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Genetic Deletion of Microsomal Prostaglandin E Synthase-1 Suppresses Mouse Mammary Tumor Growth and Angiogenesis.  

UK PubMed Central (United Kingdom)

The cyclooxygenase/prostaglandin (COX/PG) signaling pathway is of central importance in inflammation and neoplasia. COX inhibitors are widely used for analgesia and also have demonstrated activity for cancer prophylaxis. However, cardiovascular toxicity associated with this drug class diminishes their clinical utility and motivates the development of safer approaches both for pain relief and cancer prevention. The terminal synthase microsomal PGE synthase-1 (mPGES-1) has attracted considerable attention as a potential target. Overexpression of mPGES-1 has been observed in both colorectal and breast cancers, and gene knockout and overexpression approaches have established a role for mPGES-1 in gastrointestinal carcinogenesis. Here we evaluate the contribution of mPGES-1 to mammary tumorigenesis using a gene knockout approach. Mice deficient in mPGES-1 were crossed with a strain in which breast cancer is driven by overexpression of human epidermal growth factor receptor 2 (HER2/neu). Loss of mPGES-1 was associated with a substantial reduction in intramammary PGE2 levels, aromatase activity, and angiogenesis in mammary glands from HER2/neu transgenic mice. Consistent with these findings, we observed a significant reduction in multiplicity of tumors ? 1mm in diameter, suggesting that mPGES-1 contributes to mammary tumor growth. Our data identify mPGES-1 as a potential anti-breast cancer target.

Howe LR; Subbaramaiah K; Kent CV; Zhou XK; Chang SH; Hla T; Jakobsson PJ; Hudis CA; Dannenberg AJ

2013-04-01

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Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice.  

UK PubMed Central (United Kingdom)

Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which ephrin-A1 regulates angiogenesis. Furthermore, ephrin-A1 knockdown diminished, whereas overexpression of ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread.

Brantley-Sieders DM; Fang WB; Hwang Y; Hicks D; Chen J

2006-11-01

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Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice.  

Science.gov (United States)

Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which ephrin-A1 regulates angiogenesis. Furthermore, ephrin-A1 knockdown diminished, whereas overexpression of ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread. PMID:17079451

Brantley-Sieders, Dana M; Fang, Wei Bin; Hwang, Yoonha; Hicks, Donna; Chen, Jin

2006-11-01

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

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

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

2011-01-01

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Multiple Delivery of siRNA against Endoglin into Murine Mammary Adenocarcinoma Prevents Angiogenesis and Delays Tumor Growth  

Science.gov (United States)

Endoglin is a transforming growth factor-? (TGF- ?) co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA) molecules against endoglin in vitro and in vivo. Therapeutic potential in vitro was assessed in human and murine endothelial cells (HMEC-1, 2H11) by determining endoglin expression level, cell proliferation and tube formation. In vivo, the therapeutic potential of siRNA molecules was evaluated in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could not be used as single treatment, but as an adjunct to the established cytotoxic treatment approaches.

Dolinsek, Tanja; Markelc, Bostjan; Sersa, Gregor; Coer, Andrej; Stimac, Monika; Lavrencak, Jaka; Brozic, Andreja; Kranjc, Simona; Cemazar, Maja

2013-01-01

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Angiogenesis and tumor metastasis.  

UK PubMed Central (United Kingdom)

Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents.

Zetter BR

1998-01-01

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Angiogenesis and tumor metastasis.  

Science.gov (United States)

Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents. PMID:9509272

Zetter, B R

1998-01-01

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Role of Bone Marrow-Derived Stem Cells on Mammary Tumor Angiogenesis, Growth and Metastasis, and the Influence of VEGF-A and PIGF on Their Recruitment.  

Science.gov (United States)

The goal of this CDA was to investigate the regulation of Endothelial precursor cells by endothelial cell specific cytokines in mammary tumors. Initial studies anticipated a critical role of VEGF and PlGF, based on their ability to promote survival signal...

L. E. Benjamin

2005-01-01

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Interleukin-8 expression associated with canine mammary tumors.  

UK PubMed Central (United Kingdom)

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.

Zuccari DA; Castro R; Gelaleti GB; Mancini UM

2011-01-01

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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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Pten in Stromal Fibroblasts Suppresses Mammary Epithelial Tumors  

Science.gov (United States)

SUMMARY The tumor stroma is believed to contribute to some of the most malignant characteristics of epithelial tumors. However, signaling between stromal and tumor cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumors. This was associated with the massive remodeling of the extra-cellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumors ameliorated disruption of the tumor microenvironment and was sufficient to decrease tumor growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumor stroma of breast cancer patients. These findings identify the Pten-Ets2 axis as a critical stroma-specific signaling pathway that suppresses mammary epithelial tumors.

Trimboli, Anthony J.; Cantemir-Stone, Carmen Z.; Li, Fu; Wallace, Julie A.; Merchant, Anand; Creasap, Nicholas; Thompson, John C.; Caserta, Enrico; Wang, Hui; Chong, Jean-Leon; Naidu, Shan; Wei, Guo; Sharma, Sudarshana M.; Stephens, Julie A.; Fernandez, Soledad A.; Gurcan, Metin N.; Weinstein, Michael B.; Barsky, Sanford H.; Yee, Lisa; Rosol, Thomas J.; Stromberg, Paul C.; Robinson, Michael L.; Pepin, Francois; Hallett, Michael; Park, Morag; Ostrowski, Michael C.; Leone, Gustavo

2009-01-01

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Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.  

UK PubMed Central (United Kingdom)

Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.

Wallace JA; Li F; Balakrishnan S; Cantemir-Stone CZ; Pecot T; Martin C; Kladney RD; Sharma SM; Trimboli AJ; Fernandez SA; Yu L; Rosol TJ; Stromberg PC; Lesurf R; Hallett M; Park M; Leone G; Ostrowski MC

2013-01-01

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Imaging Key Biomarkers of Tumor Angiogenesis  

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

Marina V. Backer, Joseph M. Backer

2012-01-01

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INHIBITION OF ANGIOGENESIS AND TUMOR METASTASIS  

UK PubMed Central (United Kingdom)

The present invention relates to an anti L1-CAM antibody for use in a method for the treatment of a disease in a patient which can be treated by inhibition of angiogenesis, wherein the administration of said anti L1-CAM antibody results in the inhibition of angiogenesis and/or tumor metastasis.

ALTEVOGT PETER; ISSA YASMIN; BECKHOVE PHILIPP; NUMMER DANIEL

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Nanotechnology-mediated targeting of tumor angiogenesis  

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Full Text Available Abstract Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity to the drugs, and provide means for selective targeting of the tumor tissue and vasculature. The plethora of nanovectors available, in addition to the various methods available to combine them with anti-angiogenic drugs, allows researchers to fine-tune the pharmacological profile of the drugs ad infinitum. Use of nanovectors has also opened up novel avenues for non-invasive imaging of tumor angiogenesis. Herein, we review the types of nanovector and therapeutic/diagnostic agent combinations used in targeting tumor angiogenesis.

Banerjee Deboshri; Harfouche Rania; Sengupta Shiladitya

2011-01-01

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Retroviruses are believed to induce tumors by acting as insertional mutagens that activate expression of cellular protooncogenes. Indeed, almost 90% of mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/He mice show upregulation of Int protooncogenes. We have analyzed three different MMT...

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

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Principles of treatment for mammary gland tumors.  

Science.gov (United States)

The mammary glands are frequent locations for the development of tumors. In the dog and cat, early detection and rapid therapy are necessary to prevent both local and distant metastasis. In the dog, this disease can have a range of biologic behaviors, whereas in the cat it is almost always an extremely aggressive disease. Treatment options depend on tumor staging and can include surgery, radiation therapy, chemotherapy, or a combination. As we become better at early diagnosis and are able to implement aggressive therapy, we are becoming more and more successful in the treatment of this disease. In the following article, we will discuss current thoughts surrounding the diagnosis and treatment options for both canine and feline mammary gland tumors. PMID:12831071

Novosad, C Andrew

2003-05-01

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Different role of COX-2 and angiogenesis in canine inflammatory and non-inflammatory mammary cancer.  

Science.gov (United States)

Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are the most aggressive and fatal types of mammary cancer, and both have a very poor prognosis and low survival rate. Human IBC is characterised by exacerbated angiogenesis, lymphangiogenesis, and lymphangiotropism. Lymphangiotropism is also characteristic of IMC, but microvascular density (MVD) and lymphangiogenesis have not been previously studied in canine IMC. In this study immunohistochemical expression of several angiogenesis-related factors (cyclooxygenase [COX]-2, vascular endothelial growth factors A and D [VEGF-A, VEGF-D], and vascular endothelial growth factor receptor 3 [VEGFR-3]), MVD, lymphatic proliferation index (LPI), and Ki-67 tumour proliferation index (PI) were studied in 21 canine IMC samples, 20 canine high-grade malignant non-IMC mammary tumours (MMTs), and four normal mammary gland samples (NMGs). All mammary neoplasms were histologically categorised as grade III. COX-2 values were also analysed by RT-PCR in seven IMCs, six MMTs and four NMGs. The expressions of COX-2, VEGF-A, and VEGF-D were significantly higher in IMC, MVD and LPI tumours, but not PI. In MMTs, COX-2 immunoexpression was significantly associated with VEGF-A, while in IMCs COX-2 was associated with VEGF-D (lymphangiogenic factor), its receptor VEGFR-3, and LPI. These results suggested that lymphangiogenic pathway stimulation isa specific role of COX-2 in IMC angiogenesis, which justifies the use of COX-2-based targeted palliative therapies in dogs. The exacerbated angiogenesis and lymphangiogenesis and the increased expression of angiogenesis-related factors further support canine IMC as a natural model for the study of human IBC. PMID:23489848

Clemente, Mónica; Sánchez-Archidona, Ana Rodríguez; Sardón, David; Díez, Lucía; Martín-Ruiz, Asunción; Caceres, Sara; Sassi, Francesco; Dolores Pérez-Alenza, M; Illera, Juan C; Dunner, Susana; Peña, Laura

2013-03-11

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Fungal polysaccharopeptide inhibits tumor angiogenesis and tumor growth in mice.  

