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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 ...

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

2010-01-01

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

Scientific Electronic Library Online (English)

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

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

1348-13-01

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Hyperproduction of Hyaluronan in Neu-Induced Mammary Tumor Accelerates Angiogenesis through Stromal Cell Recruitment  

Science.gov (United States)

Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV promoter, the bigenic mice bearing Has2 and neu transgenes exhibited a deposition of hyaluronan matrix and aggressive growth of Neu-initiated mammary tumors. Notably, forced expression of Has2 impaired intercellular adhesion machinery and elicited cell survival signals in tumor cells. Concurrent with these alterations of tumor cells, intratumoral stroma and microvessels were markedly induced. To reveal the molecular basis of hyaluronan-mediated neovascularization, various hyaluronan samples were examined for their ability to potentiate in vivo angiogenesis. In Matrigel plug assays, basic fibroblast growth factor-induced neovascularization was elevated in the presence of either hyaluronan oligosaccharides or a hyaluronan aggregate containing versican. Administration of hyaluronan-versican aggregates, but not native hyaluronan alone, promoted stromal cell recruitment concurrently with the infiltration of endothelial cells. Taken together, these results suggest that hyaluronan overproduction accelerates tumor angiogenesis through stromal reaction, notably in the presence of versican. PMID:17322391

Koyama, Hiroshi; Hibi, Terumasa; Isogai, Zenzo; Yoneda, Masahiko; Fujimori, Minoru; Amano, Jun; Kawakubo, Masatomo; Kannagi, Reiji; Kimata, Koji; Taniguchi, Shun’ichiro; Itano, Naoki

2007-01-01

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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

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MDSCs Mediate Angiogenesis and Predispose Canine Mammary Tumor Cells for Metastasis via IL-28/IL-28RA (IFN-?) Signaling  

Science.gov (United States)

Background Myeloid-derived suppressor cells (MDSCs) function in immunosuppression and tumor development by induction of angiogenesis in a STAT3-dependent manner. Knowledge of MDSC biology is mainly limited to mice studies, and more clinical investigations using spontaneous tumor models are required. Here we performed in vitro experiments and clinical data analysis obtained from canine patients. Methods Using microarrays we examined changes in gene expression in canine mammary cancer cells due to their co-culture with MDSCs. Further, using Real-time rt-PCR, Western blot, IHC, siRNA, angiogenesis assay and migration/invasion tests we examined a role of the most important signaling pathway. Results In dogs with mammary cancer, the number of circulating MDSCs increases with tumor clinical stage. Microarray analysis revealed that MDSCs had significantly altered molecular pathways in tumor cells in vitro. Particularly important was the detected increased activation of IL-28/IL-28RA (IFN-?) signaling. The highest expression of IL-28 was observed in stage III/IV mammary tumor-bearing dogs. IL-28 secreted by MDSCs stimulates STAT3 in tumor cells, which results in increased expression of angiogenic factors and subsequent induction of angiogenesis by endothelial cells, epithelial-mesenchymal transition (EMT) and increased migration of tumor cells in vitro. Knockdown of IL-28RA decreased angiogenesis, tumor cell invasion and migration. Conclusions We showed for the first time that MDSCs secrete IL-28 (IFN-?), which promotes angiogenesis, EMT, invasion and migration of tumor cells. Thus, IL-28 may constitute an interesting target for further therapies. Moreover, the similarity in circulating MDSC levels at various tumor clinical stages between canine and human patients indicates canines as a good model for clinical trials of drugs targeting MDSCs. PMID:25075523

Mucha, Joanna; Majchrzak, Kinga; Taciak, Bart?omiej; Hellmén, Eva; Król, Magdalena

2014-01-01

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Selective blockade of tumor angiogenesis  

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Blocking tumor angiogenesis is an important goal of cancer therapy, but clinically approved anti-angiogenic agents suffer from limited efficacy and adverse side effects, fueling the need to identify alternative angiogenesis regulators. Tumor endothelial marker 8 (TEM8) is a highly conserved cell surface receptor overexpressed on human tumor vasculature. Genetic disruption of Tem8 in mice revealed that TEM8 is important for promoting tumor angiogenesis and tumor growth but dispensable for norm...

Chaudhary, Amit; St Croix, Brad

2012-01-01

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Down-Regulation of Vascular Endothelial Growth Factor by Tissue Inhibitor of Metalloproteinase-2: Effect on in Vivo Mammary Tumor Growth and Angiogenesis  

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The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43.fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells with a retroviral expression vector for ...

Hajitou, Amin; Sounni, Nor Eddine; Devy, Laetitia; Grignet-debrus, Christine; Lewalle, Jean-marc; Li, Hong; Deroanne, Christophe; Lu, He; Colige, Alain; Nusgens, Betty; Frankenne, Francis; Maron, Anne; Yeh, Patrice; Perricaudet, Michel; Chang, Yawen

2001-01-01

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Hyperproduction of Hyaluronan in Neu-Induced Mammary Tumor Accelerates Angiogenesis through Stromal Cell Recruitment : Possible Involvement of Versican/PG-M  

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Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV pr...

Koyama, Hiroshi; Hibi, Terumasa; Isogai, Zenzo; Yoneda, Masahiko; Fujimori, Minoru; Amano, Jun; Kawakubo, Masatomo; Kannagi, Reiji; Kimata, Koji; Taniguchi, Shun’ichiro; Itano, Naoki

2007-01-01

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Preclinical Molecular Imaging of Tumor Angiogenesis  

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

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

2010-01-01

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Interleukin-8 expression associated with canine mammary tumors.  

Science.gov (United States)

The use of prognostic markers for mammary cancer is important for routine diagnosis and research. Interleukin-8 (IL-8) is a chemotactic cytokine, produced by several cell types in response to inflammation. The expression, regulation and function of IL-8 in dogs are little known. Recent studies have associated angiogenesis and inflammatory processes with tumor malignancy. We investigated a possible correlation between IL-8 expression and mammary tumor prognosis in female dogs. IL-8 expression was measured in 50 dogs with mammary neoplasia by immunohistochemistry and real-time PCR. Immunohistochemical staining was done with anti-IL-8 antibodies and PCR amplifications were performed in a 7500 Fast Real-Time PCR system. Gene expression stability was analyzed by the geNorm software. Quantitative real-time PCR showed that IL-8 expression decreased in malignant mammary cells compared to normal mammary tissue, while weak immunostaining was associated with a diagnosis of carcinoma. Complementing earlier studies on IL-8 expression in several types of cancer, including mammary cancer, we conclude that IL-8 has potential for use as a prognostic marker for canine mammary neoplasia. PMID:21863548

Zuccari, D A P C; Castro, R; Gelaleti, G B; Mancini, U M

2011-01-01

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Granular-cell tumor: A rare variant of mammary tumor  

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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...

Ili? Ivan; Ran?elovi? Pavle; Ili? Ratko; ?or?evi? Lidija; Radojkovi? Danijela

2008-01-01

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Preclinical molecular imaging of tumor angiogenesis.  

Science.gov (United States)

Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin avb3 and matrix metalloproteinases (MMPs). It is predictable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

Zhu, L; Niu, G; Fang, X; Chen, X

2010-06-01

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Positive scintigraphy of tumors of mammary gland  

International Nuclear Information System (INIS)

Method of positive scintigraphy of mammary gland tumors is used to examine 52 patients: 9 patients were examined by means of 99mTc-pertechnetate, 18 - 67Ga-citrate, 15 - 75Se-sodium selenite, 9 - using 75 methionine. Reliability of radionuclide diagnosis of mammary gland tumors consisted: with 99mTc-pertechnetate - 85%, with 67Ga-citrate - 75%, 75Se-methionine - 89%, 75Se-sodium selenite - 33%

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Cimetidine inhibits angiogenesis and suppresses tumor growth.  

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Cimetidine, a histamine type-2 receptor antagonist, has been reported to improve survival of patients with cancers. However, the exact mechanisms by which cimetidine suppresses development of cancers remain to be elucidated. Solid tumors require neovascularization for their growth. Here, we investigated the effects of cimetidine on tumor growth and angiogenesis. Syngeneic colon cancer cells, CMT93 cells, were inoculated into the subcutaneous space of C57BL/6 mice. Mice were treated with either saline or cimetidine. Tumor size was measured everyday and angiogenesis was evaluated histologically. Cimetidine markedly suppressed tumor growth with reduced neovascularization in the tumor. Cimetidine had no effect on proliferation of CMT93 cells in vitro. Vascular endothelial growth factor production by cancer cells was not affected by cimetidine, while vascular-like tube formation by endothelial cells in vitro was significantly impaired in the presence of cimetidine. Our findings suggest that cimetidine suppresses tumor growth, at least in part, by inhibiting tumor-associated angiogenesis. PMID:15740937

Natori, Takeshi; Sata, Masataka; Nagai, Ryozo; Makuuchi, Masatoshi

2005-01-01

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Molecular Ultrasound Assessment of Tumor Angiogenesis  

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Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molec...

Deshpande, Nirupama; Pysz, Marybeth A.; Willmann, Ju?rgen K.

2010-01-01

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

Science.gov (United States)

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. PMID:21747968

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

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...

Banerjee Deboshri; Harfouche Rania; Sengupta Shiladitya

2011-01-01

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Molecular Ultrasound Assessment of Tumor Angiogenesis  

Science.gov (United States)

Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications. PMID:20549555

Deshpande, Nirupama; Pysz, Marybeth A.

2010-01-01

19

Tissue factor and fibrin in tumor angiogenesis.  

Science.gov (United States)

The hypercoagulability exhibited by most cancer patients leads to serious complications such as venous thromboembolism and contributes to the pathogenesis of tumor growth and metastasis by promoting angiogenesis. The key player in this vicious cycle is tissue factor (TF), the initiator of blood coagulation. Although TF normally safeguards vascular integrity by inducing hemostasis upon injury, abnormal expression of TF in different tumors and related vascular endothelial cells contributes to unnecessary clot formation in cancer patients. Clotting-dependent induction of tumor angiogenesis is primarily mediated by TF-induced generation of thrombin and subsequent deposition of cross-linked fibrin. A cross-linked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent mechanisms of TF-induced tumor angiogenesis have also been described, mediated primarily by the cytoplasmic tail of the TF receptor. TF activation could contribute to the venous thromboembolism that has been reported as a complication of the use of novel antiangiogenic agents in combination with chemotherapy. Anticoagulants, such as low-molecular-weight heparin, may act to prevent these complications both by interfering with TF-mediated activation of clotting and by directly down-regulating angiogenesis. Thus, TF may prove to be a novel target for cancer therapy. PMID:15034796

Fernandez, Patricia M; Patierno, Steven R; Rickles, Frederick R

2004-02-01

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Primary tumor dependent inhibition of tumor growth, angiogenesis, and perfusion of secondary breast cancer in bone.  

Science.gov (United States)

The systemic balance of angiogenic and anti-angiogenic factors has been proposed to play a key-role in primary tumor growth dependent growth suppression of secondary tumors. Despite the importance of the organ microenvironment to angiogenesis and microcirculation, the influence of a primary tumor on secondary bone tumors has not been investigated so far. Since breast cancer has a high propensity to spread to bone, we used an in vivo xenograft model to determine the impact of growing breast cancer cells (MCF-7) in the mammary fat pad on the microvascular properties of subsequently inoculated secondary breast cancer tumors in bone. Mice were either treated with a resection of the primary tumor (n?=?10) or no surgery (n?=?9) and intravital microscopy was performed over 25 days in bone tumors. Tumor growth in bone was temporarily suppressed by the primary tumor on days 10 and 14. While microvascular permeability and vascular diameter decreased in both groups over time, the presence of the primary tumor was accompanied by a decreased tumor perfusion on days 8 and 10 through a reduction in vessels with diameters between 5 and 20?µm. The results imply a potential benefit of a therapeutic regime in which the resection of the primary tumor is combined with an anti-angiogenic therapy in the perioperative or direct postoperative period. This might result in reduced progression of bone metastasis subsequent to excision of the primary tumor. PMID:21381098

Schaefer, Christian; Schroeder, Malte; Fuhrhop, Ina; Viezens, Lennart; Otten, Jasmin; Fiedler, Walter; Rüther, Wolfgang; Hansen-Algenstaedt, Nils

2011-08-01

 
 
 
 
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Overexpression of Activated Murine Notch1 and Notch3 in Transgenic Mice Blocks Mammary Gland Development and Induces Mammary Tumors  

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The mouse mammary tumor virus (MMTV) provirus was found to target the Notch1 gene, producing insertional mutations in mammary tumors of MMTV/neu transgenic (Tg) mice. In these mammary tumors, the Notch1 gene is truncated upstream of the transmembrane domain, and the resulting Notch1 in-tracellular domain (Notch1intra), deleted of most extracellular sequences, is overexpressed. Although Notch1intra transforms mammary epithelial cells in vitro, its role in mammary gland tumor formation in vivo ...

Hu, Chunyan; Die?vart, Anne; Lupien, Mathieu; Calvo, Ezequiel; Tremblay, Gilles; Jolicoeur, Paul

2006-01-01

22

Granular-cell tumor: A rare variant of mammary tumor  

Directory of Open Access Journals (Sweden)

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

23

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

24

Dll4-Notch signaling in regulation of tumor angiogenesis.  

Science.gov (United States)

Tumor angiogenesis is a complex process and involves the tight interplay of tumor cells, endothelial cells, phagocytes and their secreted factors, which may act as promoters or inhibitors of angiogenesis. Many signaling pathways involved in these processes such as vascular endothelial growth factor (VEGF), fibroblast growth factors, Wnt and mTOR signaling pathway. Though research has confirmed that VEGF can play an important role in tumor angiogenesis, and has designed a lot of drugs that target VEGF, both experimental and clinical studies showed that these pathways mentioned above including VEGF did not play key roles in tumor angiogenesis. With the deepening of the research, people find that of all the signaling pathways involved in tumor angiogenesis, Notch signaling is the most notable one and plays crucial role in tumor angiogenesis. It was previously recognized that the Notch signaling plays a key role only in physiological angiogenesis such as development, wound healing and pregnancy. However, an increasing number of studies have proved that Notch signaling is also involved in pathological angiogenesis such as tumor angiogenesis and plays a critical role in these processes. More importantly, compared to resistance caused by anti-VEGF or other signaling pathways, experimental evidence revealed that Notch was involved in anticancer drug resistance, indicating that targeting Notch could be a novel therapeutic approach to the treatment for cancer by overcoming drug resistance of cancer cells. More recently, research has demonstrated that Notch ligands Delta-like 4 (Dll4) plays a key role in tumor angiogenesis. Data show that Dll4 functions as a negative regulator of tumor angiogenesis and is upregulated in tumor vasculature. This review focus on recent insights into Dll4-Notch signaling in tumor angiogenesis and its mechanisms, which may be utilized for a potential pharmacological use as a target for anti-angiogenic cancer therapy. PMID:24114288

Liu, Zhaoguo; Fan, Fangtian; Wang, Aiyun; Zheng, Shizhong; Lu, Yin

2014-04-01

25

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

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 als...

Ch Ng, Ewe Seng; Jaafar, Hasnan; Tuan Sharif, Sharifah Emilia

2011-01-01

26

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

Directory of Open Access Journals (Sweden)

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

27

FTY720 inhibits tumor growth and angiogenesis.  

Science.gov (United States)

De novo malignancies and recurrence of tumors are some of the biggest threats to allograft recipients subjected to chronic immunosuppression. FTY720, a synthetic myriocin analogue, is an immunosuppressant that induces apoptosis of activated lymphocytes and prevents infiltration of lymphocytes into allografts, thereby prolonging allograft survival in a dose-dependent manner. Additionally, FTY720 was shown to prevent tumor growth and metastasis. Therefore, we examined the effect of FTY720 on angiogenesis in a HUVEC spheroid model. To substantiate our in vitro findings the effect of FTY720 was also tested in C57/B16 mice subcutaneously injected with Lewis Lung Carcinoma (LLC1) cells. After establishment of a palpable tumor the animals were treated daily with either saline or 1, 5, or 10 mg/kg FTY720. Subsequently, the tumor size was measured, periodically. In our experiments FTY720 showed a strong antiangiogenic effect, overcoming the stimulating effect of VEGF (20 ng/mL) even at subnanomolar concentrations. In vivo, FTY720 showed a dose-dependent inhibition of subcutaneous tumors, and the tumor size of animals treated with 10 mg/kg FTY720 was less than half of the size of tumors in control animals. In conclusion, FTY-720 demonstrated a strong antiangiogenic effect in vitro and a substantial antitumor effect in vivo. Presumably, the stabilizing effect of surrounding pericytes limits the effect of FTY720 in our mouse model. Therefore, a combination of FTY720 with an mTOR inhibitor might be the most favorable immunosuppressive drug combination for allograft recipients at risk for tumor development. PMID:15808563

Schmid, G; Guba, M; Papyan, A; Ischenko, I; Brückel, M; Bruns, C J; Jauch, K-W; Graeb, C

2005-01-01

28

Experimental studies on mammary tumors in rats  

International Nuclear Information System (INIS)

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

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Hybrid modeling of tumor-induced angiogenesis  

CERN Document Server

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

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

2014-01-01

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Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF-7 breast cancer xenografts and carcinogen-induced mammary tumors in rats.  

Science.gov (United States)

Lariciresinol is a dietary lignan that accounts for a significant portion of the total phytoestrogen intake from Western foods. Recent epidemiological studies suggest that high dietary intake of lignans and lariciresinol is associated with reduced breast cancer risk. However, no causal relationship between lariciresinol intake and breast cancer development has been established. In this study, we investigated for the first time the effects and possible mechanisms of action of lariciresinol on hormone responsive mammary cancer in vivo in dimethylbenz[a]anthracene induced mammary cancer in rats, and in human MCF-7 breast cancer xenografts in athymic mice. For tumor bearing rats, lariciresinol (3 or 15 mg/kg of body weight) or vehicle was administered p.o. daily for 9 weeks. For E2-maintained ovariectomized athymic mice bearing orthotopic MCF-7 tumors, control diet (AIN-93G) or lariciresinol containing diet (AIN-93G supplemented with 20 or 100 mg of lariciresinol/kg of diet) was administered for 5 weeks. In both models, lariciresinol administration inhibited the tumor growth and tumor angiogenesis. In MCF-7 cells, enterolactone significantly inhibited the E2-stimulated VEGF secretion. Moreover, in MCF-7 xenografts, lariciresinol administration enhanced tumor cell apoptosis and increased estrogen receptor beta expression. Lariciresinol and its further metabolites secoisolariciresinol, enterodiol and enterolactone were found in serum of both rats and athymic mice confirming a similar lignan metabolism pattern as in humans. These findings indicate conceivable importance of dietary lignan lariciresinol in inhibition of breast cancer development. PMID:18528864

Saarinen, Niina M; Wärri, Anni; Dings, Ruud P M; Airio, Maarit; Smeds, Annika I; Mäkelä, Sari

2008-09-01

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

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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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Endothelial cell pseudopods and angiogenesis of breast cancer tumors  

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Abstract Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sec...

Sun LuZhe; Short Nicholas; Cameron Ivan L; Elaine, Hardman W.

2005-01-01

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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

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

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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 td 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

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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

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

International Nuclear Information System (INIS)

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

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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

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

International Nuclear Information System (INIS)

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

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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

40

Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice  

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Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expressi...

Yang, Hanseul; Lee, Sungsu; Lee, Seungjoo; Kim, Kangsan; Yang, Yeseul; Kim, Jeong Hoon; Adams, Ralf H.; Wells, James M.; Morrison, Sean J.; Koh, Gou Young; Kim, Injune

2012-01-01

 
 
 
 
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Survivin and Related Proteins in Canine Mammary Tumors: Immunohistochemical Expression.  

Science.gov (United States)

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

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

2014-03-31

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Osteopontin Regulates Ubiquitin-Dependent Degradation of Stat1 in Murine Mammary Epithelial Tumor Cells  

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Full Text Available Background: Osteopontin (OPN is a secreted glycoprotein that mediates cell-matrix interactions and cellular signaling by binding with integrin (primarily ?v?3 and CD44 receptors. OPN regulates cell adhesion, chemotaxis, macrophage-directed IL-10 suppression, stressdependent angiogenesis, apoptosis prevention, anchorage-independent growth of tumor cells. However, the molecular mechanisms that define the role of OPN in tumor progression and metastasis are incompletely understood. Methods: In this study, we use a system of 4T1 and 4T07 murine mammary epithelial tumor cell lines that are divergent in both metastatic phenotype and OPN expression. 4T1 expresses OPN and hematogeneously metastasizes, whereas 4T07 does not express OPN and is highly tumorigenic but fails to metastasize. Results: Our results demonstrate that OPN regulates Stati protein degradation through the ubiquitin-proteasome pathway to alter interferon-?-dependent growth inhibition and p21 expression. We identify Stat-interacting LIM protein as the critical Stat ubiquitin E3 ligase in this setting. Conclusions: OPN regulates Stati-dependent functions, such as growth inhibition and p21 expression, in the murine mammary epithelial cells lines 4T1 and 4T07. This relationship between OPN and Stati in the context of tumor biology has not been previously examined.

Chengjiang Gao

2007-09-01

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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 D0 = 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)

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Nano to micro delivery systems: targeting angiogenesis in brain tumors  

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Full Text Available Abstract Treating brain tumors using inhibitors of angiogenesis is extensively researched and tested in clinical trials. Although anti-angiogenic treatment holds a great potential for treating primary and secondary brain tumors, no clinical treatment is currently approved for brain tumor patients. One of the main hurdles in treating brain tumors is the blood brain barrier - a protective barrier of the brain, which prevents drugs from entering the brain parenchyma. As most therapeutics are excluded from the brain there is an urgent need to develop delivery platforms which will bypass such hurdles and enable the delivery of anti-angiogenic drugs into the tumor bed. Such delivery systems should be able to control release the drug or a combination of drugs at a therapeutic level for the desired time. In this mini-review we will discuss the latest improvements in nano and micro drug delivery platforms that were designed to deliver inhibitors of angiogenesis to the brain.

Machluf Marcelle

2010-10-01

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Evaluation of Tumor Angiogenesis by MRI Study Using Iron Nanoparticles  

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

Mansour Ashoor

2010-05-01

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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

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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 stresses, including UV. Atf-2(-/-) and Atf-2(+/-) MEFs could not express a group of genes, such as Gadd45alpha, whose overexpression can induce apoptosis, in response to hypoxia. Atf-2(-/-) MEFs also had a higher saturation density than wild-type cells and expressed lower levels of Maspin, the breast cancer tumor suppressor, which is also known to enhance cellular sensitivity to apoptotic stimuli. Atf-2(-/-) MEFs underwent a lower degree of apoptosis at high cell density than wild-type cells. Atf-2(+/-) mice were highly prone to mammary tumors that expressed reduced levels of Gadd45alpha and Maspin. The ATF-2 mRNA levels in human breast cancers were lower than those in normal breast tissue. Thus, ATF-2 acts as a tumor susceptibility gene of mammary tumors, at least partly, by activating a group of target genes, including Maspin and Gadd45alpha. PMID:17189429

Maekawa, Toshio; Shinagawa, Toshie; Sano, Yuji; Sakuma, Takahiko; Nomura, Shintaro; Nagasaki, Koichi; Miki, Yoshio; Saito-Ohara, Fumiko; Inazawa, Johji; Kohno, Takashi; Yokota, Jun; Ishii, Shunsuke

2007-03-01

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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

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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

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

Scientific Electronic Library Online (English)

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

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

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Photoacoustic 3D visualization of tumor angiogenesis  

Science.gov (United States)

Photoacoustic imaging is used to obtain a range of three-dimensional images representing tumor neovascularization over a 10-day period after subcutaneous inoculation of pancreatic tumor cells in a rat. The images are reconstructed from data measured with a double-ring photoacoustic detector. The ultrasound data originates from the optical absorption by hemoglobin of 14 ns laser pulses at a wavelength of 1064 nm. Three-dimensional data is obtained by using two dimensional linear scanning. Scanning and motion artifacts are reduced using a correction method. The data is used to visualize the development of the individual blood vessels around the growing tumor, blood concentration changes inside the tumor and growth in depth of the neovascularized region. The three-dimensional vasculature reconstruction is created using VTK, which enables us to create a composition of the vasculature on day seven, eight and ten and to interactively measure tumor growth in the near future.

ten Brinke, G. A.; Kolkman, R. G. M.; Slump, C. H.; Steenbergen, W.

2008-03-01

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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...

Maekawa, Toshio; Shinagawa, Toshie; Sano, Yuji; Sakuma, Takahiko; Nomura, Shintaro; Nagasaki, Koichi; Miki, Yoshio; Saito-ohara, Fumiko; Inazawa, Johji; Kohno, Takashi; Yokota, Jun; Ishii, Shunsuke

2007-01-01

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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 that the primary mammary tumors, which develop due to elevated expression of the type I insulin-like growth factor receptor (IGF-IR) in mammary epithelial cells, most closely resemble murine tumors with basal-like or mixed gene expression profiles and with human basal-like breast cancers. Downregulation of IGF-IR transgene in MTB-IGFIR tumor-bearing mice leads to the regression of most of the tumors, followed by tumor reappearance in some of the mice. These tumors that reappear following IGF-IR transgene downregulation do not express the IGF-IR transgene and cluster with murine mammary tumors that express a mesenchymal gene expression profile and with human claudin-low breast cancers. Therefore, IGF-IR overexpression in murine mammary epithelial cells induces mammary tumors with primarily basal-like characteristics, whereas tumors that develop following IGF-IR downregulation express a gene signature that most closely resembles human claudin-low breast tumors. PMID:22020329

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

2012-07-01

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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

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

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The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA){sub 30} (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K{sup PS}) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (K{sup PS}) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and K{sup PS} values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (K{sup PS}), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy. (orig.)

