Glucocorticoids and chromosomal position modulate murine mammary tumor virus transcription by affecting efficiency of promoter utilization.  

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The rate of transcription of murine mammary tumor virus (MTV) sequences in MTV-infected rat hepatoma tissue culture cells is strongly affected by both glucocorticoid hormones and the chromosomal position of provirus integration. We have characterized MTV RNAs produced in J2.17 and M1.54, independent isolates containing, respectively, 1 and 10 proviruses integrated at distinct chromosomal loci. M1.54, but not J2.17, synthesized MTV RNA in the absence of glucocorticoids; the rate of hormone-sti...

Ucker, D. S.; Firestone, G. L.; Yamamoto, K. R.

1983-01-01

330

Terminal amino acid sequences and proteolytic cleavage sites of mouse mammary tumor virus env gene products.  

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The mature envelope glycoproteins of mouse mammary tumor virus (gp52 and gp36) were isolated by reversed-phase high-pressure liquid chromatography. The N-terminal amino acid sequence of gp36 was determined for 28 residues. The C-terminal amino acid sequences of gp52 and gp36 were determined by carboxypeptidase digestion. The N-terminal amino acid sequence of gp52 has been reported previously (L. O. Arthur et al., J. Virol. 41:414-422, 1982). These data were aligned with the predicted amino ac...

Henderson, L. E.; Sowder, R.; Smythers, G.; Oroszlan, S.

1983-01-01

331

Mouse mammary tumor viruses with functional superantigen genes are selected during in vivo infection.  

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Mouse mammary tumor virus (MMTV) encodes a superantigen that is important for viral infectivity in vivo. To determine whether superantigen function was required for infection by milk-borne MMTV, we created HYB PRO/Cla transgenic mice. These mice produced a full-length, packaged viral RNA with a frameshift mutation that caused premature termination of the superantigen protein. Young HYB PRO/Cla mice showed no deletion of their cognate V beta 14+ T cells, although they shed virus in their milk....

1995-01-01

332

Expression of human sequences related to those of mouse mammary tumor virus.  

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Sequences related to those of the mouse mammary tumor virus (MuMTV) genome have been cloned from human DNA by screening a library prepared from the DNA of a human breast cancer cell line with MuMTV gag-pol DNA. Nine distinct groups of (MuMTV-related) sequences were identified among 100 lambda recombinants by cross-hybridization experiments with subcloned fragments containing gag-pol-related DNA. The largest group, of 64 recombinants, contains the MuMTV-related sequences cloned by others. The ...

1988-01-01

333

A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth  

Science.gov (United States)

Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration. In vivo, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin. cancer vaccines | neoplasia | neovascularization | breast cancer | angiostatin

Holmgren, Lars; Ambrosino, Elena; Birot, Olivier; Tullus, Carl; Veitonmäki, Niina; Levchenko, Tetyana; Carlson, Lena-Maria; Musiani, Piero; Iezzi, Manuela; Curcio, Claudia; Forni, Guido; Cavallo, Federica; Kiessling, Rolf

2006-06-01

334

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

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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.

Castillo-Pichardo Linette

2013-01-01

335

Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors.  

Science.gov (United States)

The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis. PMID:22815804

Smart, Chanel E; Askarian Amiri, Marjan E; Wronski, Ania; Dinger, Marcel E; Crawford, Joanna; Ovchinnikov, Dmitry A; Vargas, Ana Cristina; Reid, Lynne; Simpson, Peter T; Song, Sarah; Wiesner, Christiane; French, Juliet D; Dave, Richa K; da Silva, Leonard; Purdon, Amy; Andrew, Megan; Mattick, John S; Lakhani, Sunil R; Brown, Melissa A; Kellie, Stuart

2012-01-01

336

Multivariate statistical analysis of Raman spectra to distinguish normal, tumor, lymph nodes and mastitis in mouse mammary tissues  

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Raman spectra ( > 680) of normal mammary gland, malignant mammary gland tumors, and lymph node tissues from mice injected with 4T1 tumor cells have been recorded using 785 nm excitation laser. The state of the tissues was confirmed by standard pathological tests. The multivariate statistical analysis methods (principle component analysis and discriminant functional analysis) have been used to categorize the Raman spectra. The statistical algorithms based on the Raman spectral peak heights, clearly separated tissues into six distinct classes, including mastitis, which is clearly separated from normal and tumor. This study suggests that the Raman spectroscopy can possibly perform a real-time analysis of the human mammary tissues for the detection of cancer.