UK PubMed Central (United Kingdom)

Angiogenesis is crucial to tumor growth and metastasis, and interruption of this process is a prime avenue for therapeutic intervention of tumor proliferation. The present study has made use of the S180 tumor-bearing mouse model to investigate the polysaccharopeptide, PSP, isolated from the edible mushroom Coriolus versicolor, a herbal medicine known for its anti-angiogenesis properties. Quantitative analysis of microcorrosion casting of the tumor tissue showed more angiogenic features such as dense sinusoids and hot spots, in control (untreated) than in PSP-treated animals. Immunostaining of tumor tissues with antibody against the endothelial cell marker (Factor VIII) demonstrated a positive correlation in that both the vascular density and tumor weight were lower in mice treated with PSP. Morphometric analysis of corrosion casts revealed that, even though the total amount of new vessel production was reduced, the basic tumor type-specific vascular architecture was retained. However, the expression of vascular endothelial cell growth factor (VEGF) in these tumors was suppressed. In conclusion, anti-angiogenesis should be one of the pathways through which PSP mediated its anti-tumor activity.

Ho JC; Konerding MA; Gaumann A; Groth M; Liu WK

2004-07-01

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Cytogenetic studies in a canine mammary tumor.  

Science.gov (United States)

In a 9-year-old female dog (Basset Artesian Normand) with a mammary adenocarcinoma, cytogenetic evaluation of tumor cells showed a chromosome number of 76 in most metaphases (95%). The following abnormalities were found: symmetric metacentric chromosomes 1 and 6, centric fusion 3/38, a marker X-chromosome (Xmar) and a biarmed small marker chromosome (mar). In the remaining metaphases (5%) there were additional biarmed marker chromosomes present. PMID:2357690

Mayr, B; Schleger, W; Kalat, M; Schweiger, P; Reifinger, M; Eisenmenger, E

1990-07-01

 
 
 
 
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Cytogenetic studies in a canine mammary tumor.  

UK PubMed Central (United Kingdom)

In a 9-year-old female dog (Basset Artesian Normand) with a mammary adenocarcinoma, cytogenetic evaluation of tumor cells showed a chromosome number of 76 in most metaphases (95%). The following abnormalities were found: symmetric metacentric chromosomes 1 and 6, centric fusion 3/38, a marker X-chromosome (Xmar) and a biarmed small marker chromosome (mar). In the remaining metaphases (5%) there were additional biarmed marker chromosomes present.

Mayr B; Schleger W; Kalat M; Schweiger P; Reifinger M; Eisenmenger E

1990-07-01

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Cytologic differentiation of benign from malignant canine mammary tumors.  

UK PubMed Central (United Kingdom)

Cytologic and histologic examination of 91 canine mammary masses was performed by two cytologists and two histopathologists. Ten important cytologic criteria of malignancy for canine mammary tumors were identified. A cytologic grading system for differentiation of benign from malignant mammary tumors was proposed using these criteria. With this system, approximately one fourth of the malignant mammary tumors were given a concordant cytologic diagnosis. Approximately one-half of the benign masses were given a concordant cytologic diagnosis by the two cytologists. One-half of all the tumors examined were given inconclusive cytologic diagnoses by both cytologists. The cytologic identification of spindle cells did not differentiate complex and mixed mammary tumors from simple tumors. Only five of the animals studied died of mammary cancer, precluding a critical analysis of the cytologic criteria for prediction of cancer mortality.

Allen SW; Prasse KW; Mahaffey EA

1986-11-01

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Granular-cell tumor: A rare variant of mammary tumor  

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

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

2008-01-01

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A new in vitro assay for human tumor angiogenesis: three-dimensional human tumor angiogenesis assay.  

UK PubMed Central (United Kingdom)

BACKGROUND: A human tissue-based angiogenesis assay is needed to study the biology of angiogenesis in human tumor tissue and to tailor drug selection for patients. METHODS: Fragments of tumor tissue are embedded in fibrin gels containing medium 199, endothelial growth medium, fetal bovine serum, and epsilon-aminocaproic acid. Tumor implants sprout angiogenic vessels that progressively grow into the fibrin matrix. The differential growth pattern of tumor cells and angiogenic vessels in the fibrin gel matrix separates the angiogenic vessels and the tumor stroma into independently observable regions (vessel and tumor compartments). The reproducibility of the assay was tested by using fresh tissue obtained from human tumor xenografts (IMR-32 [neuroblastoma], MDA-MB-231 [breast cancer], and LNCaP [prostate cancer]) grown in nude mice and from fresh surgical breast and thyroid cancer specimens. RESULTS: All tumor fragments studied showed angiogenic sprouting into the fibrin matrix. This created an angiogenic vessel compartment, which was separate from the tumor fragment. The capillary nature of sprouting was confirmed histologically by factor VIII immunohistochemistry. The angiogenic growth fraction was >80% in all groups studied. CONCLUSIONS: This assay may allow functional assessment of the angiogenic potential of human tumors and simultaneous evaluation of a therapeutic agent's antitumor and antiangiogenic effects by virtue of its dual-compartmental structure.

Gulec SA; Woltering EA

2004-01-01

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GH-producing mammary tumors in two dogs with acromegaly.  

UK PubMed Central (United Kingdom)

Two intact female dogs were admitted for growing mammary tumors. They had symptoms of acromegaly including weight gain, enlargement of the head, excessive skin folds, and inspiratory stridor. Serum concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-I), and insulin were elevated in the two cases. From these findings, both dogs were diagnosed with acromegaly. In case 1, the GH, IGF-I, and insulin levels subsided after removal of the focal benign mammary tumors and ovariohysterectomy. In case 2, those levels subsided after removal of only focal mammary carcinoma. In both cases, immunohistochemical investigations for GH were positive in the mammary tumor cells but not in the normal mammary glands. We concluded that GH-producing mammary tumors caused the present acromegaly.

Murai A; Nishii N; Morita T; Yuki M

2012-06-01

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Zebrafish embryo, a tool to study tumor angiogenesis.  

UK PubMed Central (United Kingdom)

Zebrafish (Danio rerio) represents a powerful model system in cancer research. Recent observations have shown the possibility to exploit zebrafish to investigate tumor angiogenesis, a pivotal step in cancer progression and target for anti-tumor therapies. Experimental models have been established in zebrafish adults, juveniles, and embryos, each one with its own advantages and disadvantages. Novel genetic tools and high resolution in vivo imaging techniques are also becoming available in zebrafish. It is anticipated that zebrafish will represent an important tool for chemical discovery and gene targeting in tumor angiogenesis. This review focuses on the recently developed tumor angiogenesis models in zebrafish, with particular emphasis to tumor engrafting in zebrafish embryos.

Tobia C; De Sena G; Presta M

2011-01-01

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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; Masahito Hagio; Toshiyuki Ishiwata

2013-01-01

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Nestin: a novel angiogenesis marker and possible target for tumor angiogenesis.  

UK PubMed Central (United Kingdom)

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.

Matsuda Y; Hagio M; Ishiwata T

2013-01-01

29

[CT and MRI imaging in tumoral angiogenesis].  

UK PubMed Central (United Kingdom)

Angiogenesis is the process of activating dormant endothelial cells to form new vessels, after stimulation and it is essential in tumor growth. In many types of cancer, angiogenesis results from the activation of oncogenes that stimulate the production of Vascular Endothelial Growth Factor (VEGF). However, these newly formed vessels have a great number of abnormalities: increased density of fragile and hyper-permeable microvessels, arterial-venous shunts, caliber abnormalities and flow instabilities susceptible to flow direction inversion according to interstitial pressure. Anti-angiogenic treatments inhibit VEGF activity, perceived as structural and functional normalization of the microvascular pattern, such as reduced density of microvessels and restored morphology of the remaining ones. Conventional imaging techniques are not sensible to these changes, at best they show tumor size stabilization, hence the need of new techniques. Microvascularization imaging can be achieved by detecting functional disturbances to blood flow and not by showing the microvasculature per se. These techniques are based in quantifying the enhancement in tumor due to the passage of contrast agent after injection or protons labeled by a magnetic field. Through these measurements, one can derive interstitial and blood volumes as well as the tissue perfusion and capillary wall permeability. Microvascular imaging has greatly benefited from the improvements seen in CT and MRI equipment allowing large volume coverage with high spatial and temporal resolutions as from the evolutions in the methods to calculate, present and compare maps of the microcirculation and it's heterogeneity. However, software to analyze microvascularization are still rare, limiting the technique's application and validation in large scale. Nevertheless, imaging of the microcirculation is useful throughout the care of the oncological patient: it can reinforce the suspicious nature of a lesion, suggest anti-angiogenic treatment efficacy in hypervascular lesions, and show early treatment response before morphological changes as in RECIST criteria.

de Bazelaire C; Calmon R; Chapellier M; Pluvinage A; Frija J; de Kerviler E

2010-01-01

30

[CT and MRI imaging in tumoral angiogenesis].  

Science.gov (United States)

Angiogenesis is the process of activating dormant endothelial cells to form new vessels, after stimulation and it is essential in tumor growth. In many types of cancer, angiogenesis results from the activation of oncogenes that stimulate the production of Vascular Endothelial Growth Factor (VEGF). However, these newly formed vessels have a great number of abnormalities: increased density of fragile and hyper-permeable microvessels, arterial-venous shunts, caliber abnormalities and flow instabilities susceptible to flow direction inversion according to interstitial pressure. Anti-angiogenic treatments inhibit VEGF activity, perceived as structural and functional normalization of the microvascular pattern, such as reduced density of microvessels and restored morphology of the remaining ones. Conventional imaging techniques are not sensible to these changes, at best they show tumor size stabilization, hence the need of new techniques. Microvascularization imaging can be achieved by detecting functional disturbances to blood flow and not by showing the microvasculature per se. These techniques are based in quantifying the enhancement in tumor due to the passage of contrast agent after injection or protons labeled by a magnetic field. Through these measurements, one can derive interstitial and blood volumes as well as the tissue perfusion and capillary wall permeability. Microvascular imaging has greatly benefited from the improvements seen in CT and MRI equipment allowing large volume coverage with high spatial and temporal resolutions as from the evolutions in the methods to calculate, present and compare maps of the microcirculation and it's heterogeneity. However, software to analyze microvascularization are still rare, limiting the technique's application and validation in large scale. Nevertheless, imaging of the microcirculation is useful throughout the care of the oncological patient: it can reinforce the suspicious nature of a lesion, suggest anti-angiogenic treatment efficacy in hypervascular lesions, and show early treatment response before morphological changes as in RECIST criteria. PMID:19858045

de Bazelaire, C; Calmon, R; Chapellier, M; Pluvinage, A; Frija, J; de Kerviler, E

2010-01-01

31

Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis  

Directory of Open Access Journals (Sweden)

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

Susan R. Ross

2010-01-01

32

Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.  