Turetschek, Karl [Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0628 (United States); Department of Radiology, University of Vienna (Austria); Preda, Anda; Shames, David M.; Novikov, Viktor; Roberts, Timothy P.L.; Fu, Yanjun; Brasch, Robert C. [Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0628 (United States); Floyd, Eugenia; Carter, Wayne O. [Pfizer Central Research, Groton, CT (United States); Wood, Jeanette M. [Oncology Research, Novartis Pharma AG, Ltd., Basel (Switzerland)

2003-03-01

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Immunological characterization of a low oncogenic mouse mammary tumor virus BALB/cNIV mice.  

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Antigenic determinants of mouse mammary tumor virus (MuMTV) from the low-mammary-tumor-incidence strain BALB/cNIV were compared by competition radioimmunoassay with those of MuMTV's isolated from several high- and low-mammary-tumor-incidence mouse strains, using rabbit hyperimmune sera against BALB/cNIV MuMTV and against MuMTV from the high-mammary-tumor-incidence strain BALB/cfC3H. Using anti-BALB/cfC3H serum in competition radioimmunoassay, BALB/cNIV MuMTV lacked antigenic determinants pres...

Vacquier, J. P.; Cardiff, R. D.; Blair, P. B.

1981-01-01

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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

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

Science.gov (United States)

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. PMID:21923938

Kuhnert, Frank; Kirshner, Jessica R; Thurston, Gavin

2011-01-01

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Longitudinal Studies of Angiogenesis in Hormone-Dependent Shionogi Tumors  

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

Trevor P. Wade

2007-07-01

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Type-2 pericytes participate in normal and tumoral angiogenesis.  

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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

 
 
 
 
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Generation and characterization of monoclonal antibodies reactive with human primary and metastatic mammary tumor cells  

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Splenic lymphocytes of mice, immunized with membrane-enriched fractions of metastatic human mammary carcinoma tissues, were fused with the NS-1 non-immunoglobulin (Ig) secreting myeloma cell line. This resulted in the generation of hybridoma cultures secreting Igs reactive in solid phase radioimmunoassays with extracts of metastatic mammary carcinoma cells from involved livers, but not to extracts of apparently normal human liver. As a result of further screening of immunoglobulin reactivities and double cloning of cultures, eleven monoclonal antibodies were chosen which demonstrated reactivities with human mammary tumor cells and not with apparently normal human tissues. These monoclonals could be placed into at least five major groups based on 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 employing the immunoperoxidase technique. (Auth.)

62

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

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

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

2014-09-01

63

Significance of Angiogenesis Determination in Pediatric Solid Tumors  

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Full Text Available Fifty one patients (27 boys and 24 girls with solid tumors whose ages ranged between 2 and 168 months were enrolled. Serum Vascular endothelial growth factor by Sandwich Enzyme linked immunosorbent assay was determined for all patients before any treatment and for 17 patients of them while in remission 6-9 months post therapy. Tissue biopsy was obtained for micro vessel count (MVC determination by staining endothelial cells for factor VIII-related antigen with the use of a standard immunoperoxidase technique. Before therapy, median concentration of serum VEGF was significantly increased in solid tumors` patients when compared to control group (p<0.001 with non significant relation to tumor type. Also, patients with different histopathologic diagnoses had comparable median MVC (tissue angiogenesis with non significant intergroup variability. Serum VEGF increased significantly in patients with neuroblastoma (n = 19 compared to those with ganglioneuroma (n = 6 while MVC values were comparable. When patients with metastatic cancer (n = 15 were compared to those with localized disease (n = 30, median VEGF levels and MVC were slightly higher in the former group, the difference did not reach statistical. In all cancer patients (n = 45, VEGF values correlated with MVC (r = 0.33, p = 0.022. After treatment, serum concentrations of VEGF dropped significantly (p<0.001 but still higher than control values (p =<0.001. Estimated OS and EFS of the whole group with malignant solid tumors patients were 86 and 72%, respectively. Serum VEGF did not correlate with outcome for the whole group of patients. Cox regression revealed that MVC (p<0.001 and stage of cancer (p<0.001 were highly associated with EFS of patients with embryonal tumors. Tumor angiogenesis can be indirectly assessed in vivo by serum VEGF measurement which is correlated with tissue MVC. Also, monitoring the levels of VEGF in patients with cancer may prove to be a useful marker for tumor status and response to treatment.

Safinaz A. El-Habashy

2006-01-01

64

Is infectivity related to the integrity of the virus of murine mammary tumor  

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From 7th international conference on mammary tumors; SaintPierre-de- Chartreuse, France (12 Jun 1972). Dealing with mammary tumors of the PS strain of mice, efforts to sediment the biological activity of cell-free extract supernatants are reported. (auth)

Viala, C.; Gorka

1972-12-31

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Mammary tumor modifiers in BALB/cJ mice heterozygous for p53.  

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BALB/c mice are predisposed to developing spontaneous mammary tumors, which are further increased in a p53 heterozygous state. C57BL/6J mice are resistant to induced mammary tumors and develop less than 1% mammary tumors in both wild-type and p53+/- states. To map modifiers of mammary tumorigenesis, we have established F1 and F2 crosses and backcrosses to BALB/cJ (N2-BALB/cJ) and C57BL/6J (N2-C57BL/6J) strains. All cohorts developed mammary carcinomas in p53+/- females, suggesting that multiple loci dominantly and recessively contributed to mammary tumorigenesis. We mapped two modifiers of mammary tumorigenesis in the BALB/cJ strain. Mtsm1 (mammary tumor susceptibility modifier), a dominant-acting modifier, is located on chromosome 7. Mtsm1 is suggestive for linkage to mammary tumorigenesis (p = 0.001). We have analyzed the Mtsm1 region to locate candidate genes by comparing it to a rat modifier region, Mcs3, which shares syntenic conservation with Mtsm1. Expression data and SNPs were also taken into account. Five potential candidate genes within Mtsm1 are Aldh1a3, Chd2, Nipa2, Pcsk6, and Tubgcp5. The second modifier mapped is Mtsm2, a recessive-acting modifier. Mtsm2 is located on chromosome X and is significantly linked to mammary tumorigenesis (p = 1.03 x 10(-7)). PMID:17557176

Koch, Joanna G; Gu, Xiangjun; Han, Younghun; El-Naggar, Adel K; Olson, Melissa V; Medina, Daniel; Jerry, D Joseph; Blackburn, Anneke C; Peltz, Gary; Amos, Christopher I; Lozano, Guillermina

2007-05-01

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Novel syngeneic mouse mammary carcinoma cell lines from aggressive ErbB2/Neu-overexpressing/PTEN-deficient tumors.  

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Breast cancer cell lines and mouse models are valuable tools for investigating the biology of and developing potential therapeutics for human breast carcinoma. The PTEN-/-/NIC mouse is a genetically engineered mouse model for ErbB2/Neu-overexpressing/?PTEN deficient breast carcinoma with histopathological and molecular features relevant to the luminal subtype of primary human breast cancer. However, the PTEN-/-/NIC model develops multifocal and aggressive mammary tumors with a short life-span, which greatly impedes its preclinical usage. To complement the genetic engineering approach and to facilitate the future application of this model, in the present study, two newly established cell lines, NICP20 and NICP21, from PTEN-/-/NIC mammary tumors are described. These NICP20 and NICP21 cells retained the crucial molecular phenotype similar to the origin, as confirmed by genotyping and western blot analysis. These cells induced tumors in immunocompetent syngeneic mice by mammary fat pad injection and produced lung metastasis when injected intravenously. Tumors induced by these cells displayed luminal?like histologic morphology and hyperactivation of Akt which are similar to PTEN-/-/NIC tumors. Immunohistochemical staining also revealed that tumors induced by the NICP20 and NICP21 cells showed a high proliferative level, comparable angiogenesis and T-cell infiltration properties similar to PTEN-/-/NIC tumors. Therefore, these NICP20 and NICP21 cells represent an alternative and useful model system to enhance our understanding of the nature of ErbB2-positive breast cancers, particularly accompanying PTEN loss and to facilitate further experimental therapeutic studies. PMID:25354531

Wang, Qingfei; Ding, Hui; Wang, Hai; Li, Ping; Liu, Baorui; Zhang, Kui

2015-01-01

67

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

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

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

2013-09-01

68

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors  

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Comparison of mammary tumor gene-expression profiles from thirteen murine models using microarrays and with that of human breast tumors showed that many of the defining characteristics of human subtypes were conserved among mouse models.

Herschkowitz, Jason I.; Simin, Karl; Weigman, Victor J.; Mikaelian, Igor; Usary, Jerry; Hu, Zhiyuan; Rasmussen, Karen E.; Jones, Laundette P.; Assefnia, Shahin; Chandrasekharan, Subhashini; Backlund, Michael G.; Yin, Yuzhi; Khramtsov, Andrey I.; Bastein, Roy; Quackenbush, John

2007-01-01

69

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

70

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

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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 t...

Masiero, M.; Simo?es, F.; Han, H.; Snell, C.; Peterkin, T.; Bridges, E.; Mangala, L.; Wu, S-y; Pradeep, S.; Li, D.; Han, C.; Dalton, H.; Lopez-berestein, G.; Tuynman, J.; Mortensen, N.

2013-01-01

71

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

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

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

2010-07-15

72

Lectin functionalized quantum dots for recognition of mammary tumors  

Science.gov (United States)

In this study we use CdS/Cd(OH) II 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) II 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) II 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.

2006-02-01

73

Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy  

International Nuclear Information System (INIS)

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

74

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

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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 t...

Luyong Zhang; Zhenzhou Jiang; Wei Shi; Han Li; Lixin Sun; Xianmin Mu

2012-01-01

75

IGFBP-3 suppresses VEGF expression and tumor angiogenesis in head and neck squamous cell carcinoma  

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Angiogenesis, the process by which new blood vessels are recruited to existing ones, is essential for tumor development. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), which modulates bioavailability of IGF, has been studied for its potential role in angiogenesis during tissue regeneration and cancer development. In this study, we assessed the role of IGFBP-3 in tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC) and human umbilical endothelial cells (HUVECs) us...

Oh, Seung-hyun; Kim, Woo-young; Lee, Ok-hee; Kang, Ju-hee; Woo, Jong-kyu; Kim, Jai-hyun; Glisson, Bonnie; Lee, Ho-young

2012-01-01

76

A Notch1 Ectodomain Construct Inhibits Endothelial Notch Signaling, Tumor Growth, and Angiogenesis  

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Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neo-vasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three dist...

Funahashi, Yasuhiro; Hernandez, Sonia L.; Das, Indranil; Ahn, Audrey; Huang, Jianzhong; Vorontchikhina, Marina; Sharma, Anshula; Kanamaru, Emi; Borisenko, Valeriya; Desilva, Dinuka M.; Suzuki, Akihiko; Wang, Xing; Shawber, Carrie J.; Kandel, Jessica J.; Yamashiro, Darrell J.

2008-01-01

77

FES kinase promotes mast cell recruitment to mammary tumors via the stem cell factor/KIT receptor signaling axis.  

Science.gov (United States)

KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow-derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerization-disrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosine-binding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT- and FES-dependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement. PMID:22589410

Kwok, Ester; Everingham, Stephanie; Zhang, Shengnan; Greer, Peter A; Allingham, John S; Craig, Andrew W B

2012-07-01

78

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

79

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

Science.gov (United States)

Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 ?M. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p.) administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms. PMID:25389450

Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba; Forestier-Roman, Ingrid; Martinez-Ferrer, Magaly; Hernandez, Eliud; Vlaar, Cornelis; Ferrer-Acosta, Yancy; Washington, Anthony V; Cubano, Luis A; Rodriguez-Orengo, Jose; Dharmawardhane, Suranganie

2014-10-01

80

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...

Sarkar, Nurul H.; Fernandes, Gabriel; Telang, Nitin T.; Kourides, Ione A.; Good, Robert A.

1982-01-01

 
 
 
 
81

Minimally Invasive Assessment of Tumor Angiogenesis by Fine Needle Aspiration and Flow Cytometry  

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The development of a new, less invasive, and more rapidly implemented method of quantifying endothelial cell density in tumors could facilitate experimental and clinical studies of angiogenesis. Therefore, we evaluated the utility of tumor fine needle aspiration (FNA) coupled with flow cytometry for assessment of tumor angiogenesis. Samples were obtained from cutaneous tumors of mice using FNA, then immunostained and assessed by flow cytometry to determine the number of CD31+ endothelial cell...

Sottnik, Joseph L.; Guth, Amanda M.; Mitchell, Leah A.; Dow, Steven W.

2010-01-01

82

PPAR? agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition  

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)? deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR? would promote tumor growth. Surprisingly, the PPAR? agonist fenofibrate pot...

Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E.; Barne?s, Carmen M.; Fannon, Michael; Laforme, Andrea M.; Chaponis, Deviney M.; Folkman, Judah; Kieran, Mark W.

2008-01-01

83

Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy  

Energy Technology Data Exchange (ETDEWEB)

Introduction: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of {beta}-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. Methods: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for {sup 99m}Tc and {sup 9}Y chelation and was further conjugated to a {alpha}{sub V}{beta}{sub 3} integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. Results: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P<.01) over time from 1.05{+-}0.03 % injected dose (%ID)/g tissue at 1 h to 4.32{+-}0.32% at 72 h. The activity in major normal tissues significantly decreased (P<.05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-{mu}Ci {sup 9}Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. Conclusion: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth.

Mitra, Amitava [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States); Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States); Nan, Anjan [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States); Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States); Papadimitriou, John C. [Department of Pathology, University of Maryland, Baltimore, MD 21201 (United States); Ghandehari, Hamidreza [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States) and Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States) and Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201 (United States)]. E-mail: hghandeh@rx.umaryland.edus; Line, Bruce R. [Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States) and Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201 (United States) and Division of Nuclear Medicine, Department of Radiology, University of Maryland, Baltimore, MD 21201 (United States)]. E-mail: bline@umm.edu

2006-01-15

84

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...

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

2008-01-01

85

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

Energy Technology Data Exchange (ETDEWEB)

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

86

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

87

Enhanced mammary progesterone receptor-A isoform activity in the promotion of mammary tumor progression by dietary soy in rats.  

Science.gov (United States)

Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-methyl-N-nitrosourea, dietary intake of soy protein isolate (SPI) reduced mammary tumor occurrence but increased incidence of more invasive tumors in tumored rats, relative to the control diet casein. Here we evaluated whether mammary tumor progression in tumor-bearing rats lifetime exposed to SPI is associated with deregulated progesterone receptor (PR) isoform expression. In histologically normal mammary glands of rats with invasive ductal carcinoma lesions, PR-A protein levels were higher for SPI- than casein-fed rats, whereas PR-B was undetectable for both groups. Increased mammary PR-A expression was associated with higher transforming growth factor-beta1, stanniocalcin-1, and CD44 transcript levels; lower E-cadherin and estrogen receptor-alpha expression; and reduced apoptotic status in ductal epithelium. Serum progesterone (ng/ml) (CAS: 25.94 +/- 3.81; SPI: 13.19 +/- 2.32) and estradiol (pg/ml) (CAS: 27.9 +/- 4.49; SPI: 68.48 +/- 23.87) levels differed with diet. However, sera from rats of both diet groups displayed comparable mammosphere-forming efficiency in human MCF-7 cells. Thus, soy-rich diets may influence the development of more aggressive tumors by enhancing PR-A-dependent signaling in premalignant breast tissues. PMID:20661826

Dave, Bhuvanesh; Wynne, Rebecca; Su, Ying; Korourian, Soheila; Chang, Jenny C; Simmen, Rosalia C M

2010-01-01

88

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

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Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances i...

Strijkers, G. J.; Kluza, E.; Tilborg, G. A. F.; Schaft, D. W. J.; Griffioen, A. W.; Mulder, W. J. M.; Nicolay, K.

2010-01-01

89

Distinct roles of DKK1 and DKK2 in tumor angiogenesis  

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Tumor angiogenesis is essential for tumor invasive growth and metastasis, and generates abnormal vascular structures unlike developmental neovessel formation. To reduce tumor vascular abnormalities such as leakage and perivascular cell coverage deficiency that limit cancer therapy effectiveness, novel therapeutic approaches focus on vessel normalization. We have previously shown that Dickkopf-1 (DKK1), a Wnt antagonist, inhibits and its homolog DKK2 enhances, angiogenesis in normal tissues. I...

Park, Hongryeol; Jung, Hyei Yoon; Choi, Hyun-jung; Kim, Dong Young; Yoo, Ji-young; Yun, Chae-ok; Min, Jeong-ki; Kim, Young-myoung; Kwon, Young-guen

2013-01-01

90

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

91

Acetyl-11-Keto-?-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

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The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-?-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg...

Pang, Xiufeng; Yi, Zhengfang; Zhang, Xiaoli; Sung, Bokyung; Qu, Weijing; Lian, Xiaoyuan; Aggarwal, Bharat B.; Liu, Mingyao

2009-01-01

92

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

93

Pale cell carcinoma: ultrastructure of a hormone-dependent mammary tumor in GR mice.  

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Pale cell carcinoma, a hormone-dependent mammary tumor in GR mice, consists mostly of islands of pale cells and dark cells, interrupted by a few areas containing keratinized cells. In this study the pale cells (electron-lucent), were arranged in bands adjacent to vascular spaces, while the dark cells, which produced mammary tumor virus, were clustered around lumens. A morphometric analysis revealed that pale cells were larger than dark cells and had other differences that indicated they were ...

Strum, J. M.

1981-01-01

94

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

Science.gov (United States)

Mammary neoplasias are the most common tumors observed in female dogs. Identification of these tumors is valuable in order to identify beneficial therapeutic agents as alternative treatments for this tumor type. Oral administration of melatonin appears to exert an oncostatic effect on mammary neoplasia and may have a possible mechanism of action through its interaction with estrogen receptors on epithelial cells. Hence, we analyzed the potential therapeutic value of melatonin in tumors that are estrogen-dependent or -independent, and established a relationship of its action with the expression of the melatonin receptors MT1 and MT2. Furthermore, we analyzed the rate of cell proliferation and apoptosis after treatment with melatonin. Cell cultures were performed using 10 canine mammary tumor fragments and were divided into estrogen receptor (ER)-positive and ER-negative tumors. The results showed that both ER-positive and ER-negative tumors had decreased cell viability and proliferation after treatment with melatonin (p<0.05), although treatment was more effective in the ER-positive tumors. Analysis of the relative expression of the MT1 and MT2 genes by quantitative PCR was performed and the data were compared with the expression of ER in 24 canine mammary tumors and the cellular response to melatonin in 10 samples. MT1 was overexpressed in ER-positive tumors (p<0.05), whereas MT2 was not expressed. Furthermore, melatonin treatment in ER-positive tumors showed an efficient oncostatic effect by inhibiting cell viability and proliferation and inducing apoptosis. These results suggest that melatonin decreased neoplastic mammary cell proliferation and viability and induced apoptosis, with greater efficacy in ER-positive tumors that have a high expression of melatonin receptor MT1. This is a strong evidence for the use of melatonin as a therapeutic agent for estrogen-dependent canine mammary tumors. PMID:25384569

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

2015-01-01

95

Calcitriol reduces thrombospondin-1 and increases vascular endothelial growth factor in breast cancer cells: implications for tumor angiogenesis.  

Science.gov (United States)

Calcitriol, a potent antineoplastic vitamin D metabolite, inhibits proliferation, induces apoptosis and slows the growth of tumors. Calcitriol also may exert either antiangiogenic or proangiogenic effects depending on the tissue. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (Tsp-1) are key factors involved in promoting and inhibiting angiogenesis, respectively. The effects of calcitriol on Tsp-1 have not been studied in the mammary gland, while VEGF regulation is not clear, since opposite outcomes have been demonstrated. Therefore, the present study was undertaken to investigate the effects of calcitriol on VEGF and Tsp-1 expression in primary breast tumor-derived cells and a panel of established breast cancer cell lines. In vivo studies in athymic mice were also performed in order to gain further insight into the biological effects of calcitriol on angiogenesis. Real time-PCR and ELISA analyses showed that calcitriol stimulated VEGF mRNA expression and protein secretion while elicited the opposite effect on Tsp-1 in 7 out of 8 cell lines studied, independently of the cell phenotype (PTsp-1 expression. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. PMID:24120914

García-Quiroz, Janice; Rivas-Suárez, Mariana; García-Becerra, Rocío; Barrera, David; Martínez-Reza, Isela; Ordaz-Rosado, David; Santos-Martinez, Nancy; Villanueva, Octavio; Santos-Cuevas, Clara L; Avila, Euclides; Gamboa-Domínguez, Armando; Halhali, Ali; Larrea, Fernando; Díaz, Lorenza

2014-10-01

96

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

97

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

98

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...

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

2010-01-01

99

Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi-1 leukemia cells  

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Histone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via the downregulation of angiogenic factors. Our previous in vitro studies demonstrated that valproic acid (VPA) exerted antitumor effects on Kasumi-1 cells, which are human acute myeloid leukemia cells with an 8;21 chromosome translocation. In the present study, the effects of VPA on tumor angiogenesis were investigated in mice transplanted with Kasumi-1 cells. Semi-quantitative reverse transcription-poly...

Zhang, Zhi-hua; Hao, Chang-lai; Liu, Peng; Tian, Xia; Wang, Li-hong; Zhao, Lei; Zhu, Cui-min

2013-01-01

100

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

 
 
 
 
101

Morelloflavone, a biflavonoid, inhibits tumor angiogenesis by targeting Rho GTPases and ERK signaling pathways  

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Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown anti-oxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness and metastasis. We demonstrated that morelloflavone could inhibit vascular endothelial...

Pang, Xiufeng; Yi, Tingfang; Yi, Zhengfang; Cho, Sung Gook; Qu, Weijing; Pinkaew, Decha; Fujise, Ken; Liu, Mingyao

2009-01-01

102

Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth  

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Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor–deficient (AT1a–/?...

Egami, Kimiyasu; Murohara, Toyoaki; Shimada, Toshifumi; Sasaki, Ken-ichiro; Shintani, Satoshi; Sugaya, Takeshi; Ishii, Masahiro; Akagi, Teiji; Ikeda, Hisao; Matsuishi, Toyojiro; Imaizumi, Tsutomu

2003-01-01

103

Modulation of prostaglandin biosynthesis in murine mammary adenocarcinoma tumor cells  

International Nuclear Information System (INIS)

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

104

Localization of mammary tumors in vivo with 131I-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 131I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of 131I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of 131I-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

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Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1?–mediated tumor apoptotic switch  

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Tumor radioresponsiveness depends on endothelial cell death, which leads in turn to tumor hypoxia. Radiation-induced hypoxia was recently shown to trigger tumor radioresistance by activating angiogenesis through hypoxia-inducible factor 1–regulated (HIF-1–regulated) cytokines. We show here that combining targeted radioiodide therapy with angiogenic inhibitors, such as canstatin, enhances direct tumor cell apoptosis, thereby overcoming radio-induced HIF-1–dependent tumor survival pathway...

Magnon, Claire; Opolon, Paule; Ricard, Marcel; Connault, Elisabeth; Ardouin, Patrice; Galaup, Ariane; Me?tivier, Didier; Bidart, Jean-michel; Germain, Ste?phane; Perricaudet, Michel; Schlumberger, Martin

2007-01-01

106

Inhibitory effect of electrolyzed reduced water on tumor angiogenesis.  

Science.gov (United States)

Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Tumor cells are exposed to higher oxidative stress compared to normal cells. Numerous reports have demonstrated that the intracellular redox (oxidation/reduction) state is closely associated with the pattern of VEGF expression. Electrolyzed reduced water (ERW) produced near the cathode during the electrolysis of water scavenged intracellular H(2)O(2) and decreased the release of H(2)O(2) from a human lung adenocarcinoma cell line, A549, and down-regulated both VEGF transcription and protein secretion in a time-dependent manner. To investigate the signal transduction pathway involved in regulating VEGF expression, mitogen-activated kinase (MAPK) specific inhibitors, SB203580 (p38 MAPK inhibitor), PD98059 (ERK1/2 inhibitor) and JNKi (c-Jun N-terminal protein kinase inhibitor) were applied. The results showed that only PD98059 blocks VEGF expression, suggesting an important role for ERK1/2 in regulating VEGF expression in A549 cells. As well, ERW inhibited the activation of extracellular signal-regulated kinase (ERK) in a time-dependent manner. Co-culture experiments to analyze in vitro tubule formation assay revealed that A549 cell-derived conditioned medium significantly stimulated the formation of vascular tubules in all analyzed parameters; tubule total area, tubule junction, number of tubules, and total tubule length. ERW counteracted the effect of A549 cell-conditioned medium and decreased total tube length (pERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK. PMID:18175936

Ye, Jun; Li, Yuping; Hamasaki, Takeki; Nakamichi, Noboru; Komatsu, Takaaki; Kashiwagi, Taichi; Teruya, Kiichiro; Nishikawa, Ryuhei; Kawahara, Takeshi; Osada, Kazuhiro; Toh, Kazuko; Abe, Masumi; Tian, Huaize; Kabayama, Shigeru; Otsubo, Kazumichi; Morisawa, Shinkatsu; Katakura, Yoshinori; Shirahata, Sanetaka

2008-01-01

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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

108

Oridonin Inhibits Tumor Growth and Metastasis through Anti-Angiogenesis by Blocking the Notch Signaling  

Science.gov (United States)

While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases. PMID:25485753

Li, Jingjie; Deng, Huayun; Song, Yajuan; Zhai, Dong; Peng, Yi; Lu, Xiaoling; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

2014-01-01

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Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth  

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Abstract Background Angiogenesis is a fundamental process that allows tumor growth by providing nutrients and oxygen to the tumor cells. Beyond the oxygen diffusion limit from a capillary blood vessel, tumor cells become apoptotic. Angiogenesis results from a balance of pro- and anti-angiogenic stimuli. Endogenous inhibitors regulate enzyme activities that promote angiogenesis. Tumor cells may express pro-angiogenic factors and hydrolytic enzymes but also kinin-degrading olig...