Dai, H.; Thakur, J. S.; Serhatkulu, G. K.; Pandya, A. K.; Auner, G. W.; Naik, R.; Freeman, D. C.; Naik, V. M.; Cao, A.; Klein, M. D.; Rabah, R.

2006-03-01

337

Changes in the secretory profile of NSCLC-associated fibroblasts after ablative radiotherapy: potential impact on angiogenesis and tumor growth  

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In the context of radiotherapy, collateral effects of ablative ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x18Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiate...

Hellevik, T.; Pettersen, I.; Berg, V.; Bruun, J.; Bartnes, K.; Busund, T. -l; Chalmers, A.; Bremnes,, R.; Martinez-zubiaurre, I.

2013-01-01

338

Benzyl Isothiocyanate Suppresses Pancreatic Tumor Angiogenesis and Invasion by Inhibiting HIF-?/VEGF/Rho-GTPases: Pivotal Role of STAT-3  

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Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cell...

Boreddy, Srinivas Reddy; Sahu, Ravi P.; Srivastava, Sanjay K.

2011-01-01

339

?-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  

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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.

Okuno Yasushi

2011-06-01

340

Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis.  

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High rate of glycolysis is a metabolic hallmark of cancer. While anaerobic glycolysis promotes energy production under hypoxia, aerobic glycolysis, the Warburg effect, offers a proliferative advantage through redirecting carbohydrate fluxes from energy production to biosynthetic pathways. To fulfill tumor cell needs, the glycolytic switch is associated with elevated glucose uptake and lactic acid release. Altered glucose metabolism is the basis of positron emission tomography using the glucose analogue tracer [18F]- fluorodeoxyglucose, a widely used clinical application for tumor diagnosis and monitoring. On the other hand, high levels of lactate have been associated with poor clinical outcome in several types of human cancers. Although lactic acid was initially considered merely as an indicator of the glycolytic flux, many evidences originally from the study of normal tissue physiology and more recently transposed to the tumor situation indicate that lactic acid, i.e. the lactate anion and protons, directly contributes to tumor growth and progression. Here, we briefly review the current knowledge pertaining to lactic acidosis and metastasis, lactate shuttles, the influence of lactate on redox homeostasis, lactate signaling and lactate-induced angiogenesis in the cancer context. The monocarboxylate transporters MCT1 and MCT4 have now been confirmed as prominent facilitators of lactate exchanges between cancer cells with different metabolic behaviors and between cancer and stromal cells. We therefore address the function and regulation of MCTs, highlighting MCT1 as a novel anticancer target. MCT1 inhibition allows to simultaneously disrupt metabolic cooperativity and angiogenesis in cancer with a same agent, opening a new path for novel anticancer therapies. PMID:22360558

Dhup, Suveera; Dadhich, Rajesh Kumar; Porporato, Paolo Ettore; Sonveaux, Pierre

2012-01-01

 
 
 
 
341

[Effect of valproic acid against angiogenesis of Kasumi-1 xenograft tumor in nude mice].  

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This study was aimed to investigate the effect of valproic acid (VPA), a histone deacetylase inhibitor, on angiogenesis of acute myeloid leukemia in vivo and vitro, and to explore its molecular mechanism. Human t (8;21) AML cell line Kasumi-1 cells were treated with VPA at different concentration for 3 d, the mRNA and protein expression levels of Ang1 and Ang2 were determined by semi-quantitative RT-PCR and Western blot respectively. Nude mice model with xenograft Kasumi-1 tumor was established by subcutaneous inoculation of Kasumi-1 cells. The CD34, Ang1 and Ang2 protein levels were analyzed by immunohistochemistry method. The mRNA and protein expression levels of Ang1, Ang2 and VEGF were determined by semi-quantitative RT-PCR and Western blot. The results showed that in vitro, VPA at 3 mmol/L downregulated the Ang mRNA relative expression level for Ang1 from 0.360 ± 0.116 to 0.040 ± 0.008, Ang2 from 0.540 ± 0.049 to 0.146 ± 0.038. The animal experiment further verified that VPA 500 mg/kg, ip, for 14 d, reduced the relative expression of Ang1, Ang2 and VEGF mRNA and proteins in Kasumi-1 tumor of nude mice, and reduced microvascular density in xenograft tumor of nude mice (8.470 ± 0.300 vs 2.600 ± 0.200). It is concluded that VPA significantly inhibits tumor angiogenesis through the regulation of angiopoietins, thereby inhibits the proliferation and metastasis of leukemia cells. PMID:23484695