Science.gov (United States)

Metastatic disease is the primary cause of death in breast cancer, the most common malignancy in Western women. Loss of E-cadherin is associated with tumor metastasis, as well as with invasive lobular carcinoma (ILC), which accounts for 10%-15% of all breast cancers. To study the role of E-cadherin in breast oncogenesis, we have introduced conditional E-cadherin mutations into a mouse tumor model based on epithelium-specific knockout of p53. Combined loss of E-cadherin and p53 resulted in accelerated development of invasive and metastatic mammary carcinomas, which show strong resemblance to human ILC. Moreover, loss of E-cadherin induced anoikis resistance and facilitated angiogenesis, thus promoting metastatic disease. Our results suggest that loss of E-cadherin contributes to both mammary tumor initiation and metastasis. PMID:17097565

Derksen, Patrick W B; Liu, Xiaoling; Saridin, Francis; van der Gulden, Hanneke; Zevenhoven, John; Evers, Bastiaan; van Beijnum, Judy R; Griffioen, Arjan W; Vink, Jacqueline; Krimpenfort, Paul; Peterse, Johannes L; Cardiff, Robert D; Berns, Anton; Jonkers, Jos

2006-11-01

33

Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.  

UK PubMed Central (United Kingdom)

Metastatic disease is the primary cause of death in breast cancer, the most common malignancy in Western women. Loss of E-cadherin is associated with tumor metastasis, as well as with invasive lobular carcinoma (ILC), which accounts for 10%-15% of all breast cancers. To study the role of E-cadherin in breast oncogenesis, we have introduced conditional E-cadherin mutations into a mouse tumor model based on epithelium-specific knockout of p53. Combined loss of E-cadherin and p53 resulted in accelerated development of invasive and metastatic mammary carcinomas, which show strong resemblance to human ILC. Moreover, loss of E-cadherin induced anoikis resistance and facilitated angiogenesis, thus promoting metastatic disease. Our results suggest that loss of E-cadherin contributes to both mammary tumor initiation and metastasis.

Derksen PW; Liu X; Saridin F; van der Gulden H; Zevenhoven J; Evers B; van Beijnum JR; Griffioen AW; Vink J; Krimpenfort P; Peterse JL; Cardiff RD; Berns A; Jonkers J

2006-11-01

34

Classification and grading of canine malignant mammary tumors  

Directory of Open Access Journals (Sweden)

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

Abbas Tavasoly; Hannaneh Golshahi; Annahita Rezaie; Mohammad Farhadi

2013-01-01

35

The novel tubulin-binding drug BTO-956 inhibits R3230AC mammary carcinoma growth and angiogenesis in Fischer 344 rats.  

UK PubMed Central (United Kingdom)

BTO-956 [methyl-3,5-diiodo-4-(4'-methoxyphenoxy)benzoate], a novel tubulin-binding drug and thyroid hormone analogue, was originally found to inhibit human carcinoma cell proliferation in vitro and to have potent growth delay activity in human breast and ovarian carcinoma xenografts in nude mice. Here we report that BTO-956 given to Fischer 344 rats also inhibits corneal angiogenesis and the growth and neovascularization of the R3230Ac rat mammary carcinoma tumor implanted in skin-fold window chambers. Hydron pellets containing recombinant human basic fibroblast growth factor (50 ng) and Sucralfate (20 microg) were implanted into surgically created corneal micropockets (day 0). BTO-956 was administrated by oral gavage (500 mg/kg, twice a day for 6 days) on days 1-6 (controls received vehicle alone). On day 7, rats received retrograde infusions of India ink via the thoracic aorta to visualize the corneal vasculature. Digitized images of slide-mounted corneas from control and treated animals were taken with a microscope. For the tumor growth and angiogenesis study, small pieces of R3230Ac tumor from a donor rat were implanted into surgically prepared window chambers (day 0). BTO-956 was given during days 5-11, and images of the tumors and their vasculature were recorded on day 12. No body weight loss was observed in either study. BTO-956 significantly inhibited corneal angiogenesis (by 50-80%), as assessed by measurements of limbal circumference displaying neovascularization, vessel length, vascularized area, and vascular area density. In the window chamber assay, tumors from treated animals were >50% smaller than tumors in control animals. In addition, vascular length densities in peripheral tumor zones were 30% less in treated compared with control animals. Together, these findings demonstrate that BTO-956 can inhibit angiogenesis induced by a growth factor in the rat cornea and in the peripheral area of implanted tumors, where tumor angiogenesis is most active.

Shan S; Lockhart AC; Saito WY; Knapp AM; Laderoute KR; Dewhirst MW

2001-08-01

36

A two-dimensional model for studying tumor angiogenesis inhibitors.  

UK PubMed Central (United Kingdom)

Inhibition of angiogenesis can attenuate tumor growth. Hence, mathematical modeling of tumor-induced angiogenesis can be a tool for predicting outcome of angiogenesis inhibitors. We have generated a two-dimensional cornea model of angiogenesis and have tested the effectiveness of the inhibitor through testing representative examples. The effects of thrombospondin and the way it interacts in the cornea with the endothelial cells and tumor angiogenic factors were examined. We were then able to define the inhibitor's role specific to our benchmark model. Finally, a thorough sensitivity analysis was performed to verify baseline values and determine the precise effects of the different parameters. Our findings can be used to design strategies involving manufacturing inhibitors to regulate the angiogenesis process.

Gao P; Yang JL; Wang H; Wu XD; Jiao SC

2013-06-01

37

[Angiogenesis--principles and significance in urologic tumors].  

Science.gov (United States)

Physiologically, angiogenesis in adults is a controlled process which plays a role, for example, in wound healing. Pathological angiogenesis is observed in tumor formation and represents a multifactorial process, in which specific angiogenic factors, as well as growth factors, extracellular matrix proteins and cell adhesion molecules are involved. Tumor growth is characterized by an imbalance in favor of angiogenic over angiogenesis-inhibiting factors. Some of the most frequently examined angiogenic factors are vascular endothelial growth factor, acidic/basic fibroblast growth factors and the platelet-derived endothelial cell growth factor. The most important angiogenesis inhibitors are angiostatin and thrombospondin. To date, the clinical relevance of tumor angiogenesis has been shown for several human tumors. For most urological tumors, the grade of tumor vessel formation, measured as microvessel density, has been associated with metastases, tumor growth and clinical course. The prognostic value of this feature of malignant growth seems to be higher than that of most of the classical and newer prognostic factors. Systematic investigations of tumor angiogenesis are becoming increasingly relevant for diagnostic and therapeutic strategies and offer opportunities for the development of new specific therapeutic approaches in clinical oncology. PMID:8999626

Strohmeyer, D; Strohmeyer, T

1996-09-01

38

Experimental studies on mammary tumors in rats  

International Nuclear Information System (INIS)

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

1989-01-01

39

INHIBITION OF ANGIOGENESIS AND TUMOR METASTASIS  

UK PubMed Central (United Kingdom)

The present invention relates to an anti L1-CAM antibody for use in a method for the treatment of a disease in a patient which can be treated by inhibition of angiogenesis, wherein the administration of said anti L1-CAM antibody results in the inhibition of angiogenesis.

ALTEVOGT PETER; ISSA YASMIN; BECKHOVE PHILIPP; NUMMER DANIEL

40

Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis  

Science.gov (United States)

The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2?/?) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2?/? mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2?/? mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2?/? tumors contained similar numbers of mitotic cells, but IRS-2?/? tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2?/? mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1?/? tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.

Nagle, Julie A.; Ma, Zhefu; Byrne, Maura A.; White, Morris F.; Shaw, Leslie M.

2004-01-01

 
 
 
 
41

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

Science.gov (United States)

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

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

2003-01-01

42

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

UK PubMed Central (United Kingdom)

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

Sunamura M; Duda DG; Ghattas MH; Lozonschi L; Motoi F; Yamauchi J; Matsuno S; Shibahara S; Abraham NG

2003-01-01

43

Chemokines as mediators of tumor angiogenesis and neovascularization  

Science.gov (United States)

Chemokines are a superfamily of structurally homologous heparin-binding proteins that influence tumor growth and metastasis. Several members of the CXC and CC chemokine families are potent inducers of neovascularization, whereas a subset of the CXC chemokines are potent inhibitors. In this paper, we review the current literature regarding the role of chemokines as mediators of tumor angiogenesis and neovascularization.

Keeley, Ellen C.; Mehrad, Borna; Strieter, Robert M.

2010-01-01

44

Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats.  

UK PubMed Central (United Kingdom)

BACKGROUND: As the worldwide breast cancer burden increases, non-invasive tools, such as ultrasonography and thermography are being increasingly sought after. N-methyl-N-nitrosourea-induced rat mammary tumors are important tools to investigate the usefulness of such imaging techniques. OBJECTIVE: This study aimed to integrate both ultrasonographic and thermographic approaches to the vascularization and the superficial temperature of chemically-induced rat mammary tumors. MATERIALS AND METHODS: Twenty-five female Sprague-Dawley rats were divided into two groups: group I (intraperitoneally administered with N-methyl-N-nitrosourea) and group II (control group). Thirty-five weeks after the administration of the carcinogen, mammary tumors were evaluated using Power Doppler, B Flow and Contrast-enhanced ultrasound, thermography and histology analyses. RESULTS: Group I animals showed an average of 2.5 mammary tumors per animal, mostly papillary and cribriform non-invasive carcinomas. B Flow detected higher counts of colour pixels than Power Doppler. Contrast-enhanced ultrasound analysis showed a centripetal enhancement order of contrast agent and clear margins. Maximum tumor temperature and thermal amplitude determined by thermography were significantly correlated with tumor volume and with color pixel density, determined by Power Doppler. CONCLUSION: B Flow was more sensitive than Power Doppler in detecting tumor vessels, but Power Doppler correlates with thermographic data concerning superficial temperature and may reflect tumor angiogenesis.