Juliano Luiz; Juliano Maria A; Monteiro Hugo P; Oliveira Vitor; Rodrigues Elaine G; Carmona Adriana K; Paschoalin Thaysa; Travassos Luiz R

2007-01-01

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The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis  

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A disintegrin and metalloprotease with thrombospondin motifs protein 1 (ADAMTS1) is a protease commonly up-regulated in metastatic carcinoma. Its overexpression in cancer cells promotes experimental metastasis, but whether ADAMTS1 is essential for metastatic progression is unknown. To address this question, we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumor model in Adamts1 knockout mice. Adamts1?/?/PyMT mice displayed significantly ...

Ricciardelli, Carmela; Frewin, Kate M.; Tan, Izza Arao; Williams, Elizabeth D.; Opeskin, Kenneth; Pritchard, Melanie A.; Ingman, Wendy V.; Russell, Darryl L.

2011-01-01

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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

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Identification of a unique mouse mammary tumor virus in the BALB/cNIV mouse strain.  

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We examined the genetic structure, in terms of restriction endonuclease recognition sites, of the milk-transmitted, low-oncogenic mouse mammary tumor virus (MuMTV) of the BALB/cNIV mouse strain. An analysis with EcoRI documented the presence of acquired cNIV proviruses in the mammary tumor DNAs of BALB/cNIV animals. A comparison of tumor DNAs digested with PstI showed that both the cNIV MuMTV and C3Hf MuMTV proviruses lacked the 4.3- and 1.1-kilobase pair fragments characteristic of C3H MuMTV...

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

1982-01-01

113

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

114

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

115

Suppressor cells in mice with murine mammary tumor virus-induced mammary tumors. I. Inhibition of mitogen-induced lymphocyte stimulation.  

Science.gov (United States)

Suppressor cell activity was present in the glass-adherent fraction of spleen cells from C3H mice bearing murine mammary tumor virus-induced mammary tumors. These cells effectively suppressed the blastogenic response of syngeneic normal lymphocytes to concanavalin A (Con A). Suppression by the spleen cells from mammary tumor-bearing mice was not dependent on DNA synthesis. Removal of the suppressor cells from spleen cell suspensions of tumor-bearing mice was not dependent on DNA synthesis. Removal of the suppressor cells from spleen cell suspensions of tumor-bearing animals (TBA) by passage of the cells on glass wool columns increased the Con A response of the remaining cells by fourfold to eightfold. Characterization of the suppressor population indicated that the cells were also adherent to nylon wool but not to plastic and contained a significantly increased proportion of surface immunoglobulin-bearing and complement receptor-bearing lymphocytes. Depletion of macrophages and T-cells did not remove the suppressive activity from the spleens of the TBA. The results were consistent with the identification of the suppressor cell as a B-cell. PMID:203703

Rudczynski, A B; Mortensen, R F

1978-01-01

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

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

Anver Miriam R

2008-04-01

117

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 LOX activates Akt through platelet derived growth factor receptor ? (PDGFR?) stimulation, resulting in increased vascula...

Baker, Ann-marie; Bird, Demelza; Welti, Jonathan C.; Gourlaouen, Morgane; Lang, Georgina; Murray, Graeme I.; Reynolds, Andrew R.; Cox, Thomas R.; Erler, Janine T.

2012-01-01

118

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

119

EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis.  

Science.gov (United States)

Tumor angiogenesis and metastatic spreading are two highly interconnected phenomena, which contribute to cancer-associated deaths. Thus, the identification of novel strategies to target angiogenesis and metastatic spreading is crucial. Polycomb genes are a set of epigenetic effectors, structured in multimeric repressive complexes. EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 lysine 27, thereby silencing several tumor-suppressor genes. EZH2 is essential for cancer stem cell self-renewal. Interestingly, cancer stem cells are thought to be the seeds of metastatic spreading and are able to differentiate into tumor-associated endothelial cells. Pre-clinical studies showed that EZH2 is able to silence several anti-metastatic genes (e.g., E-cadherin and tissue inhibitors of metalloproteinases), thereby favoring cell invasion and anchorage-independent growth. In addition, EZH2 seems to play a crucial role in the regulation of tumor angiogenesis. High EZH2 expression predicts poor prognosis, high grade, and high stage in several cancer types. Recently, a small molecule inhibitor of PRC2 (DZNeP) demonstrated promising anti-tumor activity, both in vitro and in vivo. Interestingly, DZNeP was able to inhibit cancer cell invasion and tumor angiogenesis in prostate and brain cancers, respectively. At tumor-inhibiting doses, DZNeP is not harmful for non-transformed cells. In the present manuscript, we review current evidence supporting a role of EZH2 in metastatic spreading and tumor angiogenesis. Using Oncomine datasets, we show that DZNeP targets are specifically silenced in some metastatic cancers, and some of them may inhibit angiogenesis. Based on this evidence, we propose the development of EZH2 inhibitors as anti-angiogenic and anti-metastatic therapy. PMID:22711031

Crea, Francesco; Fornaro, Lorenzo; Bocci, Guido; Sun, Lei; Farrar, William L; Falcone, Alfredo; Danesi, Romano

2012-12-01

120

Erythropoietin Promotes the Growth of Tumors Lacking Its Receptor and Decreases Survival of Tumor-Bearing Mice by Enhancing Angiogenesis1  

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Erythropoietin (Epo), a known hematopoietic growth factor, has been reported to promote tumor growth and angiogenesis in Epo receptor (EpoR)-positive tumors, but its effects on EpoR-negative tumors have not been clearly shown. Here, we show that Epo accelerates the growth of EpoR-negative tumors by promoting tumor angiogenesis. Mice were inoculated with Lewis lung carcinoma cells and treated with Epo. Erythropoietin accelerated tumor growth and increased intratumoral microvessel density, alth...

Okazaki, Tatsuma; Ebihara, Satoru; Asada, Masanori; Yamanda, Shinsuke; Niu, Kaijun; Arai, Hiroyuki

2008-01-01

 
 
 
 
121

Structural and Functional Analysis of Long Terminal Repeats of Suncus murinus Mammary Tumor Virus  

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A 2.7-kilobase (kb) cDNA sequence complementary to Suncus murinus mammary tumor virus (Sm-MTV) genomic RNA [corrected] was prepared using purified virions produced by the Sm-MT cell line, which had been established from a spontaneous mammary tumor of S. murinus. It was found, by using this cDNA in Southern hybridization experiments, that Sm-MTV was endogenous to this animal and that some 50 copies of endogenous provirus were present per haploid cellular genome. In addition, a proviral Sm-MTV ...

1988-01-01

122

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

Energy Technology Data Exchange (ETDEWEB)

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

123

Pristimerin, a triterpenoid, inhibits tumor angiogenesis by targeting VEGFR2 activation.  

Science.gov (United States)

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. PMID:22669041

Mu, Xianmin; Shi, Wei; Sun, Lixin; Li, Han; Jiang, Zhenzhou; Zhang, Luyong

2012-01-01

124

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

125

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

126

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 vascular endothelial gr...

Tsui Paulus; Rubenstein Marvin; Guinan Patrick

2005-01-01

127

Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors.  

Science.gov (United States)

Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV) as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs) and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution. PMID:23690930

Klijn, Christiaan; Koudijs, Marco J; Kool, Jaap; ten Hoeve, Jelle; Boer, Mandy; de Moes, Joost; Akhtar, Waseem; van Miltenburg, Martine; Vendel-Zwaagstra, Annabel; Reinders, Marcel J T; Adams, David J; van Lohuizen, Maarten; Hilkens, John; Wessels, Lodewyk F A; Jonkers, Jos

2013-01-01

128

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

International Nuclear Information System (INIS)

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

129

SCA-1 Identifies the Tumor-Initiating Cells in Mammary Tumors of BALB-neuT Transgenic Mice1  

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Cancer stem cells, initiating and sustaining the tumor process, have been isolated in human and murine breast cancer using different cell markers. In the present study, we aimed to evaluate the presence and characteristics of stem/tumor-initiating cells in the model of the mouse mammary neoplasia driven by the activated form of rat Her-2/neu oncogene (BALB-neuT mice). For this purpose, we generated tumor spheres from primary spontaneous BALB-neuT tumors. Tumor sphere cultures were characteriz...

Grange, Cristina; Lanzardo, Stefania; Cavallo, Federica; Camussi, Giovanni; Bussolati, Benedetta

2008-01-01

130

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

131

INFLUENCE OF ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ON MAMMARY GLAND DEVELOPMENT AND TUMOR SUSCEPTIBILITY  

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Influence of Endocrine Disrupting Compounds (EDCs) on Mammary Gland Development and Tumor Susceptibility. Suzanne E. Fenton1, and Jennifer Rayner1,2 1 Reproductive Toxicology Division, NHEERL/ORD, U.S. EPA, Research Triangle Park, NC, and 2 Department of Environmen...

132

Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo  

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Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD2 remains virtually unknown. Here we show that PGD2 receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiogenic endothelial cells highly express DP receptor, and its deficiency accelerates vascular leakage and angiogenesis. Administration of a synthetic DP agonist, BW245C, markedly suppresses tumor growth a...

Murata, Takahisa; Lin, Michelle I.; Aritake, Kosuke; Matsumoto, Shigeko; Narumiya, Shu; Ozaki, Hiroshi; Urade, Yoshihiro; Hori, Masatoshi; Sessa, William C.

2008-01-01

133

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors.  

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In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer. PMID:20018726

Hermes, Gretchen L; Delgado, Bertha; Tretiakova, Maria; Cavigelli, Sonia A; Krausz, Thomas; Conzen, Suzanne D; McClintock, Martha K

2009-12-29

134

Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo  

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We have studied the gene expression pattern of invasive primary mammary tumor cells using a unique in vivo invasion assay that isolates the invasive tumor cells by chemotaxis. One of the genes upregulated in the invasive tumor cells is Mena, an actin binding protein involved in the regulation of cell motility. There are multiple known splice variants of Mena accounted for by four alternatively included exons, +, ++, +++ and 11a. Using the in vivo invasion assay in rats and mice with mammary t...

Goswami, Sumanta; Philippar, Ulrike; Sun, Daqian; Patsialou, Antonia; Avraham, Jacob; Wang, Weigang; Di Modugno, Francesca; Nistico, Paola; Gertler, Frank B.; Condeelis, John S.

2009-01-01

135

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis  

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Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop int...

Li, Zhe; Huang, Hui; Boland, Patricia; Dominguez, Melissa G.; Burfeind, Patricia; Lai, Ka-man; Lin, Hsin-chieh; Gale, Nicholas W.; Daly, Christopher; Auerbach, Wojtek; Valenzuela, David; Yancopoulos, George D.; Thurston, Gavin

2009-01-01

136

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

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

Rinat Abramovitch

2004-09-01

137

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 ß (PDGFRß) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRß, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. Cancer Res; 73(2); 1-12. ©2012 AACR.

Baker, Ann-Marie; Bird, Demelza

2013-01-01

138

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

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

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

2013-01-01

139

Flow cytometric analysis for detection of tumor-initiating cells in feline mammary carcinoma cell lines.  

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A small population of cells known as tumor-initiating cells (TICs), which have the capacity to self-renew, differentiate, and form tumors at high frequency, has a potential role in tumor initiation, aggression, and recurrence. In human breast cancers, TICs are identified by surface markers, such as CD44 and CD24, and an aldefluor assay based on aldehyde dehydrogenase activity (ALDH(+)) using flow cytometry. However, the usefulness of surface markers CD44 and CD24 and ALDH activity in feline mammary carcinomas remains largely elusive. We attempted to identify CD44(+)CD24(-) and ALDH(+) cells using 8 feline mammary carcinoma cell lines, including FKNp, which was obtained from a primary lesion, and the capacity to generate tumor nodules was analyzed in immunodeficient mice injected with ALDH(+) FKNp-derived cells. The CD44(+)CD24(-) and ALDH(+) cells were detected in all cell lines derived from feline mammary carcinomas. Xenograft transplantation into immunodeficient mice demonstrated that as few as 1 × 10(2) ALDH(+) cells could initiate tumor growth in 1 out of 4 mice, while 1 × 10(3) ALDH(+) cells initiated tumor growth in 5 out of 6 mice. However, 1 × 10(3) ALDH(-) cells failed to initiate tumors in all the tested mice. ALDH(+)-derived tumors contained both ALDH(+) and ALDH(-) cells, indicating that ALDH(+) FKNp-derived cells had higher tumorigenicity than ALDH(-) cells. These results suggest that TICs may exist in feline mammary carcinomas, and further characterization of CD44(+)CD24(-) and ALDH(+) cells is needed to define novel therapies targeted against TICs. This study provides the foundation for elucidating the contribution of TICs in tumorigenesis. PMID:24041801

Michishita, Masaki; Otsuka, Aya; Nakahira, Rei; Nakagawa, Takayuki; Sasaki, Nobuo; Arai, Toshiro; Takahashi, Kimimasa

2013-11-15

140

Macrophages Mediate a Switch between Canonical and Non-Canonical Wnt Pathways in Canine Mammary Tumors  

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Objective According to the current hypothesis, tumor-associated macrophages (TAMs) are “corrupted” by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell–TAM interactions are complicated and controversial we aimed to better define this phenomenon. Methods and Results Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial–mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n?=?50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. Conclusions We demonstrated that TAMs mediate a “switch” between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being “corrupted” by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM–cancer cell interactions. PMID:24404146

Król, Magdalena; Mucha, Joanna; Majchrzak, Kinga; Homa, Agata; Bulkowska, Ma?gorzata; Majewska, Alicja; Gajewska, Ma?gorzata; Pietrzak, Marta; Perszko, Miko?aj; Romanowska, Karolina; Paw?owski, Karol; Manuali, Elisabetta; Hellmen, Eva; Motyl, Tomasz

2014-01-01

 
 
 
 
141

Static magnetic fields impair angiogenesis and growth of solid tumors in vivo.  

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Exposure to static magnetic fields (SMFs) results in a reduced blood flow in tumor vessels as well as in activation and adherence of platelets. Whether this phenomenon may have a significant functional impact on tumors has not been investigated as yet. The aim of our study was to evaluate the effects of prolonged exposure to SMFs on tumor angiogenesis and growth. Experiments were performed in dorsal skinfold chamber preparations of Syrian Golden hamsters bearing syngenic A-Mel-3 melanomas. On 3 d following tumor cell implantation one group of animals was immobilized and exposed to a SMF of 586 mT for three h. Control animals were immobilized for the same duration without SMF exposure. Using in vivo-fluorescence microscopy the field effects on tumor angiogenesis and microcirculation were analyzed for seven days. Tumor growth was assessed by repeated planimetry of the tumor area during the observation period. Exposure to SMFs resulted in a significant retardation of tumor growth ( approximately 30%). Furthermore, histological analysis showed an increased peri- and intratumoral edema in tumors exposed to SMFs. Analysis of microcirculatory parameters revealed a significant reduction of functional vessel density, vessel diameters and red blood cell velocity in tumors after exposure to SMFs compared to control tumors. These changes reflect retarded vessel maturation by antiangiogenesis. The increased edema after SMF exposure indicates an increased tumor microvessel leakiness possibly enhancing drug-uptake. Hence, SMF therapy appears as a promising new anticancer strategy-as an inhibitor of tumor growth and angiogenesis and as a potential sensitizer to chemotherapy. PMID:19633422

Strelczyk, Donata; Eichhorn, Martin E; Luedemann, Siiri; Brix, Gunnar; Dellian, Marc; Berghaus, Alexander; Strieth, Sebastian

2009-09-01

142

Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway  

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Full Text Available As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD, glucose (GD, and oxygen (hypoxia. These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five. This is in contrast to two other angiogenesis mediators interleukin-6 (two of five and fibroblast growth factor 2 (two of five that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4, a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy.

Yugang Wang

2013-08-01

143

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

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

1992-01-01

144

Plasma content of extracellular nucleic acids in donors and patients with mammary tumors.  

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The concentrations of extracellular DNA and RNA were measured in the plasma of donors and patients with fibroadenoma and breast cancer. The content of extracellular DNA surpassed the normal in 80% plasma samples from patients with mammary tumors. Extracellular RNA was detected in 30% plasma samples from donors and patients with breast tumors. No correlations were found between plasma concentration of extracellular DNA and size and stage of tumor growth. Hence, measurement of extracellular DNA in the plasma of patients can be used only as an accessory test for tumor diagnosis. PMID:16027882

Tamkovich, S N; Laktionov, P P; Rykova, E Yu; Starikov, A V; Skvortsova, T E; Kuznetsova, N P; Permyakova, V I; Vlasov, V V

2005-04-01

145

PPAR? agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition  

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)? deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR? would promote tumor growth. Surprisingly, the PPAR? agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR?-deficient tumors were still susceptible to fenofibrate, absence of PPAR? in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR? as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR? agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR? agonists in cancer treatment, alone and in combination with other therapies. PMID:18199835

Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E.; Barnés, Carmen M.; Fannon, Michael; Laforme, Andrea M.; Chaponis, Deviney M.; Folkman, Judah; Kieran, Mark W.

2008-01-01

146

PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition.  

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies. PMID:18199835

Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E; Barnés, Carmen M; Fannon, Michael; Laforme, Andrea M; Chaponis, Deviney M; Folkman, Judah; Kieran, Mark W

2008-01-22

147

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

148

A cell-based model exhibiting branching and anastomosis during tumor-induced angiogenesis.  

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This work describes the first cell-based model of tumor-induced angiogenesis. At the extracellular level, the model describes diffusion, uptake, and decay of tumor-secreted pro-angiogenic factor. At the cellular level, the model uses the cellular Potts model based on system-energy reduction to describe endothelial cell migration, growth, division, cellular adhesion, and the evolving structure of the stroma. Numerical simulations show: 1), different tumor-secreted pro-angiogenic factor gradient profiles dramatically affect capillary sprout morphology; 2), average sprout extension speeds depend on the proximity of the proliferating region to the sprout tip, and the coordination of cellular functions; and 3), inhomogeneities in the extravascular tissue lead to sprout branching and anastomosis, phenomena that emerge without any prescribed rules. This model provides a quantitative framework to test hypotheses on the biochemical and biomechanical mechanisms that control tumor-induced angiogenesis. PMID:17277180

Bauer, Amy L; Jackson, Trachette L; Jiang, Yi

2007-05-01

149

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.

A.P. Dutra

2004-11-01

150

Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth  

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Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor–deficient (AT1a–/–) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a–/– mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the ?-galactosidase gene was inserted into the AT1a gene locus in AT1a–/– mice, the site of ?-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a–/– mice, the major site of the ?-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a–/– mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo. PMID:12840060

Egami, Kimiyasu; Murohara, Toyoaki; Shimada, Toshifumi; Sasaki, Ken-ichiro; Shintani, Satoshi; Sugaya, Takeshi; Ishii, Masahiro; Akagi, Teiji; Ikeda, Hisao; Matsuishi, Toyojiro; Imaizumi, Tsutomu

2003-01-01

151

Micro-CT molecular imaging of tumor angiogenesis using a magnetite nano-cluster probe.  

Science.gov (United States)

Due to its high resolution, micro-CT is desirable for molecular imaging of tumor angiogenesis. However, the sensitivity of micro-CT to contrast agents is relatively low. Therefore, the purpose of this study is to develop high micro-CT sensitive molecular imaging probes for direct visualization and dynamic monitoring of tumor angiogenesis. To this end, Arg-Gly-Asp (RGD) peptides conjugated magnetite nano clusters (RGD-MNCs) were developed by assembling individual magnetite nano particles into clusters with amphiphilic (maleimide) methoxypoly(ethylene glycol)-b-poly(lactic acid) ((Mal)mPEG-PLA) copolymer and subsequently encoding RGD peptides onto the clusters for specific targeting alpha(v)beta3 integrin. The hydrodynamic size of RGD-MNCs was about 85 nm. To test its specificity, alpha(v)beta3 positive cells (H1299) were incubated with magnetite nano clusters (MNCs), RGD-MNCs or RGD-MNCs competition with free RGD peptides. Prussian Blue staining and inductively coupled plasma optical emission spectrometer (ICP-OES) measurements indicated that the cell uptake of RGD-MNCs was significantly more than that of MNCs, which could be inhibited by free RGD peptides. For detection of tumor angiogenesis, mice bearing H1299 tumors were injected intravenously with RGD-MNCs at the dose of 400 micro mol Fe/kg. Tumor angiogenic hot spots as well as individual angiogenic vessels could be clearly manifested by micro-CT imaging 12 h post injection, which was dynamically monitored with the extension of probe circulation time. Subsequent histological studies of tumor tissues verified that RGD-MNCs registered tumor angiogenic vessels. Our study demonstrated that RGD-MNC probes fabricated in this study could be used to effectively target alpha(v)beta3 integrin. Using high resolution micro-CT in combination with the probes, tumor angiogenesis could be studied dynamically. PMID:23858968

Liu, Ping; Li, Jing; Zhang, Chunfu; Xu, Lisa X

2013-06-01

152

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

153

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

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

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

2003-01-01

154

Atherosclerosis and Vascular Aging as Modifiers of Tumor Progression, Angiogenesis, and Responsiveness to Therapy  

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It is rarely considered that age-related common vascular co-morbidities may affect therapeutic outcomes of antiangiogenic therapy in cancer. Indeed, the accepted model of human disease consists of 4- to 8-week-old (young) tumor-bearing, but otherwise healthy, experimental mice, yet human cancers are diagnosed and treated in later decades of life when atherosclerosis and vascular diseases are highly prevalent. Here we present evidence that tumor growth and angiogenesis are profoundly altered i...

Klement, Halka; St Croix, Brad; Milsom, Chloe; May, Linda; Guo, Qing; Yu, Joanne L.; Klement, Petr; Rak, Janusz

2007-01-01

155

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

Science.gov (United States)

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

156

CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway  

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CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression ...

Liang, Zhongxing; Brooks, Joann; Willard, Margaret; Liang, Ke; Yoon, Younghyoun; Kang, Seunghee; Shim, Hyunsuk

2007-01-01

157

Effects of high $gamma$ irradiation doses on the mammary murine tumor virus  

Energy Technology Data Exchange (ETDEWEB)

From 7th international conference on mammary tumors; SaintPierre-de- Chartreuse, France (12 Jun 1972). Cellular extracts of mammary tumors of the PS mouse strain and suspensions of purified viral particles obtained using ultracentrifugation were gamma irradiated with 150 to 3950 kR doses. The infectivity was not only retained but actually enhanced with increasing dose: 1200, 1950, and 2500 kR. The mean age of the tumors was reduced. Electron microscopy enabled observations to be made of numerous type A and type B particles. The molecular weight of the radiation sensitive sample is less than that of ribosomal RNA; this fact indicating the possibility of only a small fraction of the viral RNA being implicated in the oncogenic function of the virus. (FR)

Gorka, C.; Mistry, P.; Mouriquand, J.

1972-12-31

158

IGFBP-3 suppresses VEGF expression and tumor angiogenesis in head and neck squamous cell carcinoma  

Science.gov (United States)

Angiogenesis, the process by which new blood vessels are recruited to existing ones, is essential for tumor development. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), which modulates bioavailability of IGF, has been studied for its potential role in angiogenesis during tissue regeneration and cancer development. In this study, we assessed the role of IGFBP-3 in tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC) and human umbilical endothelial cells (HUVECs) using adenoviral (Ad-BP3) and recombinant (rBP3) IGFBP-3. Utilizing an in vivo orthotopic tongue tumor model, we confirmed that both Ad-BP3 and rBP3 suppress the growth of UMSCC38 HNSCC cells in vivo. Ad-BP3 inhibited vascularization in tongue tumors and chorio-allantoic membrane, and suppressed angiogenesis-stimulating activities in UMSCC38 cells. In HUVECs, Ad-BP3 decreased migration, invasion, and tube formation. rBP3 also suppressed production of VEGF in HUVECs and UMSCC38 cells. IGFBP-3-GGG, a mutant IGFBP-3 with loss of IGF binding capacity, suppressed VEGF production. In addition, we found that IGFBP-3 suppressed VEGF expression, even in mouse embryonic fibroblasts from an IGF-1R-null mouse. Finally, we demonstrated that IGFBP-3-GGG inhibits tumor angiogenesis and growth to the same degree as wild-type IGFBP-3. Taken together, these results support the hypothesis that IGFBP-3 has antiangiogenic activity in HNSCC, at least in part due to IGF-independent suppression of VEGF production from vascular endothelial cells and cancer cells. PMID:22494072

Oh, Seung-Hyun; Kim, Woo-Young; Lee, Ok-Hee; Kang, Ju-Hee; Woo, Jong-Kyu; Kim, Jai-Hyun; Glisson, Bonnie; Lee, Ho-Young

2012-01-01

159

Clinically relevant immunosuppressants influence UVB-induced tumor size through effects on inflammation and angiogenesis.  

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Immunosuppressive therapies allow long-term patient and transplant survival, but are associated with increased development of UV-induced skin cancers, particularly squamous cell carcinomas. The mechanisms by which CsA, MMF, tacrolimus (TAC) or sirolimus (SRL), alone or in dual combinations, influence tumor development and progression are not completely understood. In the current study, chronically UV-exposed mice treated with SRL alone or in combination with CsA or TAC developed more tumors than mice treated with vehicle or other immunosuppressants, but the tumors were significantly smaller and less advanced. Mice treated with CsA or TAC developed significantly larger tumors than vehicle-treated mice, and a larger percentage in the CsA group were malignant. The addition of MMF to CsA, but not to TAC, significantly reduced tumor size. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain these findings. CsA enhanced both UVB-induced inflammation and tumor blood vessel density, while MMF reduced inflammation. Addition of MMF to CsA reduced tumor size and vascularity. SRL did not affect inflammation, but significantly reduced tumor vascularity. Thus the choice of immunosuppressants has important implications for tumor number, size and progression, likely due to the influence of immunosuppressants on UVB-induced inflammation and angiogenesis. PMID:17941958

Duncan, F J; Wulff, Brian C; Tober, Kathleen L; Ferketich, Amy K; Martin, Jason; Thomas-Ahner, Jennifer M; Allen, Stephanie D; Kusewitt, Donna F; Oberyszyn, Tatiana M; Vanbuskirk, Anne M

2007-12-01

160

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

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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

 
 
 
 
161

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

162

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 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

163

{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

164

Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells.  