Wang, Li-Hong; Zhang, Zhi-Hua; Zhao, Lei; Zhu, Cui-Min; Zhao, Li-Shuang; Hao, Chang-Lai

2013-02-01

342

Ultrasonic characterization of three animal mammary tumors from three-dimensional acoustic tissue models  

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This dissertation investigated how three-dimensional (3D) tissue models can be used to improve ultrasonic tissue characterization (UTC) techniques. Anatomic sites in tissue responsible for ultrasonic scattering are unknown, which limits the potential applications of ultrasound for tumor diagnosis. Accurate 3D models of tumor tissues may help identify the scattering sites. Three mammary tumors were investigated: a rat fibroadenoma, a mouse carcinoma, and a mouse sarcoma. A 3D acoustic tissue model, termed 3D impedance map (3DZM), was carefully constructed from consecutive histologic sections for each tumor. Spectral estimates (scatterer size and acoustic concentration) were obtained from the 3DZMs and compared to the same estimates obtained with ultrasound. Scatterer size estimates for three tumors were found to be similar (within 10%). The 3DZMs were also used to extract tissue-specific scattering models. The scattering models were found to allow clear distinction between the three tumors. This distinction demonstrated that UTC techniques may be helpful for noninvasive clinical tumor diagnosis.

Mamou, Jonathan M.

343

APC/?-catenin-rich complexes at membrane protrusions regulate mammary tumor cell migration and mesenchymal morphology  

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Full Text Available Abstract Background The APC tumor suppressor is mutated or downregulated in many tumor types, and is prominently localized to punctate clusters at protrusion tips in migratory cells, such as in astrocytes where it has been implicated in directed cell motility. Although APC loss is considered an initiating event in colorectal cancer, for example, it is less clear what role APC plays in tumor cell motility and whether loss of APC might be an important promoter of tumor progression in addition to initiation. Methods The localization of APC and ?-catenin was analyzed in multiple cell lines, including non-transformed epithelial lines treated with a proteasome inhibitor or TGF? to induce an epithelial-to-mesenchymal transition (EMT, as well as several breast cancer lines, by immunofluorescence. APC expression was knocked down in 4T07 mammary tumor cells using lentiviral-mediated delivery of APC-specific short-hairpin (sh RNAs, and assessed using quantitative (q reverse-transcriptase (RT-PCR and western blotting. Tumor cell motility was analyzed by performing wound-filling assays, and morphology via immunofluorescence (IF and phase-contrast microscopy. Additionally, proliferation was measured using BrdU incorporation, and TCF reporter assays were performed to determine ?-catenin/TCF-mediated transcriptional activity. Results APC/?-catenin-rich complexes were observed at protrusion ends of migratory epithelial cells treated with a proteasome inhibitor or when EMT has been induced and in tumor cells with a mesenchymal, spindle-like morphology. 4T07 tumor cells with reduced APC levels were significantly less motile and had a more rounded morphology; yet, they did not differ significantly in proliferation or ?-catenin/TCF transcriptional activity. Furthermore, we found that APC/?-catenin-rich complexes at protrusion ends were dependent upon an intact microtubule cytoskeleton. Conclusions These findings indicate that membrane protrusions with APC/?-catenin-containing puncta control the migratory potential and mesenchymal morphology of mammary tumor cells and suggest that APC loss during later stages of tumor progression might impact tumor cell dissemination or colonization.

Odenwald Matthew A

2013-01-01

344

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

1984-06-05

345

Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice.  