Faustino-Rocha AI; Silva A; Gabriel J; Teixeira-Guedes CI; Lopes C; Gil da Costa R; Gama A; Ferreira R; Oliveira PA; Ginja M

2013-07-01

45

Occurrence of mammary tumors in beagls given radium-226  

Energy Technology Data Exchange (ETDEWEB)

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

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

1994-06-01

46

Prognostic significance of tumor-induced angiogenesis in colorectal cancer  

Directory of Open Access Journals (Sweden)

Full Text Available Introduction Tumor-induced angiogenesis is a central pathogenic step in the process of tumor growth, invasion and metastasis. The aim of this study was to analyze the quantitative expression of angiogenesis in colorectal carcinoma and to determine if and how angiogenesis correlates with other clinicopathologic factors and prognosis. Material and methods This study included 40 patients who underwent curative resection of colorectal cancer at the Department of Surgery of the Senta General Hospital with complete 5 years follow-up or till death. Microvessels were identified immunohistochemically using monoclonal CD31 antibodies. The microvessel count was assessed by means of stereology with test grid M42, as well as vascular surface density in the stromal volume at the invasive front of colorectal cancer. Results Tumor-induced angiogenesis count of colorectal carcinomas statistically significantly correlated with stage of disease and histologic tumor grade There was no significant correlation between intratumoral microvessel density and sex and age of patients, localization and histologic tumor type Five-year survival rate in patients with hypervascular colorectal tumors was statistically significantly lower than in patients with hypovascular tumors Thus, microvessel density in colorectal cancer is an independent prognostic factor, but its significance is less than the importance concerning stage of disease and histologic grade of tumor. Conclusions Intratumoral microvessel density quantification in histologic specimens of colorectal carcinoma reflects the biological malignant potential of tumors and may be a useful additional predictive marker. Assessment of intratumoral microvessel count might be used for determining the pathologic stage when adjuvant therapy is concerned. Microvessel density in tumor specimens is valuable in stratifying patients in planning appropriate adjuvant and antiangiogenic therapy after surgery.

Fenyvesi Attila

2003-01-01

47

Mammary tumor occurrence in beagles given {sup 239}Pu  

Energy Technology Data Exchange (ETDEWEB)

Comparison of 120 young adult female beagles given 0.026 to 106 kBq {sup 239}Pu kg{sup -1} by intravenous injection and 63 comparable female control beagles showed that there were no significant differences in the risk of mammary tumor appearance between the two groups. This was the case for benign tumors only, for malignant tumors only, and for both malignant and benign tumors considered together. for malignant tumors the observed number was 73 as compared with 69 expected; for benign tumors, there were 131 observed and 126 expected; for all tumors (separate analysis, not just the addition of malignant plus benign), there were 199 observed and 199 expected. Chi-square analysis indicated that the p values for all these comparisons were >0.05. There were 45 controls (71.4%) with any tumor vs. 67 dogs (55.8%) given Pu (95% C.I. = 46.9% to 86.2%). No significant differences could be established (Kaplan-Meier analysis) between these two groups for survival age at diagnosis of the first mammary tumor, 11.75 {+-} 0.30 y for dogs given Pu vs. 11.90 {+-} 0.36 y for controls. We reported previously that differences in mammary cancer occurrence had been identified between this same group of control dogs and 57 female beagles given {sup 226}Ra as young adults. The present study appears to support the earlier conclusion that something other than alpha irradiation of the skeleton (both {sup 226}Ra and {sup 239}Pu deposit in bone) seems to affect the appearance of mammary cancers, since internally deposited {sup 226}Ra does appear to induce these malignancies, possibly from initial deposition in mammary tissue of the parent radionuclide or the subsequent concentration in sensitive tissue of its radioactive progeny, {sup 222}Rn or isotopes of polonium, lead, and bismuth, which are absent in the case of {sup 239}Pu. 15 refs., 5 tabs.

Lloyd, R.D.; Bruenger, F.W.; Angus, W. [Univ. of Utah, Salt Lake City, UT (United States)

1995-09-01

48

Mammary tumor occurrence in beagles given 239Pu.  

UK PubMed Central (United Kingdom)

Comparison of 120 young adult female beagles given 0.026 to 106 kBq 239Pu kg-1 by intravenous injection and 63 comparable female control beagles showed that there were no significant differences in the risk of mammary tumor appearance between the two groups. This was the case for benign tumors only, for malignant tumors only, and for both malignant and benign tumors considered together. For malignant tumors the observed number was 73 as compared with 69 expected; for benign tumors, there were 131 observed and 126 expected; for all tumors (separate analysis, not just the addition of malignant plus benign), there were 199 observed and 199 expected. Chi-square analysis indicated that the p values for all these comparisons were > 0.05. There were 45 controls (71.4%) with any tumor vs. 67 dogs (55.8%) given Pu (95% C. I. = 46.9% to 86.2%). No significant differences could be established (Kaplan-Meier analysis) between these two groups for survival age at diagnosis of the first mammary tumor, 11.75 +/- 0.30 y for dogs given Pu vs. 11.90 +/- 0.36 y for controls. We reported previously that differences in mammary cancer occurrence had been identified between this same group of control dogs and 57 female beagles given 226Ra as young adults. The present study appears to support the earlier conclusion that something other than alpha irradiation of the skeleton (both 226Ra and 239Pu deposit in bone) seems to affect the appearance of mammary cancers, since internally deposited 226Ra does appear to induce these malignancies, possibly from initial deposition in mammary tissue of the parent radionuclide or the subsequent concentration in sensitive tissue of its radioactive progeny, 22Rn or isotopes of polonium, lead, and bismuth, which are absent in the case of 239Pu.

Lloyd RD; Bruenger FW; Angus W; Taylor GN; Miller SC

1995-09-01

49

Evaluation of Tumor Angiogenesis by MRI Study Using Iron Nanoparticles  

Directory of Open Access Journals (Sweden)

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.

Fatemeh Rahimi; Shahram Akhlaghpoor; D. Sardari; Mansour Ashoor

2010-01-01

50

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

Directory of Open Access Journals (Sweden)

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

Stanis?aw Szala

2009-01-01

51

Tumor angiogenesis: a new source of pericytes.  

UK PubMed Central (United Kingdom)

Glioblastoma stem cells have been reported to directly contribute to the tumor vasculature by endothelial cell differentiation. Interestingly, a recent study demonstrates that glioblastoma stem cells preferentially differentiate into vascular pericytes to support vasculature function and tumor growth.

Liu AY; Ouyang G

2013-07-01

52

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

International Nuclear Information System (INIS)

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

1979-01-01

53

Intravital imaging of cancer stem cell plasticity in mammary tumors.  

Science.gov (United States)

It is widely debated whether all tumor cells in mammary tumors have the same potential to propagate and maintain tumor growth or whether there is a hierarchical organization. Evidence for the latter theory is mainly based on the ability or failure of transplanted tumor cells to produce detectable tumors in mice with compromised immune systems; however, this assay has lately been disputed to accurately reflect cell behavior in unperturbed tumors. Lineage tracing experiments have recently shown the existence of a small population of cells, referred to as cancer stem cells (CSCs), that maintains and provides growth of squamous skin tumors and intestinal adenomas. However, the lineage tracing techniques used in these studies provide static images and lack the ability to study whether stem cell properties can be obtained or lost, a process referred to as stem cell plasticity. Here, by intravital lineage tracing, we report for the first time the existence of CSCs in unperturbed mammary tumors and demonstrate CSC plasticity. Our data indicate that existing CSCs disappear and new CSCs form during mammary tumor growth, illustrating the dynamic nature of these cells. PMID:23225641

Zomer, Anoek; Ellenbroek, Saskia Inge Johanna; Ritsma, Laila; Beerling, Evelyne; Vrisekoop, Nienke; Van Rheenen, Jacco

2013-03-01

54

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

Directory of Open Access Journals (Sweden)

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

Huan-rong LI

2007-01-01

55

Targeting angiogenesis and the tumor microenvironment.  

UK PubMed Central (United Kingdom)

The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Active contribution of tumor-associated stromal cells to cancer progression has been recognized. Stromal elements consist of the extracellular matrix, fibroblasts of various phenotypes, and a scaffold comprised of immune and inflammatory cells, blood and lymph vessels, and nerves. This review focuses on therapeutic targets in the microenvironment related to tumor endothelium, tumor associated fibroblasts, and the extracellular matrix.

Samples J; Willis M; Klauber-Demore N

2013-10-01

56

Targeting angiogenesis and the tumor microenvironment.  

Science.gov (United States)

The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Active contribution of tumor-associated stromal cells to cancer progression has been recognized. Stromal elements consist of the extracellular matrix, fibroblasts of various phenotypes, and a scaffold comprised of immune and inflammatory cells, blood and lymph vessels, and nerves. This review focuses on therapeutic targets in the microenvironment related to tumor endothelium, tumor associated fibroblasts, and the extracellular matrix. PMID:24012392

Samples, Jennifer; Willis, Monte; Klauber-Demore, Nancy

2013-07-26

57

Experimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors.  

UK PubMed Central (United Kingdom)

Epidemiological and in vitro data have not provided conclusive evidence concerning the involvement of thyroid hormones (THs) on mammary carcinogenesis. We used an in vivo model to assess the relationship between THs, adipose tissue and breast cancer development. Female Sprague?Dawley rats were treated with a dose of 7,12-dimethylbenz(a)anthracene (15 mg/rat) at 55 days of age and were then divided into four experimental groups: hypothyroid rats (HypoT, 0.01% 6-N-propyl-2-thiouracil in drinking water), untreated control (EUT); hyperthyroid rats (HyperT, 0.25 mg/kg/day T4 s.c.) and vehicle-treated control rats. The latency of tumor appearance and the incidence and progression of tumors were determined. At sacrifice, blood samples were collected for hormone determinations and samples of tumor and mammary glands were obtained for immunohistological studies. HypoT rats had retarded growth and an increase in mammary fat. The latency was longer (p<0.0001), the incidence rate was lower (p<0.05) and tumor growth was slower in HypoT rats compared to EUT and HyperT rats. Mitotic index and PCNA immunostaining were similar in all groups. HypoT rats showed increased apoptosis (p<0.05) as evaluated by the apoptotic index and TUNEL staining. No differences in serum prolactin and progesterone were observed. However, circulating estradiol (E2) was significantly lower in HypoT and HyperT rats. Serum leptin levels were reduced in HypoT rats even though the abdominal fat mass was similar in all groups. To note, the leptin level was higher in HypoT rats that developed mammary tumors than the level in non-tumoral HypoT rats. In conclusion, hypothyroidism altered animal growth, breast morphology, body composition, leptin secretion and serum E2 enhancing apoptosis and, consequently, retarding mammary carcinogenesis in rats.