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Keratin 5 (K5) mRNA and protein are shown to be expressed in normal mammary epithelial cells in culture and are absent from tumor-derived cell lines. To extend these findings, the full complements of keratins in normal, immortalized, and tumor cells were compared. It is shown here that normal cells produce keratins K5, K6, K7, K14, and K17, whereas tumor cells produce mainly keratins K8, K18, and K19. In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mR...

Trask, D. K.; Band, V.; Zajchowski, D. A.; Yaswen, P.; Suh, T.; Sager, R.

1990-01-01

165

Monoclonal antibodies against antigens displayed on a progressively growing mammary tumor.  

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We have produced lymphocyte hybridomas between mouse myeloma cells and either spleen cells of C3H/f/C57BL/6 mice bearing the Mm5mt/c1 tumor-producing murine mammary tumor virus (MMTV) or spleen cells from Fisher rats inoculated with the same tumor. Two classes of hybridoma-secreted monoclonal antibodies were obtained. In the first class are IVC11, IIIA1, and VE7, each of which precipitated a 52,000-dalton protein from 125I-labeled purified preparations of MMTV and [3H]glucosamine-labeled Mm5m...

Tax, A.; Manson, L. A.

1981-01-01

166

L-type amino acid transporter 1 (LAT1) expression in canine mammary gland tumors.  

Science.gov (United States)

L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors, in contrast to its limited distribution and low-level expression in normal tissues. In this study, to explore the feasibility of using LAT1 expression as a molecular marker in mammary gland tumors (MGT), we performed a comparative study of LAT1 expression at the mRNA and protein levels in normal mammary gland cells and tumor cells. Conventional RT-PCR and Western blotting were performed on MGT tissues from 16 dogs and normal organs from nine healthy dogs. LAT1 expression was detected in ten of the 16 MGT patients. As is the case in human tissues, LAT1 showed limited expressional distribution in normal canine organs. For quantitative expressional comparison, extensive real-time RT-PCR was performed on mRNA samples from 53 MGT patients. The comparison demonstrated that LAT1 mRNA levels from MGT tissues were 20 times higher than those in normal mammary gland tissues. Additionally, histologically invasive MGT showed a higher expression of LAT1 than non-invasive tumors. These findings suggest that LAT1 could be a clinical marker and therapeutic target for invasive malignant MGT. PMID:23171689

Fukumoto, Shinya; Hanazono, Kiwamu; Komatsu, Takahiro; Iwano, Hidetomo; Kadosawa, Tsuyoshi; Uchide, Tsuyoshi

2013-05-01

167

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

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

Osmar Fajardo

2005-10-01

168

Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo.  

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Thalidomide was recently suggested to be angiogenesis-inhibitor following the demonstration of its activity in a rabbit cornea micropocket model. The purpose of the present study was to test its efficacy in solid tumors in mice. B16-F10 melanoma and CT-26 colon carcinoma cells were injected subcutaneously, intravenously and intraperitoneally, and mice received daily gavage of 0.3-1.0 mg thalidomide starting either two or 10 days following tumor cell injection. The tumors were measured and compared with controls. There was no growth retardation in CT-26 bearing mice nor in mice with pulmonary or peritoneal metastases of B16-F10 melanoma. In 3/7 groups of mice with SC B16-F10 tumors, growth retardation was demonstrated, however the difference was not statistically significant. All tumors eventually reached maximal size, similar to controls. Morphological evaluation of the blood vessels oriented towards the tumor revealed that in both thalidomide and control groups, all mice had developed an intact network of new blood vessels. In our model for the oral administration of thalidomide inhibition of tumor growth and angiogenesis did not occur. We hypothesize that the lack of sustained antiangiogenic response was either due to immune modulation or to tumor heterogeneity and adaptation. PMID:9042240

Gutman, M; Szold, A; Ravid, A; Lazauskas, T; Merimsky, O; Klausner, J M

1996-01-01

169

Computational Modeling of 3D Tumor Growth and Angiogenesis for Chemotherapy Evaluation  

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Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID:24404145

Tang, Lei; van de Ven, Anne L.; Guo, Dongmin; Andasari, Vivi; Cristini, Vittorio; Li, King C.; Zhou, Xiaobo

2014-01-01

170

Potential markers for detection of circulating canine mammary tumor cells in the peripheral blood.  

Science.gov (United States)

Major discrepancies exist between histological predictions and actual metastatic potential of canine mammary tumors. Detection of circulating tumor cells (CTC) has a proven prognostic value for human breast cancer but similar markers for canine CTC are lacking. In the present study a panel of 16 human CTC markers was tested for their ability to specifically and sensitively detect canine carcinoma cells in peripheral blood. PCR assays for CK19, ERBB2, EGFR, CLDN7 and ELF3 were able to sensitively detect one carcinoma cell in up to 10(7) peripheral blood leukocytes. These CTC markers are thus candidate markers for identifying canine mammary CTC in the peripheral blood and may serve as prognostic factors for metastatic behavior in the future. PMID:21051248

da Costa, A; Oliveira, J T; Gärtner, F; Kohn, B; Gruber, A D; Klopfleisch, R

2011-10-01

171

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

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

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

2008-01-01

172

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

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

Toshiyuki Ishiwata, Yoko Matsuda, Zenya Naito

2011-01-01

173

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

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

174

Frondoside a suppressive effects on lung cancer survival, tumor growth, angiogenesis, invasion, and metastasis.  

Science.gov (United States)

A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 µM) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer. PMID:23308143

Attoub, Samir; Arafat, Kholoud; Gélaude, An; Al Sultan, Mahmood Ahmed; Bracke, Marc; Collin, Peter; Takahashi, Takashi; Adrian, Thomas E; De Wever, Olivier

2013-01-01

175

Endostar attenuates melanoma tumor growth via its interruption of b-FGF mediated angiogenesis.  

Science.gov (United States)

To develop optimal therapeutics is one of the hotspots in both clinical and basic melanoma studies. Previous studies indicate that fibroblast growth factors (b-FGF/FGF-2), an angiogenesis inducer beyond VEGF, might be a potential drug target in melanoma. As a novel anti-angiogenesis peptide drug, Endostar has shown promising therapeutic efficacy in non-small cell lung cancer. However, the effect of Endostar on b-FGF-induced angiogenesis in melanoma is unraveled. To this end, both in vivo and in vitro experiments were conducted and it was found that treatment of Endostar could inhibit tumor growth, which was accompanied by decreased micro-vessel density and serum b-FGF levels in a mouse melanoma model. In addition, treatment with Endostar in blood vessel endothelial cells could reduce their proliferation, cell migration and tube formation capacity in a dosage-dependent manner. Moreover, treatment of Endostar could also attenuate b-FGF-activated phosphorylation of p38 and ERK1/2 in HUVECs. These findings indicate that Endostar might exert its anti-tumor effect via suppressing b-FGF-induced angiogenesis and b-FGF-activated MAPK signaling pathway, suggesting that Endostar might be a potential choice for clinical melanoma treatment. PMID:25597785

Xiao, Lijia; Yang, ShuCai; Hao, Jianhua; Yuan, Xue; Luo, Wei; Jiang, Liping; Hu, Yang; Fu, Zhongping; Zhang, Yun; Zou, Chang

2015-04-01

176

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

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Abstract Background Controversy exists as to the ability of human gammaherpesviruses to cause or exacerbate breast cancer disease in patients. The difficulty in conducting definitive human studies can be overcome by investigating developing breast cancer in a mouse model. In this study, we utilized mice latently infected with murine gammaherpesvirus 68 (HV-68) to question whether such a viral burden could exacerbate metastatic breast cancer disease using a mouse mammary tumor...

Chauhan Vinita S; Nelson Daniel A; Roy Lopamudra Das; Mukherjee Pinku; Bost Kenneth L

2012-01-01

177

Stimulation of basal transcription from the mouse mammary tumor virus promoter by Oct proteins.  

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The steroid hormone-inducible promoter of mouse mammary tumor virus (MMTV) contains three overlapping sequences related to the consensus octamer motif ATGCAAAT. Basal promoter activity in the absence of hormone induction from a template in which all three octamer elements were mutated was decreased by two-to threefold in in vitro transcription assays. Oct-1 protein purified from HeLa cell nuclear extracts, as well as recombinant Oct-1 expressed in bacteria, recognized MMTV octamer-related seq...

Kim, M. H.; Peterson, D. O.

1995-01-01

178

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

179

The role of hypoxia related angiogenesis in uterine smooth muscle tumors.  

Science.gov (United States)

Abstract Mechanisms of hypoxia-related angiogenesis are important for uterine smooth muscle tumors. Factors that are related to angiogenesis during hypoxia include vascular endothelial growth factor (VEGF), hypoxia inducible factor 1? (HIF1?), T-cell intracellular antigen1 (TIA1), eukaryotic translation initiation factor 2? (eIF2?) and thrombospondin 1 (TSP1). We investigated immunoreactivities of VEGF, HIF1?, TIA1, eIF2? and TSP1 using an indirect immunoperoxidase method for formalin fixed, paraffin embedded tumors that had been diagnosed as leiomyoma (LMY), cellular leiomyoma (CLM) or leiomyosarcoma (LMS). TSP1 immunoreactivity was scored as moderate, mild or minimal, while VEGF, eIF2? and TIA1 immunoreactivities were scored as mild, moderate and strong in LMY, CLM and LMS samples, respectively. HIF1? immunoreactivity was scored as mild to minimal in LMY, CLM and LMS samples, but showed no statistically significant differences among samples. Although angiogenic factors showed strong immunohistochemical staining intensity in LMS, anti-angiogenic factors showed minimal immunohistochemical intensity. There was no difference in HIF-1? immunoreactivity compared to LMY, CLM and LMS samples. We suggest that HIF1? protein synthesis could be suppressed by eIF2? and TIA1. Furthermore, VEGF could be activated by pathways such as COX2, Ras, NF-?B or c-myc instead of HIF1?. Angiogenesis could trigger and accelerate tumor development; therefore, anti-angiogenic therapy could be useful for treatment of tumors. PMID:25225843

Uluer, Et; Inan, S; Ozbilgin, K; Karaca, F; Dicle, N; Sanc?, M

2015-02-01

180

Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis.  

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Angiogenesis is involved in the development, progression and metastasis of various human cancers. Herein, we report the discovery of glipizide, a widely used drug for type 2 diabetes mellitus, as a promising anticancer agent through the inhibition of tumor angiogenesis. By high-throughput screening (HTS) of an FDA approved drug library utilizing our in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, glipizide has been identified to significantly inhibit blood vessel formation and development. Moreover, glipizide was found to suppress tumor angiogenesis, tumor growth and metastasis using xenograft tumor and MMTV-PyMT transgenic mouse models. We further revealed that the anticancer capability of glipizide is not attributed to its antiproliferative effects, which are not significant against various human cancer cell lines. To investigate whether its anticancer efficacy is associated with the glucose level alteration induced by glipizide application, glimepiride, another medium to long-acting sulfonylurea antidiabetic drug in the same class, was employed for the comparison studies in the same fashion. Interestingly, glimepiride has demonstrated no significant impact on the tumor growth and metastasis, indicating that the anticancer effects of glipizide is not ascribed to its antidiabetic properties. Furthermore, glipizide suppresses endothelial cell migration and the formation of tubular structures, thereby inhibiting angiogenesis by up-regulating the expression of natriuretic peptide receptor A. These findings uncover a novel mechanism of glipizide as a potential cancer therapy, and also for the first time, provide direct evidence to support that treatment with glipizide may reduce the cancer risk for diabetic patients. PMID:25294818

Qi, Cuiling; Zhou, Qin; Li, Bin; Yang, Yang; Cao, Liu; Ye, Yuxiang; Li, Jiangchao; Ding, Yi; Wang, Huiping; Wang, Jintao; He, Xiaodong; Zhang, Qianqian; Lan, Tian; Lee, Kenneth Ka Ho; Li, Weidong; Song, Xiaoyu; Zhou, Jia; Yang, Xuesong; Wang, Lijing

2014-10-30

 
 
 
 
181

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

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

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

2015-02-01

182

Unusual anogenital apocrine tumor resembling mammary-like gland adenoma in male perineum: a case report  

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Full Text Available Abstract A rare case of an apocrine tumor in the male perineal region is reported. A dermal cystic lesion developed in the region between the anus and scrotum of a 74-year-old Japanese male. The cystic lesion, measuring 3.5 × 5.0 cm in size, was lined by columnar or flattened epithelium with occasional apocrine features and supported by a basal myoepithelium lining. A mural nodule, measuring 1 × 1.5 cm in size, protruded into the cystic space and consisted of a solid proliferation of tubular glands with prominent apocrine secretion and basal myoepithelial cells. Immunohistochemical examination showed that the luminal cells were partially positive for gross cystic disease fluid protein 15 and human milk fat globulin 1, and the basal myoepithelial cells were positive for alpha-smooth muscle actin and S-100 protein. Estrogen and progesterone hormone receptors were focally and weakly positive for luminal epithelium. Although no mammary-like glands were present in the dermis around the tumor, this unusual apocrine tumor has been suggested to be derived from male anogenital mammary-like glands and mimic a mammary-like gland adenoma in the male perineum.

Yoshioka Takako

2010-06-01

183

Paradox between angiogenesis and oxygen effect in the treatment of tumor  

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

184

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

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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

185

Molecular characterizations of Nop16 in murine mammary tumors with varying levels of c-Myc.  

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NOP16, also known as HSPC111, has been identified as a MYC and estrogen regulated gene in in vitro studies, hence coexpression levels were strongly correlated. Importantly, high expression of NOP16 was associated with poor clinical outcome in breast cancer patients. However, coexpression of NOP16, MYC and estrogen receptor (ESR1) varied widely in tumors and cell lines suggesting that transcriptional regulation differed according to pathological environments. The goal of this study was to determine the expression patterns of Nop16, Myc and Esr1 in murine mammary tumors with disparate histopathological and molecular features. We hypothesized that tumor environments with relatively high Myc levels would have different coexpression patterns than tumor environments with relatively low Myc levels. We measured levels of Myc and Nop16 mRNA and protein in tumors from WAP-c-myc mice that were of high grade and metastasized frequently. In contrast, Myc and Nop16 mRNA and proteins levels were significantly lower in the less aggressive tumors that developed in NRL-TGF? mice. Tumors from both mouse lines express ESR1 protein and we found that Esr1 mRNA levels correlated positively with Myc levels in both models. However, Myc and Nop16 transcript levels correlated positively only in tumors from NRL-TGF? mice. We identified prominent NOP16 protein in nuclei and less prominent staining in the cytoplasm of luminal cells of ducts and lobules from normal mammary glands as well as in hyperplasias and tumors obtained from NRL-TGF? mice. This staining pattern was reversed in tumors from WAP-c-Myc mice as nuclear staining was faint or absent and cytoplasmic staining more pronounced. In summary, the regulation of expression and localization of NOP16 varies in tumor environments with high versus low MYC levels and demonstrate the importance of stratifying clinical breast cancers based on MYC levels. PMID:21863248

Kundel, Donald W; Stromquist, Emily; Greene, Amy L; Zhdankin, Olga; Regal, Ronald R; Rose-Hellekant, Teresa A

2012-04-01

186

Cross-immunity among mammary carcinomas in C3H/HE mice immunized with gamma-irradiated tumor cells  

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By immunization with gamma-irradiated (13,000 rad) tumor cells, cross-immunity between ascites mammary carcinomas and among solid mammary carcinomas in C3H/He mice was studied. The results were as follows: (1) Two ascites mammary carcinomas designated MM 46 (high vitality) and MM 48 (intermediate vitality) were used in this experiment. The immunization with the tumor of high vitality (MM 46) induced strong cross-immunity against the challenge of the tumor of intermediate vitality (MM 48). The immunization with the tumor of intermediate vitality (MM 48) induced weak cross-immunity against the challenge of the tumor of high vitality (MM 46). (2) Three solid mammary carcinomas designated MT 10 (intermediate vitality), MT 7 (high vitality) and MT X (the highest vitality) were used in this experiment. The immunization with the tumor of high vitality (MT 7) induced strong cross-immunity against the challenge of the tumor of intermediate vitality (MT 10), and induced moderate cross-immunity against the challenge of the tumor of the highest vitality (MT X). The immunization with the tumor of intermediate vitality (MT 10) induced moderate cross-immunity against the challenge of the tumor of high vitality (MT 7), but could not induce any cross-immunity against the challenge of the tumor of the highest vitality (MT X). (author)

187

Coupling of discrete random walks and continuous modeling for three-dimensional tumor-induced angiogenesis  

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The growth of new vascular networks from pre-existing capillaries (angiogenesis) plays a pivotal role in tumor development. Mathematical modeling of tumor-induced angiogenesis may help understand the underlying biology of the process and provide new hypotheses for experimentation. Here, we couple an existing deterministic continuum theory with a discrete random walk, proposing a new model that accounts for chemotactic and haptotactic cellular migration. We propose an efficient numerical method to approximate the solution of the model. The accuracy, stability and effectiveness of our algorithms permitted us to perform large-scale three-dimensional simulations which, in contrast to two-dimensional calculations, show a topological complexity similar to that found in experiments. Finally, we use our model and simulations to investigate the role of haptotaxis and chemotaxis in the mobility of tip endothelial cells and its influence in the final vascular patterns.

Vilanova, Guillermo; Colominas, Ignasi; Gomez, Hector

2014-03-01

188

Minute dosages of ???3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits  

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Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, ???3-targeted fumagillin nanoparticles were used to suppress the neovasculature and inhibit Vx-2 adenocarcinoma development using minute drug doses. Tumor-bearing rabbits were treated on days 6, 9, and 12 postimplantation with ???3-targeted fumagillin nanoparticles (30 ?g/kg), ???3-targeted nanoparticles without drug, nontargeted fumagill...

Winter, Patrick M.; Schmieder, Anne H.; Caruthers, Shelton D.; Keene, Jeffery L.; Zhang, Huiying; Wickline, Samuel A.; Lanza, Gregory M.

2008-01-01

189

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

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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

190

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

191

Oncostatin M Promotes Mammary Tumor Metastasis to Bone and Osteolytic Bone Degradation  

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Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine that has been implicated in a number of biological processes including inflammation, hematopoiesis, immune responses, development, and bone homeostasis. Recent evidence suggests that OSM may promote breast tumor invasion and metastasis. We investigated the role of OSM in the formation of bone metastases in vivo using the 4T1.2 mouse mammary tumor model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cell...

Bolin, Celeste; Tawara, Ken; Sutherland, Caleb; Redshaw, Jeff; Aranda, Patrick; Moselhy, Jim; Anderson, Robin; Jorcyk, Cheryl L.

2012-01-01

192

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

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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 ...

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

2004-01-01

193

Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis.  

Science.gov (United States)

The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin-converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms. PMID:23739345

Okwan-Duodu, Derick; Landry, Jerome; Shen, Xiao Z; Diaz, Roberto

2013-08-01

194

Inhibiting Tumor Angiogenesis in Metastatic Hormone-Refractory Prostate Cancer  

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In this NIH Clinical Center study, researchers will test whether treatment with a novel monoclonal antibody, TRC105, that targets a protein highly expressed on the surface of tumor blood vessels improves the outcome of men with metastatic castration-resistant prostate cancer.

195

Molecular Imaging in Tumor Angiogenesis and Relevant Drug Research  

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Molecular imaging, including fluorescence imaging (FMI), bioluminescence imaging (BLI), positron emission tomography (PET), single-photon emission-computed tomography (SPECT), and computed tomography (CT), has a pivotal role in the process of tumor and relevant drug research. CT, especially Micro-CT, can provide the anatomic information for ...

Xibo Ma; Jie Tian; Xin Yang; Chenghu Qin

2011-01-01

196

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

197

Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread.  

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Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment. PMID:25584895

Wong, Ping-Pui; Demircioglu, Fevzi; Ghazaly, Essam; Alrawashdeh, Wasfi; Stratford, Michael R L; Scudamore, Cheryl L; Cereser, Biancastella; Crnogorac-Jurcevic, Tatjana; McDonald, Stuart; Elia, George; Hagemann, Thorsten; Kocher, Hemant M; Hodivala-Dilke, Kairbaan M

2015-01-12

198

Matrix metalloproteinase (MMP-2 and MMP-9) and steroid receptor expressions in feline mammary tumors.  

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We evaluated the presence of estrogen (ER) and progesterone (PR) receptors, and matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) enzymes in 18 feline mammary tubulopapillary carcinomas. Immunohistochemistry was performed to localize ER, PR, MMP-2 and MMP-9 in situ. Western blotting and zymographic analyses also were performed to investigate the presence and activities of MMP-2 and MMP-9 enzymes in fresh tissue homogenates. ER immune expression was detected in five samples (27.7%) and PR was positive in sixteen (88.8%) samples. Diffuse cytoplasmic staining of MMP-2 and MMP-9 in neoplastic mammary epithelial cells, stromal fibroblasts and inflammatory cell was evident. MMP-2 and MMP-9 staining was observed also in metastasizing neoplastic cells within lymphatic vessels. MMP-2 and MMP-9 enzymes and their activities in fresh tumor homogenates were demonstrated by zymography. Comparison of MMP-9 gelatinolytic bands from tumor samples and controls revealed a statistically significant difference. We demonstrated elevated MMP-9 and MMP-2 levels in tumor samples by Western blotting; analysis of protein bands revealed 1.9-to-3 fold increase in MMP-9 in tumor samples and the difference was statistically significant. Our results suggest that the expression of MMP-9 can be an important indicator for tumor progression and the possible metastatic nature of feline tubulopapillary carcinomas. PMID:22247959

Akkoc, A; Inan, S; Sonmez, G

2012-05-01

199

Accelerated Mammary Tumor Development in Mutant Polyomavirus Middle T Transgenic Mice Expressing Elevated Levels of Either the Shc or Grb2 Adapter Protein  

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The Grb2 and Shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. To assess the role of these molecules in mammary epithelial development and tumorigenesis, we have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial cell-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mammary tumors were rarely observed in these strai...

Rauh, Michael J.; Blackmore, Valerie; Andrechek, Eran R.; Tortorice, Christopher G.; Daly, Roger; Lai, Venus Ka-man; Pawson, Tony; Cardiff, Robert D.; Siegel, Peter M.; Muller, William J.

1999-01-01

200

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 sis was found to be in thoracic mammary gland. Both estrogen and testosterone have a role in mammary cancers. The study showed that both estrogen and testosterone were important in mammary cancer diagnosis. It is suggested that sex hormones have a role in late stages in breast carcinogenesis. Estradiol, which is the main form of estrogen, affects the different stage of mammary gland carcinogenesis. Furthermore, the results indicated that Spirulina platensis may have therapeutic and protective effects (30%) on mammary cancers of Sprague-Dawely female rats chemically induced by DMBA.

 
 
 
 
201

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

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

Stefan K. Siwko

2008-07-01

202

P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis  

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The pathway involving the tumor suppressor gene TP53 can regulate tumor angiogenesis by unclear mechanisms. Here we show that p53 regulates hypoxic signaling through the transcriptional regulation of microRNA-107 (miR-107). We found that miR-107 is a microRNA expressed by human colon cancer specimens and regulated by p53. miR-107 decreases hypoxia signaling by suppressing expression of hypoxia inducible factor-1? (HIF-1?). Knockdown of endogenous miR-107 enhances HIF-1? expression and hypo...

Yamakuchi, Munekazu; Lotterman, Craig D.; Bao, Clare; Hruban, Ralph H.; Karim, Baktiar; Mendell, Joshua T.; Huso, David; Lowenstein, Charles J.

2010-01-01

203

Metastatic papillary craniopharyngioma: case study and study of tumor angiogenesis.  

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We report a case of suprasellar papillary craniopharyngioma metastatic to the temporoparietal region 2 years after its initial resection. The literature documents examples of craniopharyngioma recurrences along the surgical tract, as well as remote ipsi- and contralateral metastases via cerebrospinal fluid seeding. Ours is the second report of a craniopharyngioma of papillary type to exhibit metastatic behavior. The tumor spread opposite the side of craniotomy. Although a rare occurrence, it ...

Elmaci, Lhan; Kurtkaya-yapicier, Ozlem; Ekinci, Gazanfer; Sav, Aydin; Pamir, M. Necmettin; Vidal, Sergio; Kovacs, Kalman; Scheithauer, Bernd W.

2002-01-01

204

[SIBLING proteins: molecular tools for tumor progression and angiogenesis].  

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The small integrin-binding ligand N-linked glycoprotein (SIBLING) family consists of osteopontin (OPN), bonesialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE). These proteins, initially identified in bone and teeth, share many structural characteristics. It is now well established that they are over expressed in many tumors and play a critical role at different steps of cancer development. In this review, w...

Lamour, Virginie; Nokin, Marie-julie; Henry, Aure?lie; Castronovo, Vincenzo; Bellahcene, Akeila

2013-01-01

205

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

206

Assessment of aglepristone in dogs with mammary tumors stage V  

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Las metástasis pulmonares de tumores mamarios son generalmente la causa de muerte en las mascotas que padecen una neoplasia de glándula mamaria. Esto marca la importancia en la búsqueda de nuevos tratamientos, enfocados a la modulación de blancos moleculares, con una acción predominante en la estabilización o regresión de la enfermedad metástasica. En este estudio se evaluaron 20 perras en estadio clínico V. Las perras fueron distribuidas aleatoriamente en uno de los ...