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We tested the antineoplastic effect of the farnesyltransferase inhibitor L-744,832 in mammary and lymphoid tumors overexpressing the N-ras proto-oncogene in transgenic mice. Mice bearing mammary tumors were randomly assigned to receive daily 40 mg/kg s.c. injections of this compound (experimental group, n = 6) or vehicle (control group, n = 6) per day for 5.5 weeks. Treatment with the compound significantly reduced the mammary tumor mean growth rate in the experimental group (-0.7 mm3/day), as compared with the control group (+28.2 mm3/day; P L-744,832 or vehicle, either in vivo or in vitro (after primary culture of the same tumors), and from several in vitro treated control cell lines. In all compound-treated mammary tumors and cell lines, H-Ras was mostly unprocessed (more so after in vitro than after in vivo treatment), whereas N-Ras remained mostly processed. Both H-Ras and N-Ras remained fully processed in all vehicle-treated samples. These findings are consistent with a less intense antineoplastic effect of the treatment with the compound in our N-ras model than the effect previously reported for the same compound in H-ras transgenics. In addition, the finding that, in compound-treated mammary tumors, the N-Ras protein remains mainly processed suggests that, in our model, other proteins in addition to Ras may be a target for the compound. Our results and the previous findings of frequent N-ras activation in human hematopoietic malignancies support a role for L-744,832 in the treatment of lymphomas and of mammary carcinomas with an activated N-Ras pathway, as well as the testing of a farnesyl protein transferase inhibitor in humans to establish its clinical relevance. PMID:9515813

Mangues, R; Corral, T; Kohl, N E; Symmans, W F; Lu, S; Malumbres, M; Gibbs, J B; Oliff, A; Pellicer, A

1998-03-15

346

Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo.  

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Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment. PMID:9788974

Sharma, B; Handler, M; Eichstetter, I; Whitelock, J M; Nugent, M A; Iozzo, R V

1998-10-15

347

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

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: Portuguese Abstract in portuguese 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.

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

348

In vivo effect of alpha-bisabolol, a nontoxic sesquiterpene alcohol, on the induction of spontaneous mammary tumors in HER-2/neu transgenic mice.  

Science.gov (United States)

Breast cancer represents the most commonly diagnosed invasive malignancy in pre- and postmenopausal women in both developed and underdeveloped countries. Taking into account that treatment options, including surgery, have not been able to deal with the growing incidence of breast malignancy, it is required to develop mechanism-based novel agents for its prevention. Wide interest in some natural compounds as antiinflammatory agents and as alternative to the traditional medicines is increasing because they do not provoke any adverse effects and are effective in multiple organs, alpha-Bisabolol (BISA), a small oily sesquiterpene alcohol, was reported as chemopreventive agent in induced rat mammary carcinogenesis. The aim of the present study is to investigate the role played by two doses of BISA (via intramammary infusion) on the induction and development of mammary tumor in HER-2/neu transgenic mice as well as the BISA effect after tumor surgical resection. The main data show that (a) optimal dosage of BISA is 10 mg/mouse rather than 3.6 mg/mouse with no adverse effects (e.g., alopecia); (b) the number of the palpable tumor masses decreases in mice treated with 10 mg/mouse of BISA; (c) mice after surgical resection of the primary tumor and treatment with BISA (10 mg) are free from tumor for more weeks, after the surgical treatment; (d) using array analysis, some genes implicated in carcinogenesis mechanisms (NF-kappaBia, Map2k, Mapkl4, and HER2/ neu), angiogenesis process (Fgf), and inhibition of apoptosis (Birc5) are differently regulated after BISA treatment, with a downregulation of the HER2/neu as well as of Fgf and Birc5 genes; (e) the NK cell cytotoxicity increases in tumor-treated mice, especially after the removal of the first tumor mass. Such effectiveness could be important to achieve goals for a possible combination of BISA to conventional therapies in breast cancer and to tumor surgical removal (adjuvant therapy), as suggested for other sesquiterpene analogs. PMID:20524399

Costarelli, Laura; Malavolta, Marco; Giacconi, Robertina; Cipriano, Catia; Gasparini, Nazzarena; Tesei, Silvia; Pierpaoli, Sara; Orlando, Fiorenza; Suzuki, Hisanori; Perbellini, Luigi; Piacenza, Francesco; Emanuelli, Monica; Mocchegiani, Eugenio

2010-01-01

349

Solid-tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Purpose: The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particle-emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells.

Zhu, Xuping; Palmer, Matthew R.; Makrigiorgos, G. Mike; Kassis, Amin I.