López-Fontana CM; Sasso CV; Maselli ME; Santiano FE; Semino SN; Cuello Carrión FD; Jahn GA; Carón RW

2013-10-01

58

Genetic transmission of viruses that incite mammary tumor in mice.  

UK PubMed Central (United Kingdom)

Electron microscopy, immunofluorescence, and bioassay demonstrated the presence of a mammary tumor inciting virus in untreated mice of three different inbred strains, and in irradiated or urethan-treated mice of two other mouse strains, indicating the ubiquitous nature of this group of viruses. In general these viruses are transmitted vertically by the gametes of the mouse strain in which they naturally occur. The virus is present in every cell, although often in an incomplete form. If a mammary tumor inciting virus is introduced into a different mouse strain, only milkborne transmission will take place, after which the virus is found in a limited number of tissues. It has been speculated that mammary tumor inciting viruses are transmitted as genetic factors of the host strain to which they belong. There is some evidence that a repressor, produced by a regulator gene, controls the rate of release of such a genetically transferred virus. Repression can be abrogated by a carcinogenic treatment. The repressor would also cause resistance to a superinfecting mammary tumor inciting virus by interference with its replication.

Bentvelzen P; Daams JH; Hageman P; Calafat J

1970-09-01

59

Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis  

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The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T ...

Nagle, Julie A.; Ma, Zhefu; Byrne, Maura A.; White, Morris F.; Shaw, Leslie M.

60

Experimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors.  

Science.gov (United States)

Epidemiological and in vitro data have not provided conclusive evidence concerning the involvement of thyroid hormones (THs) on mammary carcinogenesis. We used an in vivo model to assess the relationship between THs, adipose tissue and breast cancer development. Female Sprague?Dawley rats were treated with a dose of 7,12-dimethylbenz(a)anthracene (15 mg/rat) at 55 days of age and were then divided into four experimental groups: hypothyroid rats (HypoT, 0.01% 6-N-propyl-2-thiouracil in drinking water), untreated control (EUT); hyperthyroid rats (HyperT, 0.25 mg/kg/day T4 s.c.) and vehicle-treated control rats. The latency of tumor appearance and the incidence and progression of tumors were determined. At sacrifice, blood samples were collected for hormone determinations and samples of tumor and mammary glands were obtained for immunohistological studies. HypoT rats had retarded growth and an increase in mammary fat. The latency was longer (pPCNA immunostaining were similar in all groups. HypoT rats showed increased apoptosis (p<0.05) as evaluated by the apoptotic index and TUNEL staining. No differences in serum prolactin and progesterone were observed. However, circulating estradiol (E2) was significantly lower in HypoT and HyperT rats. Serum leptin levels were reduced in HypoT rats even though the abdominal fat mass was similar in all groups. To note, the leptin level was higher in HypoT rats that developed mammary tumors than the level in non-tumoral HypoT rats. In conclusion, hypothyroidism altered animal growth, breast morphology, body composition, leptin secretion and serum E2 enhancing apoptosis and, consequently, retarding mammary carcinogenesis in rats. PMID:23912381

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

2013-08-01

 
 
 
 
61

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.

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

2011-01-01

62

Plants as useful agents for angiogenesis and tumor growth prevention  

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Full Text Available Introduction: Angiogenesis, the process of new blood vessel formation from pre-existing vessels, has important physiological roles in embryonic development, female reproduction cycle, and wound healing. It is also crucial for pathological processes in several diseases especially tumor growth and metastasis. Thereby, inhibition of angiogenesis as an addition to the conventional therapies such as chemotherapy and radiotherapy has attracted the attention of scientists. Results: Different studies have shown that botanical derivatives specifically antagonize new vessel formation in tumors without significant toxicity to normal tissues and without major adverse reactions. Furthermore, many studies have revealed that the active ingredients of these natural products inhibit tumor cell proliferation through interference with other physiological pathways such as intracellular signaling pathways. A number of studies have also demonstrated that many traditional foods especially plant derived foods have preventive potential against around one third of cancers. Therefore, plant rich diet can inhibit the progression of many chronic diseases such as malignant solid tumors which are related to angiogenesis.

Hamid-Reza Mohammadi-Motlagh; Kamran Mansouri; Ali Mostafaie

2010-01-01

63

BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors.  

UK PubMed Central (United Kingdom)

Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy.Oncogene advance online publication, 9 September 2013; doi:10.1038/onc.2013.358.

Tsuchida R; Osawa T; Wang F; Nishii R; Das B; Tsuchida S; Muramatsu M; Takahashi T; Inoue T; Wada Y; Minami T; Yuasa Y; Shibuya M

2013-09-01

64

Circulating endothelial cells as biomarkers for angiogenesis in tumor progression.  

UK PubMed Central (United Kingdom)

An increased number of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs) has been reported in cancer patients. CEPs are derived from the bone marrow and will, during angiogenesis, differentiate into endothelial cells. CECs are mature endothelial cells (ECs) released from the vessel intima during physiological endothelial turnover or as a result of tumor treatment. Preclinical studies have shown that during tumor progression, the amount of circulating CECs correlates with angiogenesis. Moreover, there is growing evidence suggesting that CECs and CEPs viability and kinetics correlate with the patient responses to anti-angiogenic therapies. Thus, circulating CECs and CEPs may act as surrogate markers to test putative therapeutic efficacy. Moreover measuring CECs and CEPs may be useful to assess effects of antiangiogenic therapy.

Martin-Padura I; Bertolini F

2009-01-01

65

Inhibition of tumor angiogenesis by globotriaosylceramide immunotargeting.  

UK PubMed Central (United Kingdom)

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

Birklé S; Desselle A; Chaumette T; Gaugler MH; Cochonneau D; Fleurence J; Dubois N; Hulin P; Aubry J; Paris F

2013-04-01

66

beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression.  

UK PubMed Central (United Kingdom)

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of beta1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional beta1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the beta1-integrin-deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as beta1-integrin-null. Animals bearing beta1-integrin-deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, beta1-integrin-deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although beta1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression.

Huck L; Pontier SM; Zuo DM; Muller WJ

2010-08-01

67

beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression.  

Science.gov (United States)

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of beta1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional beta1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the beta1-integrin-deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as beta1-integrin-null. Animals bearing beta1-integrin-deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, beta1-integrin-deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although beta1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression. PMID:20713705

Huck, L; Pontier, S M; Zuo, D M; Muller, W J

2010-08-16

68

?1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression  

Science.gov (United States)

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of ?1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional ?1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the ?1-integrin–deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as ?1-integrin–null. Animals bearing ?1-integrin–deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, ?1-integrin–deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although ?1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression.

Huck, L.; Pontier, S. M.; Zuo, D. M.; Muller, W. J.

2010-01-01

69

Mammary gland tumors in irradiated and untreated guinea pigs  

International Nuclear Information System (INIS)

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

1986-01-01

70

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

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

Thompson Devan E; Siwicky Megan D; Moorehead Roger A

2012-01-01

71

Luminol-based bioluminescence imaging of mouse mammary tumors.  

UK PubMed Central (United Kingdom)

Polymorphonuclear neutrophils (PMNs) are the most abundant circulating blood leukocytes. They are part of the innate immune system and provide a first line of defense by migrating toward areas of inflammation in response to chemical signals released from the site. Some solid tumors, such as breast cancer, also cause recruitment and activation of PMNs and release of myeloperoxidase. In this study, we demonstrate that administration of luminol to mice that have been transplanted with 4T1 mammary tumor cells permits the detection of myeloperoxidase activity, and consequently, the location of the tumor. Luminol allowed detection of activated PMNs only two days after cancer cell transplantation, even though tumors were not yet palpable. In conclusion, luminol-bioluminescence imaging (BLI) can provide a pathway towards detection of solid tumors at an early stage in preclinical tumor models.

Alshetaiwi HS; Balivada S; Shrestha TB; Pyle M; Basel MT; Bossmann SH; Troyer DL

2013-09-01

72

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Angiogenesis plays a critical role in both growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) is an endogenous mediator of tumor angiogenesis. Blocking associations of the VEGF with its corresponding receptors (KDR) have become critical for anti-tumor therapy. Acyclo-peptide ...

Deshayes, Stéphanie; Maurizot, Victor; Clochard, Marie-Claude; Berthelot, Thomas; Baudin, Cécile; Deleris, Gérard

73

Presence of a mouse mammary tumor virus-related antigen in human breast carcinoma cells and its absence from normal mammary epithelial cells.  

UK PubMed Central (United Kingdom)

Antigen(s) related to the major external glycoprotein (gp52) of mouse mammary tumor virus was detected in the human breast cancer cell line MCF-7. No such antigenic determinants were detectable in normal human mammary epithelial cells.

Yang NS; McGrath CM; Furmanski P

1978-11-01

74

Alcohol consumption promotes mammary tumor growth and insulin sensitivity.  

UK PubMed Central (United Kingdom)

Epidemiological data show that in women, alcohol has a beneficial effect by increasing insulin sensitivity but also a deleterious effect by increasing breast cancer risk. These effects have not been shown concurrently in an animal model of breast cancer. Our objective is to identify a mouse model of breast cancer whereby alcohol increases insulin sensitivity and promotes mammary tumorigenesis. Our results from the glucose tolerance test and the homeostasis model assessment show that alcohol consumption improved insulin sensitivity. However, alcohol-consuming mice developed larger mammary tumors and developed them earlier than water-consuming mice. In vitro results showed that alcohol exposure increased the invasiveness of breast cancer cells in a dose-dependent manner. Thus, this animal model, an in vitro model of breast cancer, may be used to elucidate the mechanism(s) by which alcohol affects breast cancer.

Hong J; Holcomb VB; Tekle SA; Fan B; Núñez NP

2010-08-01

75

Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1  

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

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

1995-06-01

76

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

UK PubMed Central (United Kingdom)

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.