Hermo, Guillermo; Villanueva, Miriam; Segura, Pablo; Alonso, Daniel; Gobello, Cristina

2009-01-01

207

Mammary tumor in BALB/c/Cnb mouse: differential effect between fractionated irradiations and 5-FU administration  

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The effect of 5 FU fractional doses 9 h. after the 5th and the 10th fractional irradiation on a grafted mammary tumor, was studied. The results display that the association of those two treatments has a potentialisation effect which reduces the tumoral growth during the treatment and stabilizes it after the treatment at a volume inferior to which was grafted

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Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis.  

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Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice. Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelial-barrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis. PMID:24990940

Alhusban, Ahmed; Al-Azayzih, Ahmad; Goc, Anna; Gao, Fei; Fagan, Susan C; Somanath, Payaningal R

2014-09-01

209

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 (ptumor 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

210

In vivo imaging of tumor angiogenesis using fluorescence confocal videomicroscopy.  

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Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained. We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 ?m in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools. The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability. PMID:24056503

Fitoussi, Victor; Faye, Nathalie; Chamming's, Foucauld; Clement, Olivier; Cuenod, Charles-Andre; Fournier, Laure S

2013-01-01

211

CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment.  

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Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase C? (PKC?), c-Src and hypoxia-inducible factor-1 alpha (HIF-1?) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKC?/c-Src/HIF-1? signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma. PMID:25330803

Wang, Shih-Wei; Liu, Shih-Chia; Sun, Hui-Lung; Huang, Te-Yang; Chan, Chia-Han; Yang, Chen-Yu; Yeh, Hung-I; Huang, Yuan-Li; Chou, Wen-Yi; Lin, Yu-Min; Tang, Chih-Hsin

2015-01-01

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Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1.  

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The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-?B. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment. PMID:22391561

van Beijnum, J R; Nowak-Sliwinska, P; van den Boezem, E; Hautvast, P; Buurman, W A; Griffioen, A W

2013-01-17

213

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

214

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

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

Nasim Akhtar

2004-03-01

215

Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5  

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Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors. PMID:24327603

Exertier, Prisca; Javerzat, Sophie; Wang, Baigang; Franco, Mélanie; Herbert, John; Platonova, Natalia; Winandy, Marie; Pujol, Nadège; Nivelles, Olivier; Ormenese, Sandra; Godard, Virginie; Becker, Jürgen; Bicknell, Roy; Pineau, Raphael; Wilting, Jörg; Bikfalvi, Andreas; Hagedorn, Martin

2013-01-01

216

Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo.  

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Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD(2) remains virtually unknown. Here we show that PGD(2) receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiogenic endothelial cells highly express DP receptor, and its deficiency accelerates vascular leakage and angiogenesis. Administration of a synthetic DP agonist, BW245C, markedly suppresses tumor growth as well as tumor hyperpermeability in WT mice, but not in DP-deficient mice. In a corneal angiogenesis assay and a modified Miles assay, host DP deficiency potentiates angiogenesis and vascular hyperpermeability under COX-2-active situation, whereas exogenous administration of BW245C strongly inhibits both angiogenic properties in WT mice. In an in vitro assay, BW245C does not affect endothelial migration and tube formation, processes that are necessary for angiogenesis; however, it strongly improves endothelial barrier function via an increase in intracellular cAMP production. Our results identify PGD(2)/DP receptor as a new regulator of tumor vascular permeability, indicating DP agonism may be exploited as a potential therapy for the treatment of cancer. PMID:19060214

Murata, Takahisa; Lin, Michelle I; Aritake, Kosuke; Matsumoto, Shigeko; Narumiya, Shu; Ozaki, Hiroshi; Urade, Yoshihiro; Hori, Masatoshi; Sessa, William C

2008-12-16

217

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

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Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model—an MRI Study1  

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Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF) is a potent inhibitor of collagen type ?1(I). In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI), we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous hist...

Abramovitch, Rinat; Itzik, Anna; Harel, Hila; Nagler, Arnon; Vlodavsky, Israel; Siegal, Tali

2004-01-01

219

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

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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

220

CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.  

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Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies. PMID:23747987

Prats, A C; Van den Berghe, L; Rayssac, A; Ainaoui, N; Morfoisse, F; Pujol, F; Legonidec, S; Bikfalvi, A; Prats, H; Pyronnet, S; Garmy-Susini, B

2013-09-01

 
 
 
 
221

Biodegradable nanoassemblies of piperlongumine display enhanced anti-angiogenesis and anti-tumor activities  

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Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.

Liu, Yuanyuan; Chang, Ying; Yang, Chao; Sang, Zitai; Yang, Tao; Ang, Wei; Ye, Weiwei; Wei, Yuquan; Gong, Changyang; Luo, Youfu

2014-03-01

222

[Antioxidation of flavones of wheat germ on mammary tumor of rats].  

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The effect of flavonoids of wheat germ on mammary tumor of rats induced by 7,12-dimethylben(a) anthracene (DMBA) was investigated. Sprague-Dawley female rats (50 day-old, weighted around 176 g) were randomly divided into 4 groups. The negative and positive control group were fed on stoke diet. The high and low dose test groups were fed on diets with wheat germ flavonoids 10 and 2 g/kg respectively. Except rats in the negative control group, each rat was given DMBA 15 mg dissolved in 1.5 ml vegetable oil by tube feeding. After the administration of DMBA for 24 weeks, the incidence of tumor in the high dose test group was lower than that in the positive control group. The activity of blood and liver glutathione peroxidase (GSH-Px) and peroxidase dismutase(SOD) in the test groups was significantly higher than those in the positive control group, while the MDA level was significantly lower. The results suggested that the effect of flavonoids on inducing peroxidase might be one of the chemical prevention mechanisms on mammary tumors. PMID:12561518

Wu, B; Xu, G; Zhao, X; Ren, X

2001-07-01

223

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

224

Pharmaceuticals That Cause Mammary Gland Tumors in Animals: Findings in Women  

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Risk of breast cancer in women was assessed for eight pharmaceuticals that produce mammary tumors in experimental animals, using nested case-control analyses in two cohorts with prescription records in a comprehensive medical care program. The two cohorts were: 1) earlier cohort: 78,118 female members who received prescriptions in 1969-1973, of whom 2,467 developed breast cancer, and 2) later cohort: 3,289,408 female members who received prescriptions in 1994-2006 of whom 24,528 developed bre...

Friedman, Gary D.; Jiang, Sheng-fang; Udaltsova, Natalia; Chan, James; Quesenberry, Charles P.; Habel, Laurel A.

2008-01-01

225

T cell receptor V beta repertoire in mice lacking endogenous mouse mammary tumor provirus.  

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When endogenous mouse mammary tumor virus (MMTV) superantigens (SAg) are expressed in the first weeks of life an efficient thymic deletion of T cells expressing MMTV SAg-reactive T cell receptor (TcR) V beta segments is observed. As most inbred mouse strains and wild mice contain integrated MMTV DNA, knowing the precise extent of MMTV influence on T cell development is required in order to study T cell immunobiology in the mouse. In this report, backcross breeding between BALB.D2 (Mtv-6, -7, ...

Braun, Michel Y.; Jouvin-marche, E.; Marche, P. N.; Macdonald, H. R.; Acha-orbea, H.

1995-01-01

226

Assessment of cell proliferation and prognostic factors in canine mammary gland tumors Avaliação da proliferação celular e fatores prognósticos em tumores mamários caninos  

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Three methods for the analysis of cell proliferation, mitotic index/10 high-power fields (10 HPF), mitotic index/four sets of 10 HPF (40 HPF), and MIB-1 index were evaluated in a series of canine mammary gland tumors, as well as the possible correlation between them. Fifty-six canine mammary gland tumors, including 23 benign and 33 malignant, were studied. In addition, the prognostic impact of mitotic index/10 HPF, and histological malignancy grade were evaluated in 17 malignant tumors, being...

Dutra, A. P.; Azevedo Ju?nior, G. M.; Schmitt, F. C.; Cassali, G. D.

2008-01-01

227

?-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

228

?-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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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. PMID:21639868

2011-01-01

229

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

International Nuclear Information System (INIS)

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

230

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

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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

231

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

232

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

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

Carlos Roberto Daleck

1998-03-01

233

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

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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.

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

1998-03-01

234

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

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

Saito, Teruyoshi; Dai, Tamura; Asano, Ryuji

2013-01-01

235

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

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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

236

Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo.  

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Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment. PMID:24091811

Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

2013-10-01

237

Usnic acid inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways.  

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Tumor growth depends on angiogenesis and inducing angiogenesis is one of the most important hallmarks in the cancer development. Treatment with small molecules that inhibit angiogenesis has been an effective strategy for anti-cancer therapy. Some anti-angiogenic factors are derived from traditional Chinese herbs. Usnic acid (UA), an active compound mainly found in lichens, has shown some biological and physiological activities. However, the role and mechanism of UA in tumor angiogenesis are still unknown. The aim of this study was to assess the effects of UA on tumor angiogenesis. In this study, we demonstrated that UA strongly inhibited in vivo angiogenesis in a chick embryo chorioallantoic membrane assay and vascular endothelial growth factor-induced mouse corneal angiogenesis model. In a mouse xenograft tumor model, UA suppressed Bcap-37 breast tumor growth and angiogenesis without affecting mice body weight. In an in vitro assay, UA not only significantly inhibited endothelial cell proliferation, migration and tube formation, but also induced morphological changes and apoptosis in endothelial cells. In addition, UA inhibited Bcap-37 tumor cell proliferation. Moreover, western blot analysis of cell signaling molecules indicated that UA blocked vascular endothelial growth factor receptor (VEGFR) 2 mediated Extracellular signal-regulated protein kinases 1 and 2(ERK1/2) and AKT/P70S6K signaling pathways in endothelial cells. These results provided the first evidence of the biological function and molecular mechanism of UA in tumor angiogenesis. PMID:22669534

Song, Yajuan; Dai, Fujun; Zhai, Dong; Dong, Yanmin; Zhang, Jing; Lu, Binbin; Luo, Jian; Liu, Mingyao; Yi, Zhengfang

2012-09-01

238

N-glycolylneuraminic acid biosynthesis in rat mammary tumor ascites cells  

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N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGl) are two of the most common forms of sialic acid, a compound found at the cell surface of all animal cells. The expression of NeuGl, which is thought to be synthesized from NeuAc, appears to be species-dependent, and the amounts of NeuGl change with differentiation and during malignancy. Hydroxylation of the acetyl group to glycolyl was monitored in 13762 rat mammary tumor ascites cells in which NeuGl accounts for 47% of the total sialic acid. N-acetylmannosamine-(14C-acetyl) was incubated with a crude extract of MAT-Cl cells and formation of 14C-glycolate was determined by thin-layer chromatography following methanolic HCl hydrolysis and hydroxamate derivation. Conversion of 14C-acetate to 14C-glycolate increased with time of incubation and with protein concentration, and the specific activity of MAT-Cl crude extract for the conversion was 940 + 160 pmol/h/mg protein. By ion exchange chromatography, the 14C-glycolate product was predominantly neutral, with less than 10% associated with the sialic acid fraction. The results suggest that N-acetylmannosamine is a substrate for the hydroxylase under the conditions of the assay and that N-glycolylmannosamine may be an intermediate in the biosynthesis of NeuGl in rat mammary tumor ascites cells

239

The antiparasitic drug, potassium antimony tartrate, inhibits tumor angiogenesis and tumor growth in nonsmall-cell lung cancer.  

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Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening US Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various nonsmall-cell lung cancer (NSCLC) cells with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dosage of 40 mg/kg (i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo antiangiogenesis property of PAT, which was well correlated with its tumor growth inhibition in NSCLC cells. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration, and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC cells. Further study of PAT in anticancer clinical trials may be warranted. PMID:25352499

Wang, Beibei; Yu, Weiwei; Guo, Jiawei; Jiang, Xingwu; Lu, Weiqiang; Liu, Mingyao; Pang, Xiufeng

2015-01-01

240

Danshensu has anti-tumor activity in B16F10 melanoma by inhibiting angiogenesis and tumor cell invasion.  

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Danshensu, the major water-soluble component of Radix Salviae Miltiorrhizae (Danshen), is the basic chemical structure of various salvianolic acids. This study was to evaluate the anti-tumor activity of danshensu in a series of in vitro and in vivo models. The effect of danshensu on B16F10 melanoma cell and HUVEC proliferation were assessed by MTS assay, and cell invasion and migration were investigated by transwell chamber assay. The effect of danshensu on angiogenesis was evaluated by HUVEC migration assay, tube formation assay and chick chorioallantoic membrane assay. The expression of MMP-2, -9 and VEGF in B16F10 melanoma cell were detected by western blotting after danshensu treatment. The role of danshensu in tumor metastasis in vivo was evaluated by spontaneous and experimental B16F10 melanoma metastasis model. Although danshensu had no inhibitory effect on B16F10 melanoma cell and HUVEC proliferation, it significantly inhibited B16F10 melanoma cell invasion (at 0.05, 0.5, 5 microM) and migration (at 0.5, 5 microM). It also dramatically suppressed VEGF-induced endothelial migration (at 0.5, 5 microM), tube formation in vitro (at 4, 20 microM) and new vessel formation in CAM in vivo (100 microg/egg). Danshensu (at 5, 50 microM) significantly down-regulates protein expression of MMP-2, -9 and VEGF in B16F10 melanoma cell. In animal model, danshensu (20, 40 mg/kg) also possessed inhibitory effect on lung metastasis in spontaneous (46-day treatment) and experimental (23-day treatment) B16F10 melanoma metastasis model. All these results suggest that danshensu has anti-tumor activity by affecting on tumor angiogenesis and tumor invasion. PMID:20621088

Zhang, Li-juan; Chen, Lei; Lu, Yin; Wu, Jia-ming; Xu, Bo; Sun, Zhi-guang; Zheng, Shi-zhong; Wang, Ai-yun

2010-09-25

 
 
 
 
241

Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells  

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Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells. PMID:25170920

González-Chavarría, Iván; Cerro, Rita P.; Parra, Natalie P.; Sandoval, Felipe A.; Zuñiga, Felipe A.; Omazábal, Valeska A.; Lamperti, Liliana I.; Jiménez, Silvana P.; Fernandez, Edelmira A.; Gutiérrez, Nicolas A.; Rodriguez, Federico S.; Onate, Sergio A.; Sánchez, Oliberto; Vera, Juan C.; Toledo, Jorge R.

2014-01-01

242

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

243

HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization.  

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The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor-1? (HIF1?) and activation of NF-?B in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1? and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-?B/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth. PMID:25297628

Azoitei, Ninel; Diepold, Kristina; Brunner, Cornelia; Rouhi, Arefeh; Genze, Felicitas; Becher, Alexander; Kestler, Hans; van Lint, Johan; Chiosis, Gabriela; Koren, John; Fröhling, Stefan; Scholl, Claudia; Seufferlein, Thomas

2014-12-01

244

Primary tumor cells obtained from MNU-induced mammary carcinomas show immune heterogeneity which can be modulated by low-efficiency transfection of CD40L gene.  

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The presence of CD40 on carcinoma cells is an important factor for the generation of tumor-specific responses induced by CD40 ligation. In an N-methyl-N-nitrosourea (MNU)-induced autochthonous mammary tumor model, we analyzed the immune features of primary tumor cells. Here, CD40 was frequently detected on the primary tumor cultures and selectively expressed on the malignant mammary tissue in vivo. On the other hand, every mammary tumor cell culture had a heterogeneous and reduced expression of proinflammatory TNFalpha, IL-1beta, IL-6 and CXCL1 cytokines compared to normal mammary epithelial cells. Low-efficiency transfection of CD40 ligand (CD40L) gene enhanced the expression of proinflammatory cytokines in the tumor cells and strengthened allogeneic immune reactions and costimulatory activity which may help overwhelming suppressive features of the tumor. PMID:19164932

Esendagli, Gunes; Canpinar, Gunes; Yilmaz, Guldal; Gunel-Ozcan, Aysen; Guc, M Oguz; Kansu, Emin; Guc, Dicle

2009-01-01

245

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

246

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

247

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.

2009-02-01

248

Development of a New Positron Emission Tomography Tracer for Targeting Tumor Angiogenesis: Synthesis, Small Animal Imaging, and Radiation Dosimetry  

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Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, th...

Lalush, David S.; Veleva, Anka N.; Dyer, Laura A.; Pamela Lockyer; Hong Yuan; Brandon Frederick, C.; Cam Patterson

2013-01-01

249

Mammary tumor lipids and plasma lipoproteins in DMBA-intubated rats fed olive or safflower oils.  

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The effects of feeding olive and safflower oils on lipid and fatty acid composition of mammary tumors, plasma lipids and lipoproteins, and the nuclear magnetic resonance (NMR) spectra of plasma were investigated in rats. 7-12-Dimethylbenz[a]anthracene (DMBA)- and placebo-intubated male Sprague-Dawley rats were fed 20% fat diets containing 18:2n-6 (wt/wt) from either high-linoleic safflower oil (SL, 14.6% 18:2n-6), high oleic safflower oil (SO, 3.4% 18:2n-6), olive oil (OO, 1.1% 18:2n-6), or olive oil supplemented with 18:2n-6 (OL, 3.4% 18:2n-6) for 16 weeks. Our result indicated that tumor composition of 18:1n-9 and 18:2n-6 reflected the diet, but tumor neutral lipid (NL) was more reflective of diet than was tumor phospholipid (PL). The 20:4n-6 content of tumor PL was constant in all of the dietary groups despite threefold higher levels of 18:2n-6 in tumor PL from animals fed SL than from those fed SO, OO, or OL diets. This suggests a possible feedback inhibition of delta 6-desaturase by the higher content of 18:2n-6 associated with SL feeding No diet effects were obtained for tumor total lipid, NL, PL, cholesterol, and triglyceride contents. Plasma lipoprotein changes were more reflective of diet than tumorigenesis except for apolipoprotein-E, which was lower, and for very low-density lipoprotein cholesterol and low-density lipo protein, which were higher in tumor-bearing rats. Plasma NMR analysis indicated no difference in the average line widths of the methyl and methylene resonances for tumor-bearing and nontumor-bearing rats fed any of the diets. PMID:2120682

Lasekan, J B; Ney, D M

1990-01-01

250

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

251

Oncogene Pathway Activation in Mammary Tumors Dictates FDG-PET Uptake.  

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Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[(18)F]fluoro-2-deoxy-d-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake-and that underlie the heterogeneity observed across cancers-remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1, or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1? (HIF1?) and associated negatively with PFK-2b expression and p-AMPK. The correlation between HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging. Cancer Res; 74(24); 7583-98. ©2014 AACR. PMID:25239452

Alvarez, James V; Belka, George K; Pan, Tien-Chi; Chen, Chien-Chung; Blankemeyer, Eric; Alavi, Abass; Karp, Joel S; Chodosh, Lewis A

2014-12-15

252

A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth  

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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

253

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...

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

2009-01-01

254

The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1.  

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FTY720, a sphingosine 1-phosphate (S1P) analog, acts as an immunosuppressant through trapping of T cells in secondary lymphoid tissues. FTY720 was also shown to prevent tumor growth and to inhibit vascular permeability. The MTT proliferation assay illustrated that endothelial cells are more susceptible to the anti-proliferative effect of FTY720 than Lewis lung carcinoma (LLC1) cells. In a spheroid angiogenesis model, FTY720 potently inhibited the sprouting activity of VEGF-A-stimulated endothelial cells even at concentrations that apparently had no anti-proliferative effect. Mechanistically, the anti-angiogenic effect of the general S1P receptor agonist FTY720 was mimicked by the specific S1P1 receptor agonist SEW2871. Moreover, the anti-angiogenic effect of FTY720 was abrogated in the presence of CXCR4-neutralizing antibodies. This indicates that the effect was at least in part mediated by the S1P1 receptor and involved transactivation of the CXCR4 chemokine receptor. Additionally, we could illustrate in a coculture spheroid model, employing endothelial and smooth muscle cells (SMCs), that the latter confer a strong protective effect regarding the action of FTY720 upon the endothelial cells. In a subcutaneous LLC1 tumor model, the anti-angiogenic capacity translated into a reduced tumor size in syngeneic C57BL/6 mice. Consistently, in the Matrigel plug in vivo assay, 10 mg/kg/d FTY720 resulted in a strong inhibition of angiogenesis as demonstrated by a reduced capillary density. Thus, in organ transplant patients, FTY720 may prove efficacious in preventing graft rejection as well as tumor development. PMID:17203465

Schmid, Gerald; Guba, Markus; Ischenko, Ivan; Papyan, Armine; Joka, Mareile; Schrepfer, Sabine; Bruns, Christiane J; Jauch, Karl-Walter; Heeschen, Christopher; Graeb, Christian

2007-05-01

255

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

256

Positron emission tomography imaging of CD105 expression during tumor angiogenesis  

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Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with {sup 64}Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of {sup 64}Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. {sup 64}Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 {+-} 0.5, 10.4 {+-} 2.8, and 9.7 {+-} 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with {sup 64}Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of {sup 64}Cu-DOTA-TRC105. This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway. (orig.)

Hong, Hao [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Yang, Yunan [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Third Military Medical University, Department of Ultrasound, Xinqiao Hospital, Chongqing (China); Zhang, Yin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, Robert J. [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); Leigh, Bryan R. [TRACON Pharmaceuticals, Inc., San Diego, CA (United States); Cai, Weibo [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); University of Wisconsin Carbone Cancer Center, Madison, WI (United States); University of Wisconsin - Madison, Departments of Radiology and Medical Physics, School of Medicine and Public Health, Madison, WI (United States)

2011-07-15

257

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

Science.gov (United States)

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

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

2015-01-01

258

Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis.  

Science.gov (United States)

Class 3 semaphorins (SEMA3) were first identified as glycoproteins that negatively mediate neuronal guidance by binding to neuropilin and repelling neurons away from the source of SEMA3. However, studies have shown that SEMA3s are also secreted by other cell types, including tumor cells, where they play an inhibitory role in tumor growth and angiogenesis (specifically SEMA3B and SEMA3F). SEMA3s primarily inhibit the cell motility and migration of tumor and endothelial cells by inducing collapse of the actin cytoskeleton via neuropilins and plexins. Besides binding to SEMA3s, neuropilin also binds the protumorigenic and proangiogenic ligand vascular endothelial growth factor (VEGF). Although some studies attribute the antitumorigenic and antiangiogenic properties of SEMA3s to competition between SEMA3s and VEGF for binding to neuropilin receptors, several others have shown that SEMA3s display growth-inhibitory activity independent of competition with VEGF. A better understanding of these molecular interactions and the role and signaling of SEMA3s in tumor biology will help determine whether SEMA3s represent potential therapeutic agents. Herein, we briefly review (a) the role of SEMA3s in mediating tumor growth, (b) the SEMA3 receptors neuropilins and plexins, and (c) the potential competition between SEMA3s and VEGF family members for neuropilin binding. PMID:19887479

Gaur, Puja; Bielenberg, Diane R; Samuel, Shaija; Bose, Debashish; Zhou, Yunfei; Gray, Michael J; Dallas, Nikolaos A; Fan, Fan; Xia, Ling; Lu, Jia; Ellis, Lee M

2009-11-15

259

PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors.  

Science.gov (United States)

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase. PMID:25153721

Peng, Maoyu; Emmadi, Rajyasree; Wang, Zebin; Wiley, Elizabeth L; Gann, Peter H; Khan, Seema A; Banerji, Nilanjana; McDonald, William; Asztalos, Szilard; Pham, Thao N D; Tonetti, Debra A; Tyner, Angela L

2014-08-15

260

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

Science.gov (United States)

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

 
 
 
 
261

PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors  

Science.gov (United States)

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase. PMID:25153721

Peng, Maoyu; Emmadi, Rajyasree; Wang, Zebin; Wiley, Elizabeth L.; Gann, Peter H.; Khan, Seema A.; Banerji, Nilanjana; McDonald, William; Asztalos, Szilard; Pham, Thao N.D.; Tonetti, Debra A.; Tyner, Angela L.

2014-01-01

262

Short communication: Mouse mammary tumor virus driven ?-lactalbumin expression effects on lactation and fertility of transgenic mice.  

Science.gov (United States)

?-Lactalbumin (Alac) is one of the major milk proteins. Its gene expression is restricted to epithelial cells of the lactating mammary gland. The Alac interaction with a uridine 5'-diphosphate-galactosyltransferase induces lactose synthesis, a major osmotic regulator of milk secretion. Other functions attributed to this protein include induction of apoptosis and anti-inflammatory activities. To assess if forced expression of this gene during early gestation or involution could affect mammary physiology, an Alac-encoding minigene was expressed in transgenic mice under the transcriptional regulation of the mouse mammary tumor virus promoter. The mammary expression did not interfere with gestation, resulted in a slight increase in milk yield as indirectly assessed by the 11% increased growth rate of the pups reared by transgenic females compared with that of those reared by control mice, and induced a slight delay in the early involution process, as demonstrated by histological analyses. The use of the mouse mammary tumor virus promoter resulted in Alac expression in several nonmammary tissues, such as the brain, the testis, the ovary, and the uterus. Although it did not affect male reproductive performances, it induced a female subfertile phenotype, characterized by embryonic implantation failure in the transgenic female reproductive tract. PMID:21524533

Le Guillou, S; Tilly, G; Passet, B; Lefèvre, L; Vilotte, M; Costa, J; Le Provost, F; Vilotte, J-L

2011-05-01

263

Using the Transcription Factor Inhibitor of DNA Binding 1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth  

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Tumor angiogenesis is essential for malignant growth and metastasis. Bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated tumor growth. EPC ablation can reduce tumor growth, however, the lack of a marker that can track EPCs from the BM to tumor neovasculature has impeded progress in understanding the molecular mechanisms underlying EPC biology. Here, we report the use of transgenic mouse and lentiviral models to monitor the BM-derived compartment of...