2010-01-01

350

Anticancer activity of phenolic antioxidants against breast cancer cells and a spontaneous mammary tumor  

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Full Text Available Phenolics such as ferulic, caffeic, gallic acids and curcumin were tested for their potential anti proliferative and cytotoxic properties in human breast cancer cell line (MCF-7 as well as on a spontaneous mammary adenocarcinoma tumor. As a single agent, caffeic acid showed substantial growth inhibitory activity. In combination with cisplatin it was also found to be effective. For the current study we used a chick embryo model to assess antiangiogenic activity. Curcumin and its beta cyclodextrin complex were observed to interfere with capillary formation. The selected phenolics were structurally related which allowed us to gather additional information regarding the structure - activity relationship underlying the biological activity of these bioactive compounds. It was verified that the hydroxylated acid derivatives yielded better results than the merely hydroxylated ones in these tumor systems.

Indap M

2006-01-01

351

Mammary Gland Tumor Development in Transgenic Mice Overexpressing Different Isoforms of the CDP/Cux Transcription Factor  

Canada Institute for Scientific and Technical Information (Canada)

Short CUX1 isoforms were found to be overexpressed in breast cancer cell lines, in human breast tumors and in uterine leiomyomas, suggesting that these proteins play a key role in tumor development and progression. My project consists in analyzing the effect of these CUX1 isoforms on mammary gland development and tumorigenesis. Also, I will work on the identification of targets of CUX1 that mediate its oncogenic properties. So far, I have shown that overexpressing short CUX1 isoforms leads to abnormal development of the mammary gland. Furthermore, overexpressing p75, p110 or p200 CUX1 leads to the development of mammary gland tumors in mice. These tumors seem to be of basal origin, suggesting that CUX1 promotes tumorigenesis in a precursor cell. Breast tumor patients with similar types of disease have very low chances of survival, since no specific treatment is currently available for them. Thus, my research project will enable us to gain a better understanding of the biological functions of each CUX1 isoform in mammary gland development and tumorigenesis, which could possibly lead to new therapeutic targets for the treatment of basal breast cancer.

2008-01-01

352

Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade.  

Science.gov (United States)

Traditional medicinal herb Andrographis paniculata is known to possess anti-tumor activity, and its potential active compound is the diterpenoid lactone andrographolide (ANGL). In this study, we have found that ANGL inhibits tumor growth in nude mice bearing xenografted Hep3B cancer cells, concomitant with a reduction in tumor vessel counts. ANGL inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenic responses in vitro and neoangiogenesis in vivo. We also found that ANGL inhibits VEGFA-induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream targets such as the mitogen-activated protein kinases (MAPKs). ANGL interferes with the binding of VEGFA to VEGFR2, but has no effect on VEGFR2 kinase activity in vitro. Taken together, our results indicate that ANGL possesses anti-angiogenic activity which is mediated by preventing VEGFA-induced phosphorylation and activation of VEGFR2 and MAPKs. The present study indicates that ANGL can block tumor angiogenesis and therefore represents therapeutic potential for cancer treatment. PMID:24814888

Shen, Kaikai; Ji, Lili; Lu, Bin; Xu, Chong; Gong, Chenyuan; Morahan, Grant; Wang, Zhengtao

2014-07-25

353

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

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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.

Adams, D.; De Nardo, G.; Dallas, J.; Erickson, K.; De Nardo, S.

1984-01-01

354

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

1984-06-05

355

Solid-tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis  

Science.gov (United States)

Purpose: The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particle-emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells. Methods: Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells (one-cell thick, 10 ?m diameter), viable tumor cells (25-cell thick, 250 ?m radius), and necrotic tumor region (>250 ?m from any blood vessel). Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical 10 ?m shells within the viable tumor-cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose-point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses (?100 Gy) in the vascular endothelial cells (endothelial cell mean dose) or, alternatively, at the tumor edge [tumor-edge mean dose (TEMD)] of adjacent viable tumor cells were then determined for six beta (32P, 33P, 67Cu, 90Y, 131I, and 188Re) and two alpha (211At and 213Bi) particle emitters. Results: Contrary to previous modeling in targeted radionuclide therapy dosimetry of solid tumors, the present work restricts the region of tumor viability to 250 ?m around tumor blood vessels for consistency with biological observations. For delivering ?100 Gy at the viable tumor edge (TEMD) rather than throughout a solid tumor, energetic beta emitters 90Y, 32P, and 188Re can be effective even when the radionuclide is confined to the blood vessel (i.e., no diffusion into the tumor). Furthermore, the increase in tumor-edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower-energy emitters 131I, 67Cu, and 33P relative to higher-energy emitters 90Y, 32P, and 188Re. Compared to alpha particle emitters, a ?150–400 times higher number of beta-particle-emitting radioactive atoms is required to deposit the same dose in tumor neovasculature. However, for the alpha particle emitters 211At and 213Bi to be effective in irradiating viable tumor-cell regions in addition to the vasculature, the carrier molecules must diffuse substantially from the vasculature into the viable tumor. Conclusion: The presented data enable comparison of radionuclides used for antiangiogenic therapy on the basis of their radioactive decay properties, tumor neovasculature geometry, and tumor-cell viability. For alpha particle emitters or low-energy beta particle emitters, the targeting carrier molecule should be chosen to permit the radiopharmaceutical to diffuse from the endothelial wall of the blood vessel, while for long-range energetic beta particle emitters that target neovasculature, a radiopharmaceutical that binds to newly formed endothelial cells and does not diffuse is preferable. The work is a first approximation to modeling of tumor neovasculature that ignores factors such as pharmacokinetics and targeting capability of carrier molecules. The calculations quantify the interplay between irradiation of neovasculature, the surrounding viable tumor cells, and the physical properties of commonly used radionuclides and can be used to assist estimation of radioactivity to be administered for neovasculature-targeted tumor therapy.