Masiero M; Simões FC; Han HD; Snell C; Peterkin T; Bridges E; Mangala LS; Wu SY; Pradeep S; Li D; Han C; Dalton H; Lopez-Berestein G; Tuynman JB; Mortensen N; Li JL; Patient R; Sood AK; Banham AH; Harris AL; Buffa FM

2013-08-01

77

Radioiodinated VEGF to image tumor angiogenesis in a LS180 tumor xenograft model  

International Nuclear Information System (INIS)

[en] Introduction: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF121, which displays high binding affinity for KDR, and VEGF165, which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. Methods: VEGF121 and VEGF165 were labeled with 125I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with 125I-VEGF121. Results: 125I-VEGF121 and 125I-VEGF165 exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. 125I-VEGF121 uptake in tumors was twofold higher than that of 125I-VEGF165 (9.12±98 and 4.79±1.08 %ID/g at 2 h, respectively). 125I-VEGF121 displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with 125I-VEGF165. 125I-VEGF121 accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in 125I-VEGF121 tumor accumulation correlated with degree of tumor vascularity. Conclusion: Radioiodinated VEGF121 is a promising tracer for noninvasive delineation of angiogenesis in vivo

2006-01-01

78

Radioiodinated VEGF to image tumor angiogenesis in a LS180 tumor xenograft model  

Energy Technology Data Exchange (ETDEWEB)

Introduction: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF{sub 121}, which displays high binding affinity for KDR, and VEGF{sub 165}, which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. Methods: VEGF{sub 121} and VEGF{sub 165} were labeled with {sup 125}I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with {sup 125}I-VEGF{sub 121}. Results: {sup 125}I-VEGF{sub 121} and {sup 125}I-VEGF{sub 165} exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. {sup 125}I-VEGF{sub 121} uptake in tumors was twofold higher than that of {sup 125}I-VEGF{sub 165} (9.12{+-}98 and 4.79{+-}1.08 %ID/g at 2 h, respectively). {sup 125}I-VEGF{sub 121} displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with {sup 125}I-VEGF{sub 165}. {sup 125}I-VEGF{sub 121} accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in {sup 125}I-VEGF{sub 121} tumor accumulation correlated with degree of tumor vascularity. Conclusion: Radioiodinated VEGF{sub 121} is a promising tracer for noninvasive delineation of angiogenesis in vivo.

Yoshimoto, Mitsuyoshi [Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-0942 (Japan)]. E-mail: myoshi@mhs.mp.kanazawa-u.ac.jp; Kinuya, Seigo [Department of Biotracer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8640 (Japan); Kawashima, Atsuhiro [Kanazawa Medical Center, Ishikawa 920-8650 (Japan); Nishii, Ryuichi [Department of Radiology, Fujimoto Hayasuzu Hospital, Miyazaki 885-0055 (Japan); Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Yokoyama, Kunihiko [Department of Biotracer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8640 (Japan); Kawai, Keiichi [Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-0942 (Japan); Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan)

2006-11-15

79

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 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.

2006-01-01

80

Dietary restriction permits normal parturition and lactation but suppresses mouse mammary tumor virus proviral transcription even after mammary involution.  

UK PubMed Central (United Kingdom)

Dietary restriction of C3H/Ou mice prevents development of spontaneous mammary adenocarcinoma by suppressing mammary expression of the mouse mammary tumor virus (MMTV) via a mechanism which may involve prolactin. In the present study, dietary restriction of 40% was imposed for 16 weeks on nulliparous C3H/Ou mice, interrupted by ad libitum consumption at mating and continued only during pregnancy and lactation, with 40% energy restriction reimposed at the end of lactation. The results show that mammary MMTV mRNA expression levels of chronic energy intake restricted (CEIR) mice and ad libitum fed mice are similar and elevated during early lactation, when all mice of both groups are being fed ad libitum energy levels. In spite of this, and in marked contrast, when CEIR dams are returned to 40% dietary restriction following the weaning of litters, mammary MMTV transcription is suppressed to levels 4-5-fold less than those measured in mammary glands from ad libitum fed controls. Within the 38 weeks of study, 73% of ad libitum fed uniparous mice at risk and 11% of CEIR uniparous mice at risk developed mammary tumors, yet mice of both dietary groups delivered and weaned healthy litters with comparable efficiency. When dietary restriction is maintained in CEIR mice during pregnancy and lactation, efficiency of conception and litter size are reduced, and MMTV transcription is suppressed even during lactation. Mean serum prolactin levels were not significantly different among dietary groups. These findings show that the level of MMTV transcription is rigorously influenced by dietary energy level, and that 40% dietary restriction of C3H/Ou mice not only suppresses mammary MMTV transcription and prevents mammary tumor development in uniparous mice, but also permits normal conception, gestation, lactation, and the production of healthy litters as long as the nutritional demands of gestation and lactation are met.

Engelman RW; Fukaura Y; Hamada N; Good RA; Day NK

1991-10-01

 
 
 
 
81

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-calo...

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

82

Nuclear medical molecular imaging of tumor angiogenesis: current status and future prospects.  

UK PubMed Central (United Kingdom)

OBJECTIVE: To review the current status and progress on nuclear medical molecular imaging of angiogenesis. DATA SOURCES: A literature search was performed in Medline and PubMed published in English up to May 31, 2012. The search terms were molecular imaging, nuclear medicine and angiogenesis. STUDY SELECTION: Articles studying molecular imaging of angiogenesis using radionuclide were selected and reviewed. RESULTS: Molecular imaging has been used for studying angiogenesis by targeting integrin ?V?3, VEGF/VEGFR, and matrix metalloproteinases (MMPs) with radionuclide-labeled tracers. The technology has been shown to be able to assess the angiogenesis status and/or predict the efficacy of anti-angiogenic therapy. Future directions of the research on the molecular imaging of angiogenesis include development of new tracers with better tumor targeting efficacy, desirable pharmacokinetics, and easy translation to clinical applications. CONCLUSION: Advances in molecular imaging of angiogenesis using radioculcide will make the technology a valuable tool for personalized anti-angiogenesis treatment.

Hu XD; Xing LG; Yu JM

2013-07-01

83

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

Science.gov (United States)

BST-2 restricts MMTV replication, but once infection has established, MMTV modulates BST-2 levels. MMTV-directed BST-2 modulation is tissue-specific and dependent on infection and neoplastic transformation status of cells. In the lymphoid compartment of infected mice, BST-2 expression is first upregulated and then significantly downregulated regardless of absence or presence of mammary tumors. However, in mammary gland tissues, upregulation of BST-2 expression is dependent on the presence of mammary tumors and tumor tissues themselves have high BST-2 levels. Elevated BST-2 expression in these tissues is not attributable to IFN since levels of IFN? and IFN? negatively correlate with BST-2. Importantly, soluble factors released by tumor cells suppress IFN? and IFN? but induce BST-2. These data suggest that overexpression of BST-2 in carcinoma tissues could not be attributed to IFNs but to a yet to be determined factor that upregulates BST-2 once oncogenesis is initiated. PMID:23806386

Jones, Philip H; Mahauad-Fernandez, Wadie D; Madison, Marisa N; Okeoma, Chioma M

2013-06-25

84

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

UK PubMed Central (United Kingdom)

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

Jones PH; Mahauad-Fernandez WD; Madison MN; Okeoma CM

2013-09-01

85

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

Science.gov (United States)

Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.

Jorgens, Kristina; Seufferlein, Thomas

2013-01-01

86

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

UK PubMed Central (United Kingdom)

Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.

Hollenbach M; Stoll SJ; Jörgens K; Seufferlein T; Kroll J

2013-01-01

87

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

88

The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis  

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We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but i...

Wertheim, Gerald B. W.; Yang, Thomas W.; Pan, Tien-chi; Ramne, Anna; Liu, Zhandong; Gardner, Heather P.; Dugan, Katherine D.

89

Mammalian heparanase as mediator of tumor metastasis and angiogenesis.  

Science.gov (United States)

Expression of heparan sulfate-degrading endoglycosidases, commonly referred to as heparanases, correlates with the metastatic potential of tumor cell lines, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. We purified a 50 kDa heparanase from human hepatoma and placenta and cloned a cDNA and gene encoding a protein of 543 amino acids. Only one heparanase sequence was identified, suggesting that this enzyme is the dominant endoglucuronidase in mammalian tissues. Expression of the cloned cDNA in insect and mammalian cells yielded 65 kDa and 50 kDa recombinant proteins. The 50 kDa enzyme represents an N-terminal processed enzyme that is at least 200-fold more active than the full-length 65 kDa form. Processing was demonstrated following incubation of the full-length recombinant enzyme with intact tumor cells. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and in specimens of human melanomas and carcinomas. In the colon, both the heparanase mRNA and protein are expressed already at the stage of tubulovillous adenoma, but not in the adjacent 'normal-looking' colon epithelium. Non-metastatic murine T lymphoma and melanoma cells transfected with the heparanase gene acquired a highly metastatic phenotype in vivo. Apart from its involvement in the egress of cells from the vasculature, heparanase is tightly involved in angiogenesis, both directly--by promoting invasion of endothelial cells (vascular sprouting), and indirectly--by releasing heparan sulfate-bound basic fibroblast growth factor, and generating HS degradation fragments that promote bFGF activity. The angiogenic potential of heparanase was demonstrated in vivo (Matrigel plug assay) by showing a three to fourfold increase in neovascularization induced by Eb T lymphoma cells following their transfection with the heparanase gene. The ability of heparanase to promote both tumor angiogenesis and metastasis makes it a promising target for cancer therapy. PMID:10909416

Vlodavsky, I; Elkin, M; Pappo, O; Aingorn, H; Atzmon, R; Ishai-Michaeli, R; Aviv, A; Pecker, I; Friedmann, Y

2000-07-01

90

Mammalian heparanase as mediator of tumor metastasis and angiogenesis.  

UK PubMed Central (United Kingdom)

Expression of heparan sulfate-degrading endoglycosidases, commonly referred to as heparanases, correlates with the metastatic potential of tumor cell lines, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. We purified a 50 kDa heparanase from human hepatoma and placenta and cloned a cDNA and gene encoding a protein of 543 amino acids. Only one heparanase sequence was identified, suggesting that this enzyme is the dominant endoglucuronidase in mammalian tissues. Expression of the cloned cDNA in insect and mammalian cells yielded 65 kDa and 50 kDa recombinant proteins. The 50 kDa enzyme represents an N-terminal processed enzyme that is at least 200-fold more active than the full-length 65 kDa form. Processing was demonstrated following incubation of the full-length recombinant enzyme with intact tumor cells. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and in specimens of human melanomas and carcinomas. In the colon, both the heparanase mRNA and protein are expressed already at the stage of tubulovillous adenoma, but not in the adjacent 'normal-looking' colon epithelium. Non-metastatic murine T lymphoma and melanoma cells transfected with the heparanase gene acquired a highly metastatic phenotype in vivo. Apart from its involvement in the egress of cells from the vasculature, heparanase is tightly involved in angiogenesis, both directly--by promoting invasion of endothelial cells (vascular sprouting), and indirectly--by releasing heparan sulfate-bound basic fibroblast growth factor, and generating HS degradation fragments that promote bFGF activity. The angiogenic potential of heparanase was demonstrated in vivo (Matrigel plug assay) by showing a three to fourfold increase in neovascularization induced by Eb T lymphoma cells following their transfection with the heparanase gene. The ability of heparanase to promote both tumor angiogenesis and metastasis makes it a promising target for cancer therapy.