Mellick, Albert S.; Plummer, Prue N.; Nolan, Daniel J.; Gao, Dingcheng; Bambino, Kathryn; Hahn, Mary; Catena, Raul; Turner, Vivian; Mcdonnell, Kevin; Benezra, Robert; Brink, Robert; Swarbrick, Alexander; Mittal, Vivek

2010-01-01

264

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

International Nuclear Information System (INIS)

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

265

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

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

de la Fuente Alberto

2009-12-01

266

Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth  

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Full Text Available Abstract Background Angiogenesis is a fundamental process that allows tumor growth by providing nutrients and oxygen to the tumor cells. Beyond the oxygen diffusion limit from a capillary blood vessel, tumor cells become apoptotic. Angiogenesis results from a balance of pro- and anti-angiogenic stimuli. Endogenous inhibitors regulate enzyme activities that promote angiogenesis. Tumor cells may express pro-angiogenic factors and hydrolytic enzymes but also kinin-degrading oligopeptidases which have been investigated. Results Angiogenesis induced by B16F10-Nex2 melanoma cells was studied in a co-culture with HUVEC on Matrigel. A stimulating effect on angiogenesis was observed in the presence of B16F10-Nex2 lysate and plasma membrane. In contrast, the B16F10-Nex2 culture supernatant inhibited angiogenesis in a dose-dependent manner. This effect was abolished by the endo-oligopeptidase inhibitor, JA-2. Thimet oligopeptidase (TOP and neurolysin activities were then investigated in B16F10-Nex2 melanoma cells aiming at gene sequencing, enzyme distribution and activity, influence on tumor development, substrate specificity, hydrolytic products and susceptibility to inhibitors. Fluorescence resonance energy transfer (FRET peptides as well as neurotensin and bradykinin were used as substrates. The hydrolytic activities in B16F10-Nex2 culture supernatant were totally inhibited by o-phenanthrolin, JA-2 and partially by Pro-Ile. Leupeptin, PMSF, E-64, Z-Pro-Prolinal and captopril failed to inhibit these hydrolytic activities. Genes encoding M3A enzymes in melanoma cells were cloned and sequenced being highly similar to mouse genes. A decreased proliferation of B16F10-Nex2 cells was observed in vitro with specific inhibitors of these oligopeptidases. Active rTOP but not the inactive protein inhibited melanoma cell development in vivo increasing significantly the survival of mice challenged with the tumor cells. On Matrigel, rTOP inhibited the bradykinin – induced angiogenesis. A possible regulation of the homologous tumor enzyme in the perivascular microenvironment is suggested based on the observed rTOP inhibition by an S-nitrosothiol NO donor. Conclusion Data show that melanoma cells secrete endo-oligopeptidases which have an important role in tumor proliferation in vitro and in vivo. rTOP inhibited growth of subcutaneously injected B16F10-Nex2 cells in mice. TOP from tumor cells and bradykinin in endothelial cells are two antagonist factors that may control angiogenesis essential for melanoma growth. A regulatory role of NO or S-nitrosothiols is suggested.

Juliano Luiz

2007-07-01

267

Uptake of radiolabeled alpha-fetoprotein by mouse mammary carcinomas and its usefulness in tumor scintigraphy  

International Nuclear Information System (INIS)

The ability to internalize alpha-fetoprotein (AFP) and serum albumin, which is characteristic of embryonic and fetal elements undergoing differentiation, may reappear in some cultured neoplastic cells (i.e., the MCF-7 human breast cancer cell line). The in vivo uptake of AFP by spontaneous carcinomas of the CH3/Bi mouse was investigated. Nineteen mice were given i.v. injections of approximately 10 muCi of mouse 125I-AFP (0.6 to 4 micrograms of AFP according to the specific ratio of the preparation used). Four to 7 days later, the animals were sacrificed. The radioactivity concentration in the tumor was the highest among all solid tissues examined. Tumor:liver radioactivity ratios were clearly positive [3.6 +/- 0.3 (S.E.)] in 27 of 31 specimens studied. Microscopy examination of autoradiograms from various tissue sections confirmed the selective accumulation of radioactive AFP in the tumors. In order to assess the specificity of AFP uptake by mammary tumors, 4 mice were given simultaneous injections of 125I-AFP and 131I-ovalbumin, respectively. Compared to AFP, the retention of ovalbumin was very low in all tissues studied, including the tumor. The possibility of tumor localization of radiolabeled AFP by external photoscanning was also explored. Two mice were given injections of 131I-AFP, one mouse received 131I-serum albumin, and one was given 131I-ovalbumin. Images were obtained 6 days after with a staages were obtained 6 days after with a standard gamma-camera linked to a computer with data display. About 50% of the total radioactivity retained was concentrated in the tumor areas of mice given injections of iodinated AFP, while it was only 15% in the mouse that received 131I-serum albumin

268

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

Scientific Electronic Library Online (English)

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

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

1673-16-01

269

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

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

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

1997-02-21

270

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

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

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

2014-12-01

271

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine  

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

Chao Liu

2011-01-01

272

Hemodynamic Response Imaging: A Potential Tool for the Assessment of Angiogenesis in Brain Tumors  

Science.gov (United States)

Blood oxygenation level dependence (BOLD) imaging under either hypercapnia or hyperoxia has been used to study neuronal activation and for assessment of various brain pathologies. We evaluated the benefit of a combined protocol of BOLD imaging during both hyperoxic and hypercapnic challenges (termed hemodynamic response imaging (HRI)). Nineteen healthy controls and seven patients with primary brain tumors were included: six with glioblastoma (two newly diagnosed and four with recurrent tumors) and one with atypical-meningioma. Maps of percent signal intensity changes (?S) during hyperoxia (carbogen; 95%O2+5%CO2) and hypercapnia (95%air+5%CO2) challenges and vascular reactivity mismatch maps (VRM; voxels that responded to carbogen with reduced/absent response to CO2) were calculated. VRM values were measured in white matter (WM) and gray matter (GM) areas of healthy subjects and used as threshold values in patients. Significantly higher response to carbogen was detected in healthy subjects, compared to hypercapnia, with a GM/WM ratio of 3.8 during both challenges. In patients with newly diagnosed/treatment-naive tumors (n?=?3), increased response to carbogen was detected with substantially increased VRM response (compared to threshold values) within and around the tumors. In patients with recurrent tumors, reduced/absent response during both challenges was demonstrated. An additional finding in 2 of 4 patients with recurrent glioblastoma was a negative response during carbogen, distant from tumor location, which may indicate steal effect. In conclusion, the HRI method enables the assessment of blood vessel functionality and reactivity. Reference values from healthy subjects are presented and preliminary results demonstrate the potential of this method to complement perfusion imaging for the detection and follow up of angiogenesis in patients with brain tumors. PMID:23209575

Ben Ami, Haim; Aizenstein, Orna; Blumenthal, Deborah T.; Bokstein, Felix; Corn, Benjamin W.; Ram, Zvi; Kanner, Avraham A.; Lifschitz-Mercer, Biatris; Solar, Irit; Kolatt, Tsafrir; Palmon, Mika; Edrei, Yifat; Abramovitch, Rinat

2012-01-01

273

Importance of interaction between nerve growth factor and ?9?1 integrin in glial tumor angiogenesis.  

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NGF is a growth factor for which the role in the promotion of angiogenesis is still not completely understood. We found that NGF promotes the pathological neovascularization process in glioma through a direct interaction with ?9?1 integrin, which is up-regulated on microvascular endothelial cells in cancer tissue. We propagated gHMVEC primary cells using a new method of immune-selection, and these cells demonstrated ?9?1 integrin-dependent binding of NGF in a cell adhesion assay. Moreover, NGF induced gHMVEC proliferation and chemotaxis inhibited by specific blockers of ?9?1 integrin, such as MLD-disintegrins and monoclonal antibody Y9A2. A Matrigel tube formation assay revealed that NGF significantly increased capillary-like growth from gHMVEC to a level comparable to treatment with VEGF. The snake venom disintegrin, VLO5, inhibited the agonistic effect of both growth factors, whereas the effect of Y9A2 was not statistically significant. Angiogenesis exogenously induced by NGF  was also ?9?1-integrin dependent in an embryonic quail CAM system. However, angiogenesis pathologically induced by developing glioma in this system was only sensitive for inhibition with MLD-disintegrin, suggesting a more complex effect of cancer cells on the neovascularization process. The anti-angiogenic effect of MLD-disintegrins is probably related to their pro-apoptotic ability induced in activated tumoral endothelial cells. Therefore, the molecular basis of these disintegrins may be useful for developing new angiostatic pharmaceuticals for application in cancer therapy. PMID:22611032

Walsh, Erin M; Kim, Richard; Del Valle, Luis; Weaver, Michael; Sheffield, Joel; Lazarovici, Philip; Marcinkiewicz, Cezary

2012-07-01

274

BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.  

Science.gov (United States)

BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. PMID:25239453

Bai, Feng; Chan, Ho Lam; Scott, Alexandria; Smith, Matthew D; Fan, Cheng; Herschkowitz, Jason I; Perou, Charles M; Livingstone, Alan S; Robbins, David J; Capobianco, Anthony J; Pei, Xin-Hai

2014-11-01

275

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

276

Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.  

Science.gov (United States)

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-? and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk. PMID:24832086

Montales, Maria Theresa E; Melnyk, Stepan B; Simmen, Frank A; Simmen, Rosalia C M

2014-09-01

277

Cultivation of mouse mammary tumor cells derived from DD/Tbr, 3  

International Nuclear Information System (INIS)

The factors affecting production of MuMTV by DD-762 cells, an established cell line from a spontaneous mammary tumor in a DD/Tbr mouse, were examined. When the cells were seeded and cultures medium were refreshed at every 3 - 4 day intervals without passage of cells, virus production began after exponential pase of cell growth and attained to peaks at every 10 - 12 days intervals up to approximately 60 days after seeding. MuMTV production was dependent on cell seeding density. Seeding at higher cell density, virus release occurred earlier. Maximum amount of MuMTV was observed with the medium containing 10 ?g INS, 5 ?g DXM and 10% FCS. The RDDP activities in the culture fluid were rapidly inactivated by incubation at 370C. (author)

278

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

Scientific Electronic Library Online (English)

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

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

2002-12-01

279

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

Science.gov (United States)

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

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

2011-12-01

280

Improved Magnetic Resonance Molecular Imaging of Tumor Angiogenesis by Avidin-Induced Clearance of Nonbound Bimodal Liposomes1  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Angiogenic, that is, newly formed, blood vessels play an important role in tumor growth and metastasis and are a potential target for tumor treatment. In previous studies, the ?v?3 integrin, which is strongly expressed in angiogenic vessels, has been used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticulate contrast agents for magnetic resonance imaging-based visualization of angiogenesis. In the present study, the target-to-background ratio was increased by diminishing the nons...

Tilborg, Geralda Af; Mulder, Willem Jm; Schaft, Daisy Wj; Reutelingsperger, Chris Pm; Griffioen, Arjan W.; Strijkers, Gustav J.; Nicolay, Klaas

2008-01-01

 
 
 
 
281

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

DEFF Research Database (Denmark)

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

Nielsen, Flemming U.; Daugård, Preben

2001-01-01

282

Disruption of tumor neovasculature by microbubble enhanced ultrasound: a potential new physical therapy of anti-angiogenesis.  

Science.gov (United States)

Tumor angiogenesis is of vital importance to the growth and metastasis of solid tumors. The angiogenesis is featured with a defective, leaky and fragile vascular construction. Microbubble enhanced ultrasound (MEUS) cavitation is capable of mechanical disruption of small blood vessels depending on effective acoustic pressure amplitude. We hypothesized that acoustic cavitation combining high-pressure amplitude pulsed ultrasound (US) and circulating microbubble could potentially disrupt tumor vasculature. A high-pressure amplitude, pulsed ultrasound device was developed to induce inertial cavitation of circulating microbubbles. The tumor vasculature of rat Walker 256 was insonated percutaneously with two acoustic pressures, 2.6 MPa and 4.8 MPa, both with intravenous injection of a lipid microbubble. The controls were treated by the ultrasound only or sham ultrasound exposure. Contrast enhanced ultrasound (CEUS) and histology were performed to assess tumor circulation and pathological changes. The CEUS results showed that the circulation of Walker 256 tumors could be completely blocked off for 24 hours in 4.8 MPa treated tumors. The CEUS gray scale value (GSV) indicated that there was significant GSV drop-off in both of the two experimental groups but none in the controls. Histology showed that the tumor microvasculature was disrupted into diffuse hematomas accompanied by thrombosis, intercellular edema and multiple cysts formation. The 24 hours of tumor circulation blockage resulted in massive necrosis of the tumor. MEUS provides a new, simple physical method for anti-angiogenic therapy and may have great potential for clinical applications. PMID:22178162

Liu, Zheng; Gao, Shunji; Zhao, Yang; Li, Peijing; Liu, Jia; Li, Peng; Tan, Kaibin; Xie, Feng

2012-02-01

283

Diminished Expression of Transcription Factors Nuclear Factor ?B and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice  

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Interactions between malignant tumors and the host immune system shape the course of cancer progression. The molecular basis of such interactions is the subject of immense interest. Proinflammatory cytokines produced by macrophages are critical mediators of immune responses that contribute to the control of the advancement of neoplasia. We have shown that the expressions of interleukin 12 (IL-12) and inducible nitric oxide synthase (iNOS) are decreased in macrophages from mammary tumor–bear...

Torroella-kouri, Marta; Ma, Xiaojing; Perry, Giselle; Ivanova, Milena; Cejas, Pedro J.; Owen, Jennifer L.; Iragavarapu-charyulu, Vijaya; Lopez, Diana M.

2005-01-01

284

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

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

Michelly Kheidy Borges Battisti

2013-05-01

285

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

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Flow cytometric analysis of DNA content was performed on 28 samples of canine mammary tumors. Nine of them were benign and 19 were malignant. All benign tumors and 11 malignant tumors (57.9%) were diploid (P<0.05). Form the aneuploid tumors, five (26.3%) were hyperdiploid, one (5.3%) hypodiploid, one (5.3%) near triploid and one (5.3%) multiploid. The analysis of the expression of the markers PR and CD31 revealed a significant difference between diploid and aneuploid tumors (P<0.05). The immu...

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

2007-01-01

286

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

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

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

2011-01-01

287

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model  

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To visualize tumor angiogenesis using the MRI contrast agent, Gd- DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. MR imaging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model

Jun, Hong Young; Yin, Hong Hua; Kim, Sun Hee; Park, Seong Hoon; Kim, Hun Soo; Yoon Kwon Ha Yoon [Wonkwang University School of Medicine, Iksan (Korea, Republic of)

2010-08-15

288

A preliminary study of the relationship between helical CT enhancement and tumor angiogenesis in gastric carcinoma  

International Nuclear Information System (INIS)

Objective: The aim of the study is to investigate the relationship between CT enhancement and tumor angiogenesis in gastric carcinoma (GC) and seek for a noninvasive and efficient way to predict the malignancy and prognosis of GC. Methods: The study included 27 histopathologically proven GC patients. Plain scan and triphasic incremental helical CT were performed in all cases. Hypotonic agent and water-filling method were used in 27 patients. Nonionic contrast medium was administrated with a power injector at the flow rate of 3 ml/s. The triphasic spiral scans were obtained at 25 s( arterial-dominant phase), 80 s (portal venous-dominant slides were carefully prepared for the monoclonal antibody phase) and 180 s (equilibrium phase) after the start of intravenous injection. The CT attenuation was measured both before and after enhancement. Histopathological anti-human factor VIII related antigen (F8RA) and polyclonal antibody anti-human vascular endothelial growth factor (VEGF ) were used for immunohistochemical staining, and calculation of tumormicrovessel density (MVD) and VEGF expression rate of tumor cells was performed. The contrast-enhancement imaging features of GC lesions were correlatively studied with tumor MVD and VEGF expression. Results: The accuracy of helical CT in determining T, N and M staging of GC was 77.8%, 74.1% and 100% respectively, and the accuracy of the total TNM staging was 81.5%. Peak attenuation (PA) of CT enhancement in GC lesions was 40-80 of CT enhancement in GC lesions was 40-80 HU (mean 62.83), MVD was 4-27 (mean 15.35). VEGF expression rate was 5%-65%. There was significant correlation between PA and MVD (r=0.708, t=5.015). MVD and PA of strong positive VEGF expression group (expression percentage >30%) were evidently higher than those of negative (expression percentage <10%) and weak positive (10 < expression percentage < 20%) groups (0.02 < P < 0.05 and 0.025 < P < 0.05 respectively). The histological differentiation of GC was also positively correlated with VEGF expression rate. Conclusion: The peak attenuation of CT enhancement reflects VEGF-related tumor angiogenesis in gastric carcinoma, therefore the malignancy and prognosis of GC is possible to be predicted preoperatively in CT images. (authors)

289

Gadd45a Suppresses Tumor Angiogenesis via Inhibition of the mTOR/STAT3 Protein Pathway*  

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Gadd45a, a p53-regulated and DNA damage-inducible gene, is implicated in protection against tumor malignancy, although the underlying mechanism remains to be defined further. Here we demonstrate that Gadd45a plays an important role in suppression of tumor angiogenesis. Gadd45a deletion significantly increases microvessel density in tumors and stimulates an angiogenic response in a chicken embryo chorioallantoic membrane assay. Disruption of endogenous Gadd45a promotes tube formation and migration of endothelial cells. We further show that Gadd45a deletion increases phosphorylation of STAT3 at Ser-727 and, in turn, elevates the STAT3 transcriptional activity. This process substantially induces both expression and secretion of VEGFa, a STAT3 responsive gene, and promotes tumor angiogenesis. Interestingly, Gadd45a is able to physically associate with mammalian target of rapamycin (mTOR), a kinase that mediates Ser-727 phosphorylation of STAT3. The interaction of Gadd45a with mTOR suppresses STAT3 phosphorylation at Ser-727 and leads to down-regulated expression of VEGFa. Further analysis reveals that Gadd45a overexpression attenuates the association between mTOR and STAT3, whereas Gadd45a disruption strengthens this interaction, indicating that Gadd45a suppression of STAT3 phosphorylation is mainly through the dissociation of mTOR with STAT3. Taken together, these findings provide the first evidence that Gadd45a inhibits tumor angiogenesis via blocking of the mTOR/STAT3 pathway. PMID:23329839

Yang, Fang; Zhang, Weimin; Li, Dan; Zhan, Qimin

2013-01-01

290

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

International Nuclear Information System (INIS)

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

291

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

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

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

1990-01-01

292

Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis  

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Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10{sup -5} mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

Chen, Pei-Lin, E-mail: pchen@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Easton, Alexander S., E-mail: alexander.easton@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

2010-01-01

293

Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis  

International Nuclear Information System (INIS)

Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10-5 mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

294

In vivo inhibition of the estrogen sulfatase enzyme and growth of DMBA-induced mammary tumors by melatonin.  

Science.gov (United States)

Melatonin inhibits the growth of different kinds of neoplasias, especially breast cancer, by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces sulfatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. In this study, to investigate the in vivo sulfatase-inhibitory properties of melatonin, this indoleamine was administered to ovariectomized rats bearing DMBA-induced mammary tumors, and treated with estrone sulfate. In castrated animals, the growth of estrogen-sensitive mammary tumors depends on the local conversion of biologically inactive estrogens to bioactive unconjugated estrogens. Ovariectomy significantly reduced the size and the number of the tumors while the administration of estrone sulfate to ovariectomized animals stimulated tumor growth, an effect which was suppressed by melatonin. The uterine weight of ovariectomized rats, which depends on the local synthesis of estrogens, was increased by estrone sulfate, except in those animals which were also treated with melatonin. The growth-stimulatory effects of estrone sulfate on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in estrone sulfate-treated rats. Melatonin counteracted the stimulatory effects of estrone sulfate on sulfatase activity and expression and incubation with melatonin decreased the sulfatase activity of tumors from control animals. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by down-regulating the sulfatase pathway of the tumoral tissue. PMID:20370689

González, Alicia; Alvarez-García, Virginia; Martínez-Campa, Carlos; Mediavilla, María Dolores; Alonso-González, Carolina; Sánchez-Barceló, Emilio J; Cos, Samuel

2010-05-01

295

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

DEFF Research Database (Denmark)

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

Østergaard, Leif; Tietze, Anna

2013-01-01

296

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

International Nuclear Information System (INIS)

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

297

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

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

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

2011-01-01

298

Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo  

International Nuclear Information System (INIS)

This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous 'take rate' in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation

299

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

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Full Text Available 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. Results In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME, inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P? Conclusions 6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.

Bellou Sofia

2012-05-01

300

Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer.  

Science.gov (United States)

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-?B and NF-?B-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-?B pathway. PMID:24324975

Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; Rea, Domenica; Arra, Claudio

2013-01-01

 
 
 
 
301

Relationship between expression of urokinase-type plasminogen activator and tumor angiogenesis in epithelial ovarian carcinoma  

Directory of Open Access Journals (Sweden)

Full Text Available Objective To explore the expression of urokinase-type plasminogen activator(uPA in epithelial ovarian carcinoma(EOC and the relationship of the expression to microvessel density.Methods SP immunohistochemical staining was performed to determine the expression of uPA in ovarian cancer(85 cases,borderline ovarian tumor(16 cases,benign ovarian tumor(39 cases and normal ovarian tissue(24 cases.Microvessels in ovarian cancer were marked by CD34,and microvessel density(MVD was determined by direct count.The relationship between uPA and MVD was analyzed.The 85 patients with epithelial ovarian cancer were followed up.Results The highest positive rate of uPA existed in the patients with EOC.There was a correlation between the expression of uPA and MVD and the differentiation of EOC,clinical stage,lymphatic metastasis,omental metastasis,and 5 years survival rate.A significant positive correlation was found between the expression of uPA in EOC and MVD(r=0.56,P=0.02.Conclusion uPA may promote the angiogenesis of EOC,and participate in the occurrence,development,invasion and metastasis of ovarian cancer.The detection of uPA and MVD may be used as an indicator of biological behaviors and prognosis of ovarian cancer.

Ping NAN

2011-06-01

302

Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways.  

Science.gov (United States)

Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways. PMID:25111127

Tong, Qingyi; Qing, Yong; Wu, Yang; Hu, Xiaojuan; Jiang, Lei; Wu, Xiaohua

2014-12-01

303

Three-dimensional imaging of the metabolic state of c-MYC-induced mammary tumor with the cryo-imager  

Science.gov (United States)

This study imaged the metabolic state of a growing tumor and the relationship between energy metabolism and the ability of glucose uptake in whole tumor tissue with cryo-imaging at 77° K. A MTB/TOM mouse model, bearing c-MYC-induced mammary tumor, was very rapidly freeze-trapped 2 hrs post Pyro-2DG injection. The fluorescence signals of oxidized flavoprotein (Fp), reduced pyridine nucleotide (PN), pyro-2DG, and the reflection signal of deoxy-hemoglobin were imaged every 100 ?m from the top surface to the bottom of the tumor sequentially, 9 sections in total. Each of the four signals was constructed into 3D images with Amira software. Both Fp and PN signals could be detected in the growing tumor regions, and a higher reduction state where was shown in the ratio images. The necrotic tumor regions displayed a very strong Fp signal and weak PN signal. In the bloody extravasation regions, Fp and PN signals were observably diminished. Therefore, the regions of high growth and necrosis in the tumor could be determined according to the Fp and PN signals. The content of deoxy-hemoglobin (Hb) in the tumor was positively correlated with the reduced PN signal. Pyro-2DG signal was only evident in the growing condition region in the tumor. Normalized 3D cross-correlation showed that Pyro-2DG signal was similar to the redox ratio. The results indicated that glucose uptake in the tumor was consistent with the redox state of the tumor. And both Pyro-2DG and mitochondrial NADH fluorescence showed bimodal histograms suggesting that the two population of c-MYC induced mammary tumor, one of which could be controlled by c-MYC transgene.

Zhang, Zhihong; Liu, Qian; Luo, Qingming; Zhang, Min Z.; Blessington, Dana M.; Zhou, Lanlan; Chodosh, Lewis A.; Zheng, Gang; Chance, Britton

2003-07-01

304

Survival of mouse mammary gland transplants of normal, hyperplastic, and tumor tissues exposed to X-rays  

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Mouse mammary tissues, including ducts, prelactating lobules, hyperplastic outgrowth lines, and tumors, were exposed to varying doses of X-rays and then transplanted to fat pads of nonirradiated BALB/c mice for study. Estimates of the dose of radiation that would allow survival of 50% of the transplants (SD50) were made with the use of probit analysis. Nearly all duct and lobule transplants survived doses of X-rays from 0 to 800 rad. The survival rate declined rapidly following doses above 800 rad, and the calculated SD50 was 1,020 and 1,260 rad for mammary ducts and lobules, respectively. The three hyperplastic outgrowth lines tested gave very different results. Hyperplastic line Z5C1 transplants had better than 90% survival at doses up to 1,200 rad and an SD50 between 1,200 and 1,600 rad. Hyperplastic line Z5D transplants had an SD50 of between 800 and 1,200 rad. Hyperplastic line D1 transplants had a better than 90% survival following doses of 0-600 rad and an SD50 between 600 and 800 rad. The survival of tumor transplants was 100% following doses of X-rays up to 1,200 rad; the SD50 was in excess of 1,600 rad. The mouse mammary transplantation system can be used to study the direct effect of X-rays on normal, premalignant, and malignant mammary tissues and provides a basis for the study of the radiobiology of mammary tissues

305

Effect of thyroid hormone-nitric oxide interaction on tumor growth, angiogenesis, and aminopeptidase activity in mice.  