Zhu, Xuping; Palmer, Matthew R.; Makrigiorgos, G. Mike; Kassis, Amin I.

2010-01-01

356

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)

Full Text Available SciELO Brazil | Language: English Abstract in portuguese 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.

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.

357

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  

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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.

Debora A.P.C. Zuccari

2009-02-01

358

Tissue distribution of 2- and 4-(/sup 203/Hg)-estradiol in mammary-tumor-bearing rats  

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The newly synthesized 2-(/sup 203/Hg)-estradiol-17 beta and 4-(/sup 203/Hg)-estradiol-17 beta were injected into Fischer female rats bearing transplanted mammary adenocarcinomas and into Sprague-Dawley female rats bearing spontaneous mammary tumors. Four days after injection, tumor to blood ratios (and uterine to blood ratios) in the various groups were between 5 and 14, compared to a ratio of unity observed in normal mammary glands. When injected into male rats, the accumulation of 4-(/sup 203/Hg)-estradiol in the prostate and in the epididimis was very low. With minute doses of 4-(/sup 203/Hg)-estradiol injected into healthy male rats, the whole-body retention of the drug was found to decrease exponentially with time, and biphasic first order kinetics were observed. With pharmacological doses of the same drug, the clearance exhibited a biphasic pattern.

Shani, J.; Lieberman, L.M.; Samuni, A.; Schlesinger, T.; Cais, M.

1982-01-01

359

Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.  

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Most patients with ovarian cancer are diagnosed late in progression and often experience tumor recurrence and relapses due to drug resistance. Surface expression of matrix metalloprotease (MMP)-14 on ovarian cancer cells stimulates a tumor-stromal signaling pathway that promotes angiogenesis and tumor growth. In a cohort of 92 patients, we found that MMP-14 was increased in the serum of women with malignant ovarian tumors. Therefore, we investigated the preclinical efficacy of a MMP-14 monoclonal antibody that could inhibit the migratory and invasive properties of aggressive ovarian cancer cells in vitro. MMP-14 antibody disrupted ovarian tumor-stromal communication and was equivalent to Avastin in suppressing blood vessel growth in mice harboring Matrigel plugs. These effects on angiogenesis correlated with downregulation of several important angiogenic factors. Furthermore, mice with ovarian cancer tumors treated with anti-MMP-14 monotherapy showed a marked and sustained regression in tumor growth with decreased angiogenesis compared with immunoglobulin G (IgG)-treated controls. In a model of advanced peritoneal ovarian cancer, MMP-14-dependent invasion and metastasis was effectively inhibited by intraperitoneal administration of monoclonal MMP-14 antibody. Together, these studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer. PMID:23423981

Kaimal, Rajani; Aljumaily, Raid; Tressel, Sarah L; Pradhan, Rutika V; Covic, Lidija; Kuliopulos, Athan; Zarwan, Corrine; Kim, Young B; Sharifi, Sheida; Agarwal, Anika

2013-04-15

360

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN  

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Full Text Available Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNFalpha (1 ng/ml. Membranal EMMPRIN expression was increased in the co-cultures (by 3-4 folds, p<0.01, as was the secretion of MMP-9 and VEGF (by 2-5 folds for both MMP-9 and VEGF, p<0.01, relative to the single cultures with TNFalpha. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2-3 folds, p<0.05, only in the A498 co-culture via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway.