Vlodavsky I; Elkin M; Pappo O; Aingorn H; Atzmon R; Ishai-Michaeli R; Aviv A; Pecker I; Friedmann Y

2000-07-01

91

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

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In vivo expression of the mouse mammary tumor virus (MMTV) is restricted to a few organs, with the highest rate of transcription found in the mammary gland. Using a series of mammary and nonmammary murine cell lines, we have identified two regulatory elements, located upstream of the hormone respons...

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

92

Role of thymosin beta4 in tumor metastasis and angiogenesis.  

UK PubMed Central (United Kingdom)

BACKGROUND: Expression of the small peptide thymosin beta4 is associated with angiogenesis induction, accelerated wound healing, and the metastatic potential of tumor cells. However, little is known about the mechanism(s) by which thymosin beta4 promotes metastasis. METHODS: Northern blot analysis and immunohistochemistry were used to examine thymosin beta4 expression in mouse melanoma B16 cell lines and in B16-F10 cells derived from metastatic mouse lung tumors, respectively. B16-F10 cells infected with adenoviruses containing a thymosin beta4 expression vector or an empty vector were injected subcutaneously and intravenously into C57BL/6 mice to evaluate tumor growth and metastatic potential, respectively. In vitro assays were used to study cell migration, invasion, matrix metalloproteinase activity, cell proliferation, and angiogenic activity of adenovirus-infected B16-F10 cells. Statistical significance of all results was analyzed by two-tailed Student's t tests. RESULTS: Thymosin beta4 mRNA was expressed in primary cultured B16-F10 cells derived from lung metastases and in B16-F10 cells that had formed lung tumors after being injected into mice but not in the B16-F1, B16-F10, or B16-BL6 cell lines. The mean tumor sizes in mice 20 days after injection with B16-F10 cells infected with thymosin beta4-expressing adenovirus and with control adenovirus were 21.7 mm (95% confidence interval [CI] = 17.7 to 25.7 mm) and 13.3 mm (95% CI = 11.1 to 15.3 mm), respectively (difference = 8.4 mm; P =.036). The mean numbers of metastatic lung nodules in mice (n = 20) 2 weeks after intravenous injection with thymosin beta4-expressing adenovirus and with control adenovirus were 46.7 (95% CI = 35.0 to 57.7) and 10.9 (95% CI = 6.2 to 15.6), respectively (difference = 35.8 metastatic lung nodules, P<.001). Thymosin beta4 overexpression was associated with a mean 2.3-fold increase (95% CI = 1.9- to 2.7-fold increase; P<.001) in B16-F10 cell migration and a mean 4.4-fold increase (95% CI = 3.3- to 5.5-fold increase; P<.001) in the number of blood vessels in solid tumors derived from injected B16-F10 cells but had no effect on cell invasion, proliferation, or matrix metalloproteinase activity. This induction of angiogenesis by thymosin beta4 was associated with induction of vascular endothelial growth factor expression. CONCLUSION: Thymosin beta4 may stimulate tumor metastasis by activating cell migration and angiogenesis.

Cha HJ; Jeong MJ; Kleinman HK

2003-11-01

93

Alcohol consumption suppresses mammary tumor metastasis in a syngeneic tumor transplantation model.  

Science.gov (United States)

Epidemiological studies indicate a positive correlation between alcohol consumption and the risk of developing breast cancer. However, little is known about whether alcohol consumption affects breast cancer metastasis. Considering that the primary cause of death in breast cancer patients is due to metastasis, further insight into whether alcohol consumption influences disease progression and survival is needed. We tested the effect of alcohol consumption on breast cancer metastasis using the 4T1.2 syngeneic mammary tumor model in Balb/c mice. The treatment groups included a High-consuming group (18 % w/v alcohol in drinking water), a Moderate-consuming group (5 % w/v), a Low-consuming group (1 % w/v), and a Water-drinking control group. 4T1.2 mammary tumor cells were injected orthotopically into the mammary fat pad. Metastases were enumerated in lungs and in distant mammary glands 4 weeks after injection. Consumption of High alcohol protected against metastasis, as High-consuming mice typically had 65-75 % fewer metastases compared to Water-drinking controls. A suggestive reduction in tumor spread was observed in the Moderate-drinking group, although the effects did not reach statistical significance. Consumption of the Low alcohol dose did not affect metastasis. CXCR4 expression in the primary tumors was significantly reduced by High alcohol consumption; however, expression of this chemokine receptor in the primary tumor did not correlate with metastatic potential. Additional studies were conducted to test for possible direct effects of 0.3 % w/v ethanol on tumor cell proliferation, migration, invasion, and colony formation of 4T1.2 cells in vitro. Our results indicate that, for this murine model, alcohol consumption does not exacerbate tumor metastasis, and that High alcohol consumption reduces tumor spread. PMID:23117853

Vorderstrasse, Beth A; Wang, Tao; Myers, Annette K; Wyrick, Katherine L; Meadows, Gary G

2012-11-02

94

Alcohol consumption suppresses mammary tumor metastasis in a syngeneic tumor transplantation model.  

UK PubMed Central (United Kingdom)

Epidemiological studies indicate a positive correlation between alcohol consumption and the risk of developing breast cancer. However, little is known about whether alcohol consumption affects breast cancer metastasis. Considering that the primary cause of death in breast cancer patients is due to metastasis, further insight into whether alcohol consumption influences disease progression and survival is needed. We tested the effect of alcohol consumption on breast cancer metastasis using the 4T1.2 syngeneic mammary tumor model in Balb/c mice. The treatment groups included a High-consuming group (18 % w/v alcohol in drinking water), a Moderate-consuming group (5 % w/v), a Low-consuming group (1 % w/v), and a Water-drinking control group. 4T1.2 mammary tumor cells were injected orthotopically into the mammary fat pad. Metastases were enumerated in lungs and in distant mammary glands 4 weeks after injection. Consumption of High alcohol protected against metastasis, as High-consuming mice typically had 65-75 % fewer metastases compared to Water-drinking controls. A suggestive reduction in tumor spread was observed in the Moderate-drinking group, although the effects did not reach statistical significance. Consumption of the Low alcohol dose did not affect metastasis. CXCR4 expression in the primary tumors was significantly reduced by High alcohol consumption; however, expression of this chemokine receptor in the primary tumor did not correlate with metastatic potential. Additional studies were conducted to test for possible direct effects of 0.3 % w/v ethanol on tumor cell proliferation, migration, invasion, and colony formation of 4T1.2 cells in vitro. Our results indicate that, for this murine model, alcohol consumption does not exacerbate tumor metastasis, and that High alcohol consumption reduces tumor spread.

Vorderstrasse BA; Wang T; Myers AK; Wyrick KL; Meadows GG

2012-12-01

95

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

UK PubMed Central (United Kingdom)

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.

Kwok E; Everingham S; Zhang S; Greer PA; Allingham JS; Craig AW

2012-07-01

96

Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors  

Energy Technology Data Exchange (ETDEWEB)

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

Hubbard, N.E.

1987-01-01

97

Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors  

International Nuclear Information System (INIS)

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

1987-01-01

98

Comparative characteristics of mammary glands cancer in humans and animals  

Directory of Open Access Journals (Sweden)

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

Vorobyova ?.V.; Terentyuk G.S.; Bucharskaya A.B.

2012-01-01

99

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

International Nuclear Information System (INIS)

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

2005-01-01

100

The role of ?3-integrins in tumor angiogenesis: context is everything.  

UK PubMed Central (United Kingdom)

Integrins are a family of cell-extracellular matrix adhesion molecules that play important roles in tumor angiogenesis. ?v?3-Integrin has received much attention as a potential anti-angiogenic target because it is upregulated in tumor-associated blood vessels. Agents targeting ?v?3-integrin are now showing some success in phase III clinical trails for the treatment of glioblastoma, but the exact function of this integrin in tumor angiogenesis is still relatively unknown. This review highlights some of the recent data illustrating that ?3-integrins play both pro-angiogenic and anti-angiogenic roles in tumor angiogenesis depending on the context. Specifically we will discuss how the following differentially influence ?3-integrin's role in tumor angiogenesis: first, cell-matrix interactions, second, ?3-integrin inhibitor doses, third, cell type, and fourth, other interacting molecules.

Robinson SD; Hodivala-Dilke KM

2011-10-01

 
 
 
 
101

Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer.  

Science.gov (United States)

In many cases, solid tumors exhibit numerous and highly permeable blood vessels. For a long time, this observation drew little attention. In the early 70's, however, Folkman proposed for the first time the potential relevance of tumor angiogenesis (formation of new vessels) for tumor growth and metastasis (6). He realized that tumors up to a diameter of 1-2 mm could be nurtured with oxygen and energy simply by diffusion (prevascular phase). Further growth, however, would require newly formed blood vessels. He hypothesized that (assuming the formation of new vessels was essential for tumor growth) pharmacological inhibition of angiogenesis could be developed as a new, more specific form of tumor treatment. In recent years, several groups have investigated the pathophysiology of tumor angiogenesis. Folkman's hypothesis that tumor growth is dependent on the formation of new vessels was supported by several experiments: Implants of different tumors into an avascular cornea initially have a slow growth rate that increases exponentially after infiltration of new vessels into the tumors (9). Inversely, the growth rate of solid tumors decreases with increasing distance to the supplying capillaries (27). The onset of neovascularization at the bases of human melanomas is directly associated with tumor growth and metastasis (25). Experiments with transgenic mice have demonstrated that the transition from hyperplastic to malignant cell growth occurs parallel to the onset of angiogenesis (7). Tumor vessel density has been shown to be associated with tumor progression and the clinical course in many human tumors (e.g. of the breast, lung, colon, cervix, prostate and bladder). Aside from the basic research on the formation of new (tumor) vessels, it is the therapeutic potential of various inhibitors of angiogenesis, some of which are currently tested in clinical (phase I/II) studies, that deserves special scientific attention. This review gives an overview of the relevance of angiogenesis for tumor growth, especially for renal cancers. It also discusses the potential advantages and disadvantages of different anti-angiogenic therapeutic approaches. PMID:10365145

Strohmeyer, D

102

The effect of undecanones and their derivatives on tumor angiogenesis and VEGF content.  