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This study evaluated the effects of thyroid hormone-NO interaction on tumor development, vascularization, vascular endothelial growth factor (VEGF), and aminopeptidase (AP) activity in a murine model of implanted Lewis's carcinoma. Experiments were performed in male CBA-C57 mice. Animals were untreated (controls) or treated with: T4, the antithyroid drug methimazole, the NO inhibitor L-NAME, T4+L-NAME, methimazole+NAME, the ?vß3 integrin antagonist tetrac, T4+tetrac, the iNOS inhibitor aminoguanidine (AG), and T4 + AG; all treatments were for 6 weeks except for tetrac, administered for the last 11 days. Mice were subcutaneously inoculated with 1 × 10(6) exponentially growing Lewis carcinoma 3LL cells into the dorsum. Study variables 9 days later were tumor weight (TW), Hb content, an index of tumor vascularization, VEGF, and AP activity. T4 produced parallel increases in TW and angiogenesis. L-NAME reduced TW and angiogenesis in control, hyperthyroid, and hypothyroid mice, whereas AG had no effect on these variables. Tetrac arrested TW in normal and T4-treated mice but did not decrease angiogenesis in T4-treated animals. Negative correlations were found between TW and AP activity in tumors from control hyper- and hypothyroid groups and an inverse relationship was observed between TW and AP activities in tetrac-treated mice. T4 enhances TW and angiogenesis, in which NO participates, but requires activation of integrin ?vß3 to promote carcinogenesis. NO blockade reduces TW, regardless of the thyroid status. Thyroid hormone negatively modulates AP activity in the tumor. Accordingly, blockade of the membrane TH receptor ?vß3 integrin reduces TW associated with an increase in AP activity. PMID:24549786

Carmona-Cortés, Javier; Rodríguez-Gómez, Isabel; Wangensteen, Rosemary; Banegas, Inmaculada; García-Lora, Ángel M; Quesada, Andrés; Osuna, Antonio; Vargas, Félix

2014-06-01

306

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 its subcellular localization, a yeast two-hybrid screen was performed. Ribosomal protein L9 (RPL9 or L9), an essential component of the large ribosomal subunit and a putative tumor suppressor, was identified as a Gag binding partner. Overexpression of L9 in cells expressing the MMTV(C3H) provirus resulted in specific, robust accumulation of Gag in nucleoli. Förster resonance energy transfer (FRET) and coimmunoprecipitation analyses demonstrated that Gag and L9 interact within the nucleolus, and the CA domain was the major site of interaction. In addition, the isolated NC domain of Gag localized to the nucleolus, suggesting that it contains a nucleolar localization signal (NoLS). To determine whether L9 plays a role in virus assembly, small interfering RNA (siRNA)-mediated knockdown was performed. Although Gag expression was not reduced with L9 knockdown, virus production was significantly impaired. Thus, our data support the hypothesis that efficient MMTV particle assembly is dependent upon the interaction of Gag and L9 in the nucleoli of infected cells. PMID:23135726

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

307

Nodular pseudoangiomatous stromal hyperplasia of mammary stroma in a case showing rapid tumor growth.  

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Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign breast disease that presents as a localized breast mass. Breast tissue affected by PASH is characterized by a dense, collagenous proliferation of mammary stroma, forming interanastomosing capillary-like spaces. The importance of this benign lesion lies in distinguishing it from low grade angiosarcoma. We report a case of a 38-year-old woman who presented with a rapidly growing breast tumor. She visited our hospital with a complaint of a painless right breast mass. Physical examination revealed a 3.6 x 2.2 cm, oval, elastic-firm, well-defined and easily movable mass. Mammograms revealed no discrete mass or calcifications. Sonographic examination revealed a 3.5 x 2.5 x 2.2 cm, oval, well-defined and homogenous hypoechoic mass without a cyst. A fine-needle aspiration sample of the breast mass showed some clusters of epithelial cells with small papillary structures and many scattered stromal cells with naked nuclei. Based on these findings, a provisional diagnosis of fibroadenoma was made and the patient was followed up. One year after the first visit, the mass enlarged rapidly and a follow-up mammogram revealed an 8.2 x 5.5 cm circumscribed mass without calcifications. Given the history of rapid growth of the mass, tumor excision was performed. The excised tumor was well demarcated and had a smooth external surface. Histologic examination revealed normal breast ducts and lobules, and specific proliferative epithelial changes were not seen. The lobular and duct structure of the breast parenchyma were separated by an increased amount of stroma. The fibrous stroma contained numerous anastomosing slit-like spaces. Isolated spindle cells appeared intermittently at the margins of the spaces resembled endothelial cells. Immunohistochemical staining showed that endothelial cells lining true blood vessels were positive for Factor VIII-related antigen, but the spindle cells were negative for Factor VIII. Pseudoangiomatous stromal hyperplasia was diagnosed. PMID:16286916

Taira, Naruto; Ohsumi, Shozo; Aogi, Kenjiro; Maeba, Takahiro; Kawamura, Susumu; Nishimura, Rieko; Takashima, Shigemitsu

2005-01-01

308

Effect of selenodiglutathione on the metabolism of canine mammary tumor cells  

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Selenodiglutathione (SDG) has been shown to be an effective inhibitor of tumor growth. The present studies were designed to evaluate altered metabolism in canine mammary tumor cells (CMT-13) exposed to various concentrations of SDG. Addition of SDG at 0.025 ?g Se/ml did not inhibit growth of CMT-13 cells after 24 h of incubation. At this concentration of SDG, approximately 25% of 75Se-35S-SDG was retained in these tumor cells after 24 h of incubation. The nuclear fraction contained 96% of the 75Se and 35S radioactivity. The ratio of 75Se to 35S was 1 to 4.5 in the whole cell and in the nuclear fraction. SDG increased glutathione peroxidase activity by 40% compared to CMT-13 cells not exposed to SDG. Glutathione reductase activity was decreased by 63% by the addition of SDG. In addition, supplemental SDG resulted in a 55% decrease in GSH content but did not alter GSSG concentrations. After 4d of incubation, SDG at 0.1 and 0.5 ?g Se/ml caused a 43 and 58% inhibition of growth of CMT-13 cells. Addition of GSH (100?M) partially prevented, 68% and 54%, the growth inhibition caused by SDG at concentrations of 0.1 and 0.5 ?g Se per ml respectively during the 4d incubation period. Preincubation of CMT-13 cells with GSH for 48 h before addition of SDG (0.5 ?g Se/ml) completely prevented the growth inhibition caused by this seleno-compound

309

Virus-specific cytotoxic activity to mammary tumor cells of sera from normal and tumor-bearing mice with inhibition at low dilutions.  

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Sera from normal mice and mice bearing murine mammary tumor virus (MTV)-induced tumors showed cytotoxic reactions to the MTV-producing Mm5mt/c1 cell line. The reaction could be blocked by the addition of MTV, but not of purified gp52 and p28. In sera from tumor bearers, cytotoxic responses ranged from 15 to 66%; reactivity was generally highest when the serum was diluted 32 to 128 times. The cytotoxic sera from the normal animals showed a much lower activity; again, there was a lack of cytoto...

Creemers, P.

1981-01-01

310

Comparison of angiogenesis-related factor expression in primary tumor cultures under normal and hypoxic growth conditions  

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Full Text Available Abstract Background A localized hypoxic environment occurs during tumor growth necessitating an angiogenic response or tumor necrosis results. Novel cancer treatment strategies take advantage of tumor-induced vascularisation by combining standard chemotherapeutic agents with angiogenesis-inhibiting agents. This has extended the progression-free interval and prolonged survival in patients with various types of cancer. We postulated that the expression levels of angiogenesis-related proteins from various primary tumor cultures would be greater under hypoxic conditions than under normoxia. Methods Fifty cell sources, including both immortalized cell lines and primary carcinoma cells, were incubated under normoxic conditions for 48 hours. Then, cells were either transferred to a hypoxic environment (1% O2 or maintained at normoxic conditions for an additional 48 hours. Cell culture media from both conditions was collected and analyzed via an ELISA-based assay to determine expression levels of 11 angiogenesis-related factors: VEGF, PDGF-AA, PDGF-AA/BB, IL-8, bFGF/FGF-2, EGF, IP-10/CXCL10, Flt-3 ligand, TGF-?1, TGF-?2, and TGF-?3. Results A linear correlation between normoxic and hypoxic growth conditions exists for expression levels of eight of eleven angiogenesis-related proteins tested including: VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-?1, TGF-?2, EGF, and IP-10. For VEGF, the target of current therapies, this correlation between hypoxia and higher cytokine levels was greater in primary breast and lung carcinoma cells than in ovarian carcinoma cells or tumor cell lines. Of interest, patient cell isolates differed in the precise pattern of elevated cytokines. Conclusion As linear correlations exist between expression levels of angiogenic factors under normoxic and hypoxic conditions in vitro, we propose that explanted primary cells may be used to probe the in vivo hypoxic environment. Furthermore, differential expression levels for each sample across all proteins examined suggests it may be possible to build a predictor for angiogenesis-related anticancer agents, as each sample has a unique expression profile. Further studies should be performed to correlate in vitro protein expression levels of angiogenesis-related factors with in vivo patient response.

Brower Stacey L

2008-07-01

311

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

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

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

2008-01-01

312

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

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

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

2010-12-17

313

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

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

314

pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia  

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Full Text Available Retinoblastoma 1 (pRb and the related pocket proteins, retinoblastoma-like 1 (p107 and retinoblastoma-like 2 (p130 (pRbf, collectively, play a pivotal role in regulating eukaryotic cell cycle progression, apoptosis, and terminal differentiation. While aberrations in the pRb-signaling pathway are common in human cancers, the consequence of pRbf loss in the mammary gland has not been directly assayed in vivo. We reported previously that inactivating these critical cell cycle regulators in divergent cell types, either brain epithelium or astrocytes, abrogates the cell cycle restriction point, leading to increased cell proliferation and apoptosis, and predisposing to cancer. Here we report that mouse mammary epithelium is similar in its requirements for pRbf function; Rbf inactivation by T121, a fragment of SV40 T antigen that binds to and inactivates pRbf proteins, increases proliferation and apoptosis. Mammary adenocarcinomas form within 16 mo. Most apoptosis is regulated by p53, which has no impact on proliferation, and heterozygosity for a p53 null allele significantly shortens tumor latency. Most tumors in p53 heterozygous mice undergo loss of the wild-type p53 allele. We show that the mechanism of p53 loss of heterozygosity is not simply the consequence of Chromosome 11 aneuploidy and further that chromosomal instability subsequent to p53 loss is minimal. The mechanisms for pRb and p53 tumor suppression in the epithelia of two distinct tissues, mammary gland and brain, are indistinguishable. Further, this study has produced a highly penetrant breast cancer model based on aberrations commonly observed in the human disease.

Simin Karl

2004-01-01

315

Enhancement of Drug Resistance by Lysophosphatidic Acid Receptor-3 in Mouse Mammary Tumor FM3A Cells  

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Lysophosphatidic acid (LPA) acts as a simple phospholipid that interacts with G protein-coupled transmembrane LPA receptors. Recently, it has been reported that each LPA receptor plays different biological roles in acquisition of the malignant property of tumor cells. In this study, to assess the involvement of LPA receptor-3 (LPA3) in cell survival after treatment with anticancer drugs, we generated Lpar3-expressing FM3A-a3A9 cells from mouse mammary tumor FM3A cells and ex...

Fukui, Rie; Kato, Kohei; Okabe, Kyoko; Kitayoshi, Misaho; Tanabe, Eriko; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

2012-01-01

316

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

International Nuclear Information System (INIS)

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 other eight groups contain MuMTV-related sequences that have not been described previously. The gag-pol regions of one recombinant from each of the nine groups were hybridized to RNA prepared from five human breast cancer cell lines, from placenta, and from two cell lines derived from other malignancies. RNAs were detected by probes for several of the groups. The RNAs ranged in size from 1.2 to 12 kilobases. Probes for six of the groups detected large RNAs that could represent transcripts of full-length proviral DNA. Two of the probes detected RNA in one breast cancer cell line only. Most of the RNAs were detected in more than one cell line

317

Mouse mammary tumor virus-like gene sequences are present in lung patient specimens  

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Full Text Available Abstract Background Previous studies have reported on the presence of Murine Mammary Tumor Virus (MMTV-like gene sequences in human cancer tissue specimens. Here, we search for MMTV-like gene sequences in lung diseases including carcinomas specimens from a Mexican population. This study was based on our previous study reporting that the INER51 lung cancer cell line, from a pleural effusion of a Mexican patient, contains MMTV-like env gene sequences. Results The MMTV-like env gene sequences have been detected in three out of 18 specimens studied, by PCR using a specific set of MMTV-like primers. The three identified MMTV-like gene sequences, which were assigned as INER6, HZ101, and HZ14, were 99%, 98%, and 97% homologous, respectively, as compared to GenBank sequence accession number AY161347. The INER6 and HZ-101 samples were isolated from lung cancer specimens, and the HZ-14 was isolated from an acute inflammatory lung infiltrate sample. Two of the env sequences exhibited disruption of the reading frame due to mutations. Conclusion In summary, we identified the presence of MMTV-like gene sequences in 2 out of 11 (18% of the lung carcinomas and 1 out of 7 (14% of acute inflamatory lung infiltrate specimens studied of a Mexican Population.

Rodríguez-Padilla Cristina

2011-09-01

318

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

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The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (PHep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy. PMID:21093415

Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin; Cai, Liuxin

2010-12-17

319

Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells.  

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Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-?1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control. PMID:25217495

Chu, Shu-Chen; Yu, Cheng-Chia; Hsu, Li-Sung; Chen, Kuo-Shuen; Su, Mei-Yu; Chen, Pei-Ni

2014-12-01

320

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells.  

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We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

Hoeppner, Luke H; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P; Wang, Enfeng; Yang, Ping; Roden, Anja C; Peikert, Tobias; Molina, Julian R; Mukhopadhyay, Debabrata

2015-01-01

 
 
 
 
321

Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats  

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Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further tested with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues

322

Potent anti-angiogenesis and anti-tumor activity of a novel human anti-VEGF antibody, MIL60.  

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Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor (VEGF) has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin (the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM). MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation (the IC50 value of MIL60 was 31±6.4 ng/ml and that of Avastin was 47±8.1 ng/ml), migration (8 µg/ml or 0.8 µg/ml MIL60 versus the control: Ptube formation (2 µg/ml or 0.2 µg/ml MIL60 versus the control: P<0.05) via the VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis (MIL60 versus N.S.: P=0.0007; Avastin versus N.S.: P=0.00046). These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers. PMID:24608894

Yang, Jing; Wang, Qun; Qiao, Chunxia; Lin, Zhou; Li, Xinying; Huang, Yifei; Zhou, Tingting; Li, Yan; Shen, Beifen; Lv, Ming; Feng, Jiannan

2014-05-01

323

The investigation of tumoral angiogenesis with HIF-1 alpha and microvessel density in women with endometrium cancer  

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Full Text Available Objective: Hypoxia inducible factor 1 alpha (HIF-1? is a nuclear protein upregulated in response to reduced cellular oxygen concentration which therefore acts as a marker for hypoxia. The aim of this study was to determine tumoral angiogenesis with immunohistochemical markers in endometrium cancer and its relation with stage, grade, survival rates and other prognostic factors.Material and Methods: Using the database in our Gynecologic Oncology clinic, we selected 94 patients who were diagnosed with endometrial cancer and underwent primary surgery at our institution between 2001 and 2010. Tissue microarrays believed to demonstrate the optimum part of the tumor were reprepared from the paraffin blocks. Angiogenesis and microvessel density (MVD were investigated with the aid of HIF-1? and CD34 antibodies. Results: High expression of HIF-1? was significantly more frequent in advanced grade endometrial cancers (p=0.044. HIF-1? expression was highly correlated with CD34 expression in the tumor cells (p<0.001. However lack of relation among stage, overall survival rates and histological types were analyzed with HIF-1?. When we compared HIF-1? positive and negative cases with cervical, adnexial, lymphovascular and myometrial invasion, there was no difference between these groups. MVD was evaluated with CD34 and it was remarkable and significantly different on advanced grade tumors (r=0.268; p=0.009. A similar significant difference was observed between the high expression of CD34 and type II endometrial cancer histology (p<0.001. However, there was no relationship between the MVD and stage or survival rates.Conclusion: High expression of HIF-1? is associated with tumoral angiogenesis in endometrial adenocarcinomas. Further studies targeting HIF-1? for disrupting mechanisms essential for tumor growth in endometrium cancer will be significant investigations in the future.

Aysun Aybatl?

2012-03-01

324

The investigation of tumoral angiogenesis with HIF-1 alpha and microvessel density in women with endometrium cancer  

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Objective Hypoxia inducible factor 1 alpha (HIF-1?) is a nuclear protein upregulated in response to reduced cellular oxygen concentration which therefore acts as a marker for hypoxia. The aim of this study was to determine tumoral angiogenesis with immunohistochemical markers in endometrium cancer and its relation with stage, grade, survival rates and other prognostic factors. Material and Methods Using the database in our Gynecologic Oncology clinic, we selected 94 patients who were diagnosed with endometrial cancer and underwent primary surgery at our institution between 2001 and 2010. Tissue microarrays believed to demonstrate the optimum part of the tumor were reprepared from the paraffin blocks. Angiogenesis and microvessel density (MVD) were investigated with the aid of HIF-1? and CD34 antibodies. Results High expression of HIF-1? was significantly more frequent in advanced grade endometrial cancers (p=0.044). HIF-1? expression was highly correlated with CD34 expression in the tumor cells (p<0.001). However lack of relation among stage, overall survival rates and histological types were analyzed with HIF-1?. When we compared HIF-1? positive and negative cases with cervical, adnexial, lymphovascular and myometrial invasion, there was no difference between these groups. MVD was evaluated with CD34 and it was remarkable and significantly different on advanced grade tumors (r=0.268; p=0.009). A similar significant difference was observed between the high expression of CD34 and type II endometrial cancer histology (p<0.001). However, there was no relationship between the MVD and stage or survival rates. Conclusion High expression of HIF-1? is associated with tumoral angiogenesis in endometrial adenocarcinomas. Further studies targeting HIF-1? for disrupting mechanisms essential for tumor growth in endometrium cancer will be significant investigations in the future. PMID:24627673

Aybatl?, Aysun; Say?n, Cenk; Kaplan, Petek Balkanl?; Varol, Füsun; Altaner, ?emsi; Süt, Necdet

2012-01-01

325

No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women  

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Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer.

Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L. E.; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A.; Torres, Javier; Fuentes-Pananá, Ezequiel M.

2013-10-01

326

No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with breast cancer in Mexican women.  

Science.gov (United States)

Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer. PMID:24131889

Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L E; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A; Torres, Javier; Fuentes-Pananá, Ezequiel M

2013-01-01

327

Targeted contrast-enhanced ultrasound imaging of angiogenesis in an orthotopic mouse tumor model of renal carcinoma.  

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Previous studies have reported that microbubbles bearing targeting ligands to molecular markers of angiogenesis can be successfully detected by ultrasound imaging in various animal models of solid cancer. In the present study, we sought to investigate the activity of microbubbles targeted to vascular endothelial growth factor receptor 2 (VEGFR2) in an orthotopic model of renal cell carcinoma (RCC). Microbubbles conjugated to an anti-VEGFR2 antibody (MBV) were compared with microbubbles conjugated to an isotype control antibody (MBC) or naked microbubbles (MBN). An orthotopic mouse model of human RCC was established by surgically implanting an established tumor within the renal capsule in mice. Tumor growth and blood flow were verified by B-mode and color Doppler ultrasound imaging. VEGFR2 expression within the tumor and renal parenchyma was detected by immunohistochemistry. The duration of contrast enhancement of MBV was much longer than those of MBN and MBC when assessed over 10 min. The baseline-subtracted contrast intensity within the tumor was higher for MBV than for MBC and MBN (p < 0.01). Additionally, the contrast intensity for MBV was significantly higher in the tumor region than in normal parenchyma (p < 0.01). Microbubbles targeting VEGFR2 exhibit suitable properties for imaging angiogenesis in orthotopic models of renal cell carcinoma, with potential applications in life science research and clinical medicine. PMID:24613557

Wei, Shuping; Fu, Ninghua; Sun, Yu; Yang, Zhijian; Lei, Li; Huang, Pengfei; Yang, Bin

2014-06-01

328

Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo  

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Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

Vassiliki Kostourou

2004-07-01

329

Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma.  

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Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244-TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244-TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1?, VEGF?, IL-8 and TGF?1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo. PMID:25275595

Grazia, G; Vegetti, C; Benigni, F; Penna, I; Perotti, V; Tassi, E; Bersani, I; Nicolini, G; Canevari, S; Carlo-Stella, C; Gianni, A M; Mortarini, R; Anichini, A

2014-01-01

330

Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway.  

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Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, has been assigned anticancer activities, but its mechanism is not well understood. Here, we investigated whether Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, Celastrol abrogated VEGF-induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis. PMID:20160026

Pang, Xiufeng; Yi, Zhengfang; Zhang, Jing; Lu, Binbin; Sung, Bokyung; Qu, Weijing; Aggarwal, Bharat B; Liu, Mingyao

2010-03-01

331

Endogenous Mouse Mammary Tumor Viruses (Mtv: New Roles for an Old Virus in Cancer, Infection and Immunity  

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Full Text Available Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV and endogenous (Mtv forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.

GeorgePunkosdy

2013-11-01

332

Global Tumor RNA Expression in Early Establishment of Experimental Tumor Growth and Related Angiogenesis following Cox-Inhibition Evaluated by Microarray Analysis  

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Full Text Available Altered expression of COX-2 and overproduction of prostaglandins, particularly prostaglandin E2, are common in malignant tumors. Consequently, non-steroidal anti-inflammatory drugs (NSAIDs attenuate tumor net growth, tumor related cachexia, improve appetite and prolong survival. We have also reported that COX-inhibition (indomethacin interfered with early onset of tumor endothelial cell growth, tumor cell proliferation and apoptosis. It is however still unclear whether such effects are restricted to metabolic alterations closely related to eicosanoid pathways and corresponding regulators, or whether a whole variety of gene products are involved both up- and downstream effects of eicosanoids. Therefore, present experiments were performed by the use of an in vivo, intravital chamber technique, where micro-tumor growth and related angiogenesis were analyzed by microarray to evaluate for changes in global RNA expression caused by indomethacin treatment. Indomethacin up-regulated 351 and down-regulated 1852 genes significantly (p < 0.01; 1066 of these genes had unknown biological function. Genes with altered expression occurred on all chromosomes. Our results demonstrate that indomethacin altered expression of a large number of genes distributed among a variety of processes in the carcinogenic progression involving angiogenesis, apoptosis, cell-cycling, cell adhesion, inflammation as well as fatty acid metabolism and proteolysis. It remains a challenge to distinguish primary key alterations from secondary adaptive changes in transcription of genes altered by cyclooxygenase inhibition.

Kent Lundholm

2007-01-01

333

Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism.  

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Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti?estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet?depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO?injected group was increased significantly compared with the late TPO?injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer. PMID:25502723

Yuan, Lei; Liu, Xishi

2015-04-01

334

Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer.  

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The chemokine CXCL12 has a decisive role in tumor progression by mediating pro-angiogenic and pro-metastatic effects through its receptor CXCR4. The CXCL12 pathway is connected with another chemokine, CXCL11, through its second receptor CXCR7. CXCL11 also binds to the CXCR3 receptor. CXCL11 function in tumor angiogenesis is likely receptor dependent because CXCR3 predominantly mediates angiostatic signals whereas CXCR7 mediated signaling is rather angiogenic. We therefore studied the interaction of CXCL12 and CXCL11 in an in vivo model of colorectal cancer metastasis. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice. The animals received either peritumoral application of CXCL11 or intraperitoneal injections with neutralizing antibodies against CXCL11, CXCL12 or both. Tumor growth characteristics, angiogenesis, cell migration, invasive tumor growth, tumor cell proliferation and apoptosis were studied by intravital fluorescence microscopy and immunohistochemistry during an observation period of 14 days. Local exposure to CXCL11 significantly stimulated tumor growth compared to controls and enhanced invasive growth characteristics without affecting tumor angiogenesis and tumor cell migration. Neither CXCL11 nor CXCL12-blockade had a significant impact on tumor growth and angiogenesis, whereas the combined neutralization of CXCL11 and CXCL12 almost completely abrogated tumor vessel formation. As a consequence, tumor growth and invasive growth characteristics were reduced compared to the other groups. The results of the present study underline the interaction of CXCL12 and CXCL11 during tumor angiogenesis. The combined blockade of both signaling pathways may provide an interesting anti-angiogenic approach for anti-tumor therapy. PMID:24493023

Rupertus, Kathrin; Sinistra, Janine; Scheuer, Claudia; Nickels, Ruth M; Schilling, Martin K; Menger, Michael D; Kollmar, Otto

2014-02-01

335

Deleted in Malignant Brain Tumors 1 is Present in the Vascular Extracellular Matrix and Promotes Angiogenesis  

DEFF Research Database (Denmark)

OBJECTIVE: Deleted in malignant brain tumors 1 (DMBT1) belongs to the scavenger receptor cysteine-rich superfamily of proteins and is implicated in innate immunity, cell polarity, and differentiation. Here we studied the role of DMBT1 in endothelial cells. METHODS AND RESULTS: DMBT1 was secreted into the extracellular matrix (ECM) by endothelial cells in vitro and in situ and the presence of DMBT1 in the ECM increased endothelial cell adherence. Endothelial cell-derived DMBT1 associated with galectin-3 (coprecipitation), and human recombinant DMBT1 bound EGF, vascular endothelial growth factor and Delta-like (Dll) 4 (specific ELISAs). Compared to cells from wild-type mice, endothelial cells from DMBT1(-/-) mice demonstrated reduced migration, proliferation, and tube formation. In vivo recovery from hindlimb ischemia was attenuated in DMBT1(-/-) animals as was vascular endothelial growth factor -induced endothelial sprouting from isolated aortic rings; the latter response could be rescued by the addition of recombinant DMBT1. The Notch pathway is involved in multiple aspects of vascular development, including arterial-venous differentiation and we found that endothelial cells from DMBT1(-/-) mice expressed more EphrinB2 than cells from wild-type mice. Levels of Dll1, Dll4, Hes1, Hey1, and EphB4, on the other hand, were increased. CONCLUSIONS: Taken together, the results of this study indicate that DMBT1 functions as an important endothelium-derived ECM protein that is able to bind angiogenic factors and promote adhesion, migration, proliferation, and angiogenesis as well as vascular repair. Mechanistically, DMBT1 interacts with galectin-3 and modulates the Notch signaling pathway as well as the differential expression of ephrin-B2 and EphB4.