MichalAmitRahat

2013-07-01

 
 
 
 
361

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  

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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...

2009-01-01

362

Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.  

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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 new drug 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. PMID:23814493

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-07-01

363

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

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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.

Salvesen Gerd S

2009-12-01

364

Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of tumor growth and tumor angiogenesis of mouse ehrlich ascites tumor in vivo.  

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A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 3(a-e) were synthesized by nucleophilic substitution reaction of 1-benzhydryl-piperazine with different sulfonyl chlorides and were characterized by 1H NMR, LC/MS, FTIR and elemental analysis. In the present study, the compounds 3(a-e) exhibited in vivo inhibition of Ehrlich ascites tumor (EAT) cell growth and increased the Median Survival Time (MST) and %ILS of EAT bearing mice. Further treatment of derivatives in vivo resulted in reduction of EAT cell number and ascites formation. The efficacy of the derivatives to inhibit the angiogenesis in vivo was evaluated in tumor bearing mice peritoneum and chorio allantoic membrane (CAM) model. The compounds suppressed the blood vessel formation in vivo in mice peritoneum and in CAM. Among the compounds studied, 3e demonstrated highest tumor inhibitory and anti-angiogenic effects against mouse tumor. However, this phenomenon needs detailed investigation. PMID:18782043

Kumar, C S Ananda; Chandru, H; Sharada, A C; Thimmegowda, N R; Prasad, S B Benaka; Kumar, M Karuna; Rangappa, K S

2008-09-01

365

Murine mammary tumor virus pol-related sequences in human DNA: characterization and sequence comparison with the complete murine mammary tumor virus pol gene  

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Sequences in the human genome with homology to the murine mammary tumor virus (MMTV) pol gene were isolated from a human phage library. Ten clones with extensive pol homology were shown to define five separate loci. These loci share common sequences immediately adjacent to the pol-like segments and, in addition, contain a related repeat element which bounds this region. This organization is suggestive of a proviral structure. The authors estimate that the human genome contains 30 to 40 copies of these pol-related sequences. The pol region of one of the cloned segments (HM16) and the complete MMTV pol gene were sequenced and compared. The nucleotide homology between these pol sequences is 52% and is concentrated in the terminal regions. The MMTV pol gene contains a single long open reading frame encoding 899 amino acids and is demarcated from the partially overlapping putative gag gene by termination codons and a shift in translational reading frame. The pol sequence of HM16 is multiply terminated but does contain open reading frames which encode 370, 105, and 112 amino acids residues in separate reading frames. The authors deduced a composite pol protein sequence for HM16 by aligning it to the MMTV pol gene and then compared these sequences with other retroviral pol protein sequences. Conserved sequences occur in both the amino and carboxyl regions which lie within the polymerase and endonuclease domains of pol, respectively

1986-01-01

366

Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis.  

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Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis and ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells and provide access to the systemic circulation. In addition to well established growth factors and inflammatory mediators that promote capillary sprouting and endothelial cell growth and migration, an emerging body of evidence supports a previously unrecognized function for axon guidance molecules in regulation of blood vessel development. Here we show that semaphorin 4D (Sema4D), a protein originally shown to regulate axonal growth cone guidance in the developing central nervous system through its receptor, plexin-B1, is highly expressed in cell lines derived from head and neck squamous cell carcinomas (HNSCCs) at both the protein and message level. Immunohistochemical analysis of a large collection of HNSCC specimens revealed high levels of Sema4D in a cell surface pattern in invading islands of transformed epithelial cells, but not in normal and noninvasive dysplastic epithelium. A similar pattern was observed in malignant cells from prostate, colon, breast, and lung cancer tissues. When shed from HNSCC cells, Sema4D stimulates endothelial cell migration, which can be prevented by Sema4D-blocking antibodies and by Sema4D knockdown. Furthermore, knocking down Sema4D by lentiviral expression of Sema4D shRNA reduces dramatically the size and vascularity of HNSCC tumor xenografts. These findings indicate that expression of Sema4D is a frequently used strategy by which a wide variety of carcinomas may promote angiogenesis, and therefore is a possible therapeutic target for the treatment of these malignancies. PMID:16754882

Basile, John R; Castilho, Rogerio M; Williams, Vanessa P; Gutkind, J Silvio

2006-06-13