Müller-Enbergs, Helmut; Hu, Jiong

2012-01-01

336

Rapid analysis of vessel elements (RAVE): a tool for studying physiologic, pathologic and tumor angiogenesis.  

Science.gov (United States)

Quantification of microvascular network structure is important in a myriad of emerging research fields including microvessel remodeling in response to ischemia and drug therapy, tumor angiogenesis, and retinopathy. To mitigate analyst-specific variation in measurements and to ensure that measurements represent actual changes in vessel network structure and morphology, a reliable and automatic tool for quantifying microvascular network architecture is needed. Moreover, an analysis tool capable of acquiring and processing large data sets will facilitate advanced computational analysis and simulation of microvascular growth and remodeling processes and enable more high throughput discovery. To this end, we have produced an automatic and rapid vessel detection and quantification system using a MATLAB graphical user interface (GUI) that vastly reduces time spent on analysis and greatly increases repeatability. Analysis yields numerical measures of vessel volume fraction, vessel length density, fractal dimension (a measure of tortuosity), and radii of murine vascular networks. Because our GUI is open sourced to all, it can be easily modified to measure parameters such as percent coverage of non-endothelial cells, number of loops in a vascular bed, amount of perfusion and two-dimensional branch angle. Importantly, the GUI is compatible with standard fluorescent staining and imaging protocols, but also has utility analyzing brightfield vascular images, obtained, for example, in dorsal skinfold chambers. A manually measured image can be typically completed in 20 minutes to 1 hour. In stark comparison, using our GUI, image analysis time is reduced to around 1 minute. This drastic reduction in analysis time coupled with increased repeatability makes this tool valuable for all vessel research especially those requiring rapid and reproducible results, such as anti-angiogenic drug screening. PMID:21694777

Seaman, Marc E; Peirce, Shayn M; Kelly, Kimberly

2011-01-01

337

Catalyser-21TM, a mineral water derived from leaf soil, inhibits tumor cell invasion and angiogenesis  

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Catalyser-21TM is a mineral water derived from natural leaf soil containing various organic and inorganic substances. Previous reports suggested a possibility that Catalyser-21TM has antioxidative potential and could inhibit angiogenesis and cancer cell invasiveness. Angiogenesis is a prerequisite for cancer cells to spread to surrounding tissues. Vascular endothelial growth factor (VEGF) is a major angiogenic factor in the formation of blood capillaries by cancer cells to supply nutrients an...

Ye, Jun; Li, Yuping; Hamasaki, Takeki; Nakamichi, Noboru; Kawahara, Takeshi; Osada, Kazuhiro; Teruya, Kiichiro; Kato, Yuko; Toh, Kazuko; Abe, Masumi; Katakura, Yoshinori; Noguchi, Katsumi; Shirahata, Sanetaka

2007-01-01

338

Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells  

International Nuclear Information System (INIS)

The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors, whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors. TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines, as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 ?M with the exception of the T-47-D cells. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cellsmmary carcinoma cells

339

Kisspeptin-10, a KISS1-derived decapeptide, inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and FAK/Rho GTPase activation.  

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Kisspeptin-10 (Kp-10), a decapeptide derived from the primary translation product of KISS1 gene, has been reported previously to be a key hormone for puberty and an inhibitor for tumor metastasis via the activation of G protein-coupled receptor 54. However, whether Kp-10 inhibits angiogenesis, which is critical for tumor growth and metastasis and other human diseases, is still unknown. Here we show that Kp-10 significantly inhibits human umbilical vein endothelial cell (HUVEC) migration, invasion, and tube formation, key processes in angiogenesis. Using chicken chorioallantoic membrane assay and vascular endothelial growth factor (VEGF)-induced mouse corneal micropocket assay, we show that Kp-10 inhibits angiogenesis in vivo. Furthermore, Kp-10 inhibits tumor growth in severe combined immunodeficient mice xenografted with human prostate cancer cells (PC-3) through inhibiting tumor angiogenesis, whereas Kp-10 has little effect on the proliferation of HUVECs and human prostate cancer cells. In deciphering the underlying molecular mechanisms, we show that Kp-10 suppresses VEGF expression by inhibiting the binding of specificity protein 1 to VEGF promoter and by blocking the activation of c-Src/focal adhesion kinase and Rac/Cdc42 signaling pathways in HUVECs, leading to the inhibition of tumor angiogenesis. PMID:19671799

Cho, Sung-Gook; Yi, Zhengfang; Pang, Xiufeng; Yi, Tingfang; Wang, Ying; Luo, Jian; Wu, Zirong; Li, Dali; Liu, Mingyao

2009-09-01

340

KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth.  

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Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 play a central role in angiogenesis, which is necessary for solid tumors to expand and metastasize. Specific inhibitors of VEGFR-2 tyrosine kinase are therefore thought to be useful for treating cancer. We showed that the quinazoline urea derivative KRN633 inhibited tyrosine phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant tyrosine kinases showed that KRN633 was highly selective for VEGFR-1, -2, and -3. KRN633 also blocked the activation of mitogen-activated protein kinases by VEGF, along with human umbilical vein endothelial cell proliferation and tube formation. The propagation of various cancer cell lines in vitro was not inhibited by KRN633. However, p.o. administration of KRN633 inhibited tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats. KRN633 also caused the regression of some well-established tumors and those that had regrown after the cessation of treatment. In these models, the trough serum concentration of KRN633 had a more significant effect than the maximum serum concentration on antitumor activity. KRN633 was well tolerated and had no significant effects on body weight or the general health of the animals. Histologic analysis of tumor xenografts treated with KRN633 revealed a reduction in the number of endothelial cells in non-necrotic areas and a decrease in vascular permeability. These data suggest that KRN633 might be useful in the treatment of solid tumors and other diseases that depend on pathologic angiogenesis. PMID:15634658

Nakamura, Kazuhide; Yamamoto, Atsushi; Kamishohara, Masaru; Takahashi, Kazumi; Taguchi, Eri; Miura, Toru; Kubo, Kazuo; Shibuya, Masabumi; Isoe, Toshiyuki

2004-12-01

 
 
 
 
341

Overexpression of inhibitor of DNA-binding (ID-1 protein related to angiogenesis in tumor advancement of ovarian cancers  

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Full Text Available Abstract Background The inhibitor of DNA-binding (ID has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers. Methods Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patient prognosis was analyzed with a 36-month survival rate. Microvessel counts were determined by immunohistochemistry for CD34 and factor VIII-related antigen. Results ID-1 histoscores and mRNA levels both significantly (p Conclusion ID-1 increased in ovarian cancer cells during tumor progression. Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers.

Tamaya Teruhiko

2009-12-01

342

Association of preoperative radiation effect with tumor angiogenesis and vascular endothelial growth factor in oral squamous cell carcinoma  

International Nuclear Information System (INIS)

This study examined the relationship between tumor angiogenesis and the radiation-induced response, evaluated based on pathological changes, in oral squamous cell carcinoma patients treated with preoperative radiation therapy. Forty-one cases of squamous cell carcinoma treated with preoperative radiation therapy were investigated. Tumor angiogenesis was assessed by scoring the intratumor microvessel density (IMVD). Expression of vascular endothelial growth factor (VEGF) was also evaluated before and after preoperative radiotherapy. There was no correlation between IMVD in the specimens before therapy and the pathological response to radiation therapy. However, radiation therapy decreased IMVD in the specimens after therapy. A significant association was observed between VEGF expression and resistance to radiation therapy: only 4 of the 21 patients whose tumors exhibited a high level (2+ or 3+) of VEGF staining experienced a major (3+ or 4+) pathological response to radiation therapy. Furthermore, an increasing level of VEGF expression after radiation therapy was observed in non-effective (0 to 2+) response cases. These results suggest that VEGF expression and the induction of this protein are related to radiosensitivity and could be used to predict the effects of preoperative radiation therapy on oral squamous cell carcinoma. (author)

343

EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer  

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1,25-Dihydroxyvitamin D3 and several of its analogs, such as EB1089, induce growth arrest and apoptosis of breast cancer cells in culture. EB1089 has also been shown to limit growth of xenografts in nude mice and carcinogen-induced mammary tumors in rats. Coupled with the fact that the vitamin D receptor is highly expressed in a large proportion of breast tumors, these data suggest that it may be a broad spectrum therapeutic target. We utilized a transgenic model of hormone-induced mammary ca...

Milliken, Erin L.; Zhang, Xiaoxue; Flask, Chris; Duerk, Jeffrey L.; Macdonald, Paul N.; Keri, Ruth A.

2005-01-01

344

Epidemiological studies of canine neoplasms with special reference to mutational analysis of p53 gene in canine mammary tumors by PCR-SSCP  

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Epidemiological studies of canine neoplasms with special reference to mutational analysis of p53 gene in canine mammary tumors by PCR-SSCP were carried out to know age wise, sex wise and breed wise incidence of neoplastic conditions in canine and to study the mutations in exon 4 and exon 8 of p53 gene segment in canine mammary tumors. The epidemiological study was conducted by analyzing available data of last ten years (1996-2005) of 175 specimens of canine neoplasms at Departm...

Pawar, Sanjay J.

2006-01-01

345

Phyllodes tumor of the breast: role of Axl and ST6GalNAcII in the development of mammary phyllodes tumors.  

Science.gov (United States)

Phyllodes tumor exhibits an aggressive growth. The expression of many biological markers has been explored to discriminate between different grades of phyllodes tumor and to predict their behavior. The purpose of this study was to evaluate the implications of Axl and ST6GalNAcII in phyllodes tumors. Real-time PCR, Western blot, and immunohistochemical were used to analyze differential expression of ST6GalNAcII and Axl in phyllodes tumor (PT) cell lines and tissue specimens. RNAi assay, ECM invasion assay, and tumorigenicity assay were used to analyze the altered expression of ST6GalNAcII gene effects on the expression of Axl and invasive ability of phyllodes tumor cells in vitro and in vivo. Compared to benign tumors, borderline and malignant ones showed a remarkable increase in mRNA levels of Axl and ST6GalNAcII gene, and it was higher in malignant tumor cells than in borderline tumor cells. When ST6GalNAcII was silenced, compared to the control, the expression level of Axl was significantly reduced in malignant tumor cell transfectants and knockdown of ST6GalNAcII gene significantly inhibited invasive activity in malignant tumor cells. The high expression of ST6GalNAcII and Axl was significantly correlated with tumor grade and distance metastasis by immunohistochemical analysis. Axl and ST6GalNAcII expression increases with increasing tumor grade in mammary phyllodes tumors. ST6GalNAc II might be participated in the glycosylation of Axl, and this Axl glycosylation may mediate the tumorigenicity, invasion, and distant metastasis of PT cells. PMID:24961352

Ren, Dongliang; Li, Yanyan; Gong, Yanxin; Xu, Jingchao; Miao, Xiaolong; Li, Xiangnan; Liu, Chen; Jia, Li; Zhao, Yongfu

2014-10-01

346

Characterization of protein marker expression, tumorigenicity, and doxorubicin chemoresistance in two new canine mammary tumor cell lines.  

Science.gov (United States)

BackgroundCanine mammary tumors (CMTs) are the most common type of cancer found in female dogs. Establishment and evaluation of tumor cell lines can facilitate investigations of the biological mechanisms of cancer. Different cell models are used to investigate genetic, epigenetic, and cellular pathways, cancer progression, and cancer therapeutics. Establishment of new cell models will greatly facilitate research in this field. In the present study, we established and characterized two new CMT cell lines derived from a single CMT.ResultsWe established two cell lines from a single malignant CMT specimen: DTK-E and DTK-SME. Morphologically, the DTK-E cells were large, flat, and epithelial-like, whereas DTK-SME cells were round and epithelial-like. Doubling times were 24 h for DTK-E and 18 h for DTK-SME. On western blots, both cell lines expressed cytokeratin AE1, vimentin, cytokeratin 7 (CK7), and heat shock protein 27 (HSP27). Moreover, investigation of chemoresistance revealed that DTK-SME was more resistant to doxorubicin-induced apoptosis than DTK-E was. After xenotransplantation, both DTK-E and DTK-SME tumors appeared within 14 days, but the average size of DTK-SME tumors was greater than that of DTK-E tumors after 56 days.ConclusionWe established two new cell lines from a single CMT, which exhibit significant diversity in cell morphology, protein marker expression, tumorigenicity, and chemoresistance. The results of this study revealed that the DTK-SME cell line was more resistant to doxorubicin-induced apoptosis and exhibited higher tumorigenicity in vivo than the DTK-E cell line. We anticipate that the two novel CMT cell lines established in this study will be useful for investigating the tumorigenesis of mammary carcinomas and for screening anticancer drugs. PMID:25267010

Hsiao, Yen-Ling; Hsieh, Tai-Zu; Liou, Chian-Jiun; Cheng, Yeong-Hsiang; Lin, Chung-Tien; Chang, Chi-Yao; Lai, Yu-Shen

2014-09-30

347

Radiolabeling of Monoclonal Anti-CD105 with {sup 177}Lu for Tumor Diagnosis and Therapy via Angiogenesis Targeting  

Energy Technology Data Exchange (ETDEWEB)

Currently, great interest is focused on angiogenesis and on its potential clinical implications in cancer. An intriguing approach relies on the selective targeting of the surface molecules over-expressed on endothelial cells of tumor-associated blood vessels. CD105 or Endoglin is a cell membrane glycoprotein representing a prime vascular target to implement innovative antibody-based diagnostic and therapeutic strategies. It is a component of the receptor complex of the Transforming Growth Factor (TGF-{beta}), a pleiotropic cytokine involved in cellular proliferation, differentiation and migration.

Lee, So-Young; Felipe, Penelope M; Hong, Young-Don; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2008-10-15

348

A comparison of 3D-CTA and 4D-CE-MRA for the dynamic monitoring of angiogenesis in a rabbit VX2 tumor  

International Nuclear Information System (INIS)

Purpose: To compare three-dimensional computed tomography angiography (3D-CTA) and four-dimensional contrast-enhanced magnetic resonance angiography (4D-CE-MRA) for the in vivo monitoring of tumor angiogenesis. Materials and methods: VX2 tumors were implanted into the right thigh muscle of 30 New Zealand white rabbits. The animals were randomly assigned to 5 groups, which, respectively, were scanned by 3D-CTA and 4D-CE-MRA on day 4, 7, 10, 13, or 16 after tumor implantation. After scanning, tumors were resected and processed for conventional histology and CD-31 immunohistochemistry. Tumor volume measurements derived from CT and MR imaging were compared with histopathological data. The minimum tumor diameter and the number of new tumor blood vessels detectable by 3D-CTA and 4D-CE-MRA were also compared. Results: There were no significant differences in the tumor volume measurements derived from CT, MR, and histological analysis. The minimum diameter of tumor vessels detectable by 3D-CTA (0.68 ± 0.07 mm) was significantly less than that by 4D-CE-MRA (0.85 ± 0.12 mm) (P = 0.005). The number of tumor vessels detected by each imaging method was not significantly different until day 13 after implantation, when 3D-CTA detected a greater number (P < 0.001). The morphologic process of tumor angiogenesis was demonstrated dynamically by 3D-CTA and 4D-CE-MRA in vivo. Conclusions: Tumor angiogenesis can be dynamically monitored in vivo by 3D-CTA and 4D-CE-MRA. Of the two methods3D-CTA and 4D-CE-MRA. Of the two methods, 3D-CTA has better spatial resolution, but 4D-CE-MRA allows temporal resolution of tumor angiogenesis.

349

CdS-Cd(OH)2 core shell quantum dots functionalized with Concanavalin A lectin for recognition of mammary tumors  

International Nuclear Information System (INIS)

We report the use of CdS/Cd(OH)2 quantum dots functionalized with glutaraldehyde and conjugated to concanavalin-A (Con-A) lectin to investigate cell alterations regarding carbohydrate profile in human mammary tissues diagnosed as fibroadenoma (benigne tumor). The Con-A lectin is a biomolecule which binds specifically to glucose/mannose residues present in the cellular membrane. These bioconjugated-particles were incubated with tissue sections of normal and to Fibroadenoma, a benign type of mammary tumor. The tissue sections were deparafinized, hydrated in graded alcohol and treated with a solution of Evans Blue in order to avoid autofluorescence. The fluorescence intensity of QD-Con-A stained tissues showed different patterns which reflect the carbohydrate expression of glucose/mannose in fibroadenoma when compared to the detection of the normal carbohydrate expression. The pattern of inespecific labeling of the tissues with glutharaldehyde functionalized CdS/Cd(OH)2 quantum dots is compared to the targeting driven by the Con-A lectin. The preliminary findings reported here support the use of CdS/Cd(OH)2 quantum dots as specific probes of cellular alterations possibiliting their use in diagnostics. (copyright 2006 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

350

Assessment of cell proliferation and prognostic factors in canine mammary gland tumors Avaliação da proliferação celular e fatores prognósticos em tumores mamários caninos  

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Full Text Available Three methods for the analysis of cell proliferation, mitotic index/10 high-power fields (10 HPF, mitotic index/four sets of 10 HPF (40 HPF, and MIB-1 index were evaluated in a series of canine mammary gland tumors, as well as the possible correlation between them. Fifty-six canine mammary gland tumors, including 23 benign and 33 malignant, were studied. In addition, the prognostic impact of mitotic index/10 HPF, and histological malignancy grade were evaluated in 17 malignant tumors, being seven ductal and 10 metaplastic carcinomas. The three methods used to evaluate cell proliferation were correlated with the prognostic impact of mitotic index/10 HPF and histological malignancy grade. The results showed a strong association between mitotic figure counts and MIB-1 index (PAvaliaram-se três métodos de proliferação celular, índice mitótico/10 campos de grande aumento (10 CGA, quatro vezes 10 CGA (40 CGA e índice de marcação por MIB-1, em uma série de tumores mamários caninos, e as possíveis correlações entre estes métodos. Foram estudados 56 tumores mamários caninos, 23 benignos e 33 malignos. Foi também avaliado o impacto prognóstico do índice mitótico (10 CGA e o grau histológico maligno em 17 tumores malignos, sete carcinomas ductais e 10 carcinomas metaplásicos. A correlação entre os três métodos para avaliar a proliferação celular e o impacto prognóstico do índice mitótico por 10 CGA e o grau histológico maligno foi realizada. Os resultados mostraram que existe uma forte associação entre contagem de mitose e o índice de marcação por MIB-1(P<0,0001 e correlação entre contagem de mitoses em 40 CGA e índice de marcação por MIB-1 e entre índice mitótico em 10 CGA e 40 CGA (P<0,05. Observou-se correlação entre os três métodos de avaliação da proliferação celular e os fatores prognósticos semelhante aos estudos de câncer de mama humano.

A.P. Dutra

2008-12-01

351

Total alkaloids of Rubus alceifolius Poir inhibit tumor angiogenesis through suppression of the Notch signaling pathway in a mouse model of hepatocellular carcinoma.  

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Angiogenesis, which has a critical role in human tumor growth and development, is tightly regulated by the Notch signaling pathway. Total alkaloids are active components of the plant Rubus alceifolius Poir, which is used for the treatment of various types of cancer. A previous study by our group showed that the total alkaloids of Rubus alceifolius Poir (TARAP) induced hepatocellular carcinoma (HCC) cell apoptosis through the activation of the mitochondria-dependent pathway in vitro and in vivo, as well as inhibited angiogenesis in a chick embryo chorioallantoic membrane model. In the present study, to further analyze the specific mechanisms underlying the antitumor activity of TARAP, a HCC xenograft mouse model was used to assess the effect of TARAP on angiogenesis in vivo. TARAP was found to suppress the expression of vascular endothelial growth factor (VEGF) A and VEGF receptor-2 in tumor tissues, which resulted in the inhibition of tumor angiogenesis. In addition, TARAP treatment was observed to inhibit the expression of Notch1, delta-like ligand 4 and jagged 1, which are key mediators of the Notch signaling pathway. The present study identified that the inhibition of tumor angiogenesis through the suppression of the Notch signaling pathway may be one of the mechanisms through which TARAP may be effective in the treatment of cancer. PMID:25333354

Zhao, Jinyan; Lin, Wei; Cao, Zhiyun; Zhuang, Qunchuan; Zheng, Liangpu; Peng, Jun; Hong, Zhenfeng

2015-01-01

352

Myeloid cell leukemia-1 is associated with tumor progression by inhibiting apoptosis and enhancing angiogenesis in colorectal cancer  

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Myeloid cell leukemia-1 (Mcl-1) is a highly expressed anti-apoptotic Bcl-2 protein in cancer. Therefore, inhibition of its expression induces apoptosis in cancer cells and enhances sensitivity to cancer treatment. The aims of this study were to evaluate whether Mcl-1 affects the oncogenic behaviors of colorectal cancer cells, and to document the relationship of its expression with various clinicopathological parameters in colorectal cancer. Mcl-1 knockdown induced apoptosis by activating cleaved caspase-3 and -9, and increasing the expression of the pro-apoptotic protein, PUMA. Mcl-1 knockdown induced cell cycle arrest by decreasing cyclin D1, CDK4 and 6, and by increasing p27 expression. Mcl-1 knockdown decreased both endothelial cell invasion and tube formation, and decreased the expression of VEGF. The phosphorylation level of STAT3 was decreased by Mcl-1 knockdown. The mean apoptotic index value of Mcl-1 positive tumors was significantly lower than that of Mcl-1 negative tumors. The mean microvessel density value of Mcl-1 positive tumors was significantly higher than that of negative tumors. Mcl-1 expression was significantly increased in colorectal cancer, also associated with tumor stage, lymph node metastasis, and poor survival. These results indicate Mcl-1 is associated with tumor progression through its inhibition of apoptosis and enhancement of angiogenesis in colorectal cancer. PMID:25628923

Lee, Wan-Sik; Park, Young-Lan; Kim, Nuri; Oh, Hyung-Hoon; Son, Dong-Jun; Kim, Mi-Young; Oak, Chan-Young; Chung, Cho-Yun; Park, Hyung-Chul; Kim, Jong-Sun; Myung, Dae-Seong; Cho, Sung-Bum; Kim, Hyun-Soo; Joo, Young-Eun

2015-01-01

353

Comparison of Expression Profiles of Metastatic versus Primary Mammary Tumors in MMTV-Wnt-1 and MMTV-Neu Transgenic Mice  

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Full Text Available Distant metastases of human breast cancers have been suggested to be more different from each other than from their respective primary tumors, based on expression profiling. The mechanism behind this lack of similarity between individual metastases is not known. We used cDNA microarrays to determine the expression profiles of pulmonary metastases and primary mammary tumors in two distinct transgenic models expressing either the Neu or the Wnt-1 oncogene from the mouse mammary tumor virus long terminal repeat (MMTV LTR. We found that pulmonary metastases are similar to each other and to their primary tumors within the same line. However, metastases arising in one transgenic mouse line are very different from either metastases or primary tumors arising in the other line. In addition, we found that, like their primary tumors, lung metastases in Wnt-1 transgenic mice harbor both epithelial and myoepithelial tumor cells and cells that express the putative progenitor cell marker keratin 6. Our data suggest that both gene expression profiles and cellular heterogeneity are preserved after breast cancer has spread to distant sites, and that metastases are similar to each other when their primary tumors were induced by the same oncogene and from the same subset of mammary cells.

Shixia Huang

2008-02-01

354

Obesity and perinatal TCDD exposure increases mammary tumors in FVB mice  

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Risk of breast cancer has been consistently shown to correlate to total lifetime exposure to estrogens. Because both TCDD exposure and the state of obesity interact with the estrogen pathway, we wanted to investigate how TCDD and obesity interact with mammary cancer susceptibili...

355

Obesity and perinatal TCDD exposure increases mammary tumor incidence in FVB mice  

Science.gov (United States)

Breast cancer risk consistently correlates with total lifetime exposure to estrogens. Because both TCDD and adipocytes impact the estrogen pathway, we examined how TCDD and obesity interact to alter mammary cancer susceptibility. At 12.5 days post conception, we exposed FVB fema...

356

Oligomer procyanidins (F2) isolated from grape seeds inhibits tumor angiogenesis and cell invasion by targeting HIF-1? in vitro.  

Science.gov (United States)

Overexpression of hypoxia-inducible factor-1 (HIF-1) ?, a transcription factor which immortalizes tumors by inducing expression of the genes involved in cell survival, migration and angiogenesis, is closely associated with poor prognosis, increased risk of metastasis and increased mortality. Oligomer procyanidins (F2), a natural fraction from grape seeds, has been demonstrated to have antioxidant and antitumor activities, however the antitumor effect of F2 targeting HIF-1? remains unknown. The present study showed that F2 markedly decreased HIF-1? and the expression of its target genes in cancer cells through inactivating the EGFR-PI3K-AKT-mTOR and MAPK-ERK1/2 pathways. Moreover, F2 suppressed vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 expressions, followed by the inhibition of tumor angiogenesis and cell invasion in a HIF-1?-dependent manner. Collectively, these findings indicate that the antitumor effect of F2 is, at least in part, mediated by suppressing HIF-1?-dependent pathway, and suggest that F2 may be a potentially useful agent for treatment of human cancer. PMID:25385044

Zheng, Hong Li; Yang, Jingyu; Hou, Yue; Sun, Baoshan; Zhang, Qingchun; Mou, Yanhua; Wand, Lihui; Wu, Chunfu