Science.gov (United States)

The in vivo effects of some derivatives of aliphatic ketones (2-undecanone, 3-undecanone, 4-undecanone and their derivatives) on L-1 sarcoma tumor angiogenesis and VEGF content were studied in Balb/c mice. Mice that inhaled 10% solution of 3-undecanone(3-on) or 1% solution of 2-undecanone propylene acetal (Acpr2) for 3 days after tumor cells implantation, presented lower neovascular response measured by tumor-induced cutaneous angiogenesis test (TIA) and lower tumor VEGF content in 5-days tumors, than non-inhaled controls. Other substances presented various effects on tumor VEGF concentration and angiogenesis. Histological examination of lesions collected from mice inhaled Acpr2, or non-inhaled controls, revealed small diffused areas of necrosis in the former group. In both groups, slight to moderate inflammatory infiltrations were seen at the tumor's margin. In Acpr2 group, there were less small blood vessels at tumor's margin than in the control group. PMID:21077438

Gibka, J; Wasiuty?ski, A; Skopi?ska-Rózewska, E; Siwicki, A K; Chorostowska-Wynimko, J; Sommer, E; Mazurkiewicz, M; Gli?ski, M; Skurzak, H; Wójcik, R; Jung, L

2010-01-01

103

Tumor angiogenesis in colorectal cancer, correlation with tumor extension and invasion  

Directory of Open Access Journals (Sweden)

Full Text Available Tumor angiogenesis shown by Microvessel Count (MVC) or Microvessel Density (MVD), is assessed by several studies as prognostic factor in some types of tumors, and also in colorectal carcinoma. This article is payed to correlation between clincopathologic factors and tumor angiogenesis. In this study, immunohistochemical techniques are used for vascular evaluation in specimens from twenty-nine colorectal carcinoma, and stained for Factor VIII-Related Antigen (F8RA) by using monoclonal antibody. Uni and multivariate analysis disclosed that total MVC was higher in tumor [76.3±33 (×100=2.5 mm²/field) and 29.8±11 (×200=0.785 mm²/field)] than in normal tissue [37.7±15.8 (×100) and 17.6±7.8 (×200)], (P=0.022, P=0.000009). Microvessel quantification was significantly higher in stage D (115±36.6, ×100 and 26.7±6.4, ×200, P=0.002 and P=0.04). In this study MVD has correlation with vascular invasion (P=0.024, ×100 and P=0.007, ×200), the mean tumor vessel count although was increased with clinicophatologic findings such as age<60 years, male, right colon involvement, infiltrating type, mucinous carcinoma, transmural penetration, grade III, lymphatic and perineural invasion, but was not statistically significant. Lymph node and hematogenous metastasis and size of tumor also, was not important. As a conclusion, MVD was increased in tumor and has shown correlation with metastasis, and vascular invasion. Resulting angiogenesis increase risk of metastasis.

Javadi P; Haeri H

2001-01-01

104

Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice.  

UK PubMed Central (United Kingdom)

Iron is essential for the growth of all cells, including tumor cells. The authors previously reported that a variety of transplantable tumors grew faster and larger in mice that were on an iron-rich diet compared with those on an iron-deficient diet. In this study the authors examined the relationship between iron in the diet and development of tumors in mice that are known to develop spontaneous tumors--C3H/HeN-MTV+(C3H-MTV+) mice that were congenitally infected with mammary tumor virus. These mice have a greater than 96% chance of developing mammary tumors between the ages of 7.2 and 9.2 months. Fifteen C3H-MTV+ weanlings were given a low-iron diet (5 mg iron/kg diet), and 15 were given diets with normal amounts of iron (180 mg Fe/kg diet). Thirteen of the 15 mice from the low-iron group and all 15 mice from the normal-iron group developed tumors. The average tumor growth rate in the normal-iron group was 112%/wk, compared with 62%/wk for the low-iron group. The difference in tumor growth rate between the two groups was significant (P = 0.02 by Student's t test). In this study, low iron intake did not prevent tumor development, but the results confirm the authors' previous report that iron nutrition of the host affects tumor growth; tumors grow better in an iron-rich environment. High levels of iron in the diet may enhance tumor growth, and this should be considered when treating patients with cancer.

Hann HW; Stahlhut MW; Menduke H

1991-12-01

105

A 'tete-a tete' between cancer stem cells and endothelial progenitor cells in tumor angiogenesis.  

UK PubMed Central (United Kingdom)

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

Kaur S; Bajwa P

2013-08-01

106

Simultaneous production of casein and mammary tumor virus in mouse mammary epithelial cells grown on floating collagen gels.  

UK PubMed Central (United Kingdom)

Simultaneous production of casein and mammary tumor virus (MTV) was analyzed in monolayer cultures of mammary epithelial cells from pregnant BALB/cfC3H mice. A comparison of the 2 cell culture substrata, plastic culture dish and floating collagen gel, showed that the latter supported a much higher degree of simultaneous casein and MTV production in the presence of insulin, cortisol and prolactin in serum-free culture medium. Importance of floating collagen gel was further shown by delaying the flotation of gels. When the release of gels was delayed, there were concomitant delays in the increase of casein and MTV production. These results indicate that hormones, nature of substratum and flotation regulate the degree of differentiation of mammary epithelial cells in vitro.

Enami J; Yang J; Nandi S

1979-02-01

107

Imaging of integrins as biomarkers for tumor angiogenesis.  

UK PubMed Central (United Kingdom)

The integrin family plays important roles during tumor angiogenesis, the formation of new blood vessels from pre-existing vasculature. Traditional structural and functional imaging techniques are not sufficient for early lesion detection, patient stratification, or monitoring the therapeutic efficacy against cancer. Molecular imaging, the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems, can fulfill these goals. In this review article, we will summarize the current state-of-the-art of imaging integrin (alpha(2)beta(1), alpha(3)beta(1), alpha(4)beta(1), alpha(v)beta(3), and alpha(v)beta(6)) expression using either single molecular imaging modality (magnetic resonance imaging, ultrasound, optical, single photon emission computed tomography, and positron emission tomography) or a combination of different modalities. For clinical translation, radionuclide-based imaging will have broad potential applications in cancer patients and the currently available clinical data (exclusively on integrin alpha(v)beta(3) so far) will be discussed in detail. The design, optimization, and characterization of imaging agents targeting integrins will be presented and areas needing extensive future research effort will be discussed. In the new era of personalized medicine, fast clinical translation and incorporation of integrin imaging into anti-cancer clinical trials will be critical for the maximum benefit of cancer patients.

Cai W; Niu G; Chen X

2008-01-01

108

Immunohistochemical and molecular analysis of caveolin-1 expression in canine mammary tumors.  

Science.gov (United States)

Caveolin-1 (Cav-1) is a structural protein present in invaginations of the cell membrane. In human breast cancer, the cav-1 gene is believed to be a tumor suppressor gene associated with inhibition of tumor metastasis. However, little is known about its expression, regulation and function in canine mammary tumors. Expression levels of cav-1 were investigated using real-time PCR and immunohistochemical detection with an anti-human Cav-1 antibody. Gene expression stability of different samples was analyzed using the geNorm software. Mammary tumors from 51 female dogs were compared to normal mammary tissue from 10 female dogs. Malignant mammary cells showed a loss of Cav-1 expression by quantitative RT-PCR and weak Cav-1 staining by immunohistochemistry compared to normal mammary gland tissue. There was a significant relationship between outcome and immunostaining as well as with tumor size, indicating that caveolin subexpression has a positive predictive value and is related to higher survival and smaller tumor size. Our findings indicate that Cav-1 is a potential prognostic marker for canine mammary tumors. PMID:22370882

Zuccari, D A P C; Castro, R; Gavioli, A F; Mancini, U M; Frade, C S; Leonel, C

2012-01-27

109

Immunohistochemical and molecular analysis of caveolin-1 expression in canine mammary tumors.  

UK PubMed Central (United Kingdom)

Caveolin-1 (Cav-1) is a structural protein present in invaginations of the cell membrane. In human breast cancer, the cav-1 gene is believed to be a tumor suppressor gene associated with inhibition of tumor metastasis. However, little is known about its expression, regulation and function in canine mammary tumors. Expression levels of cav-1 were investigated using real-time PCR and immunohistochemical detection with an anti-human Cav-1 antibody. Gene expression stability of different samples was analyzed using the geNorm software. Mammary tumors from 51 female dogs were compared to normal mammary tissue from 10 female dogs. Malignant mammary cells showed a loss of Cav-1 expression by quantitative RT-PCR and weak Cav-1 staining by immunohistochemistry compared to normal mammary gland tissue. There was a significant relationship between outcome and immunostaining as well as with tumor size, indicating that caveolin subexpression has a positive predictive value and is related to higher survival and smaller tumor size. Our findings indicate that Cav-1 is a potential prognostic marker for canine mammary tumors.

Zuccari DA; Castro R; Gavioli AF; Mancini UM; Frade CS; Leonel C

2012-01-01

110

MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.  

UK PubMed Central (United Kingdom)

Bone marrow-derived endothelial progenitor cells (EPC) contribute to the angiogenesis-dependent growth of tumors in mice and humans. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. miRNAs have emerged as key regulators of several cellular processes including angiogenesis; however, whether miRNAs contribute to bone marrow-mediated angiogenesis has remained unknown. Here, we show that genetic ablation of miRNA-processing enzyme Dicer, specifically in the bone marrow, decreased the number of circulating EPCs, resulting in angiogenesis suppression and impaired tumor growth. Furthermore, genome-wide deep sequencing of small RNAs revealed tumor EPC-intrinsic miRNAs including miR-10b and miR-196b, which have been previously identified as key regulators of HOX signaling and adult stem cell differentiation. Notably, we found that both miR-10b and miR-196b are responsive to vascular endothelial growth factor stimulation and show elevated expression in human high-grade breast tumor vasculature. Strikingly, targeting miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth in mice. Targeting these miRNAs may constitute a novel strategy for inhibiting tumor angiogenesis.

Plummer PN; Freeman R; Taft RJ; Vider J; Sax M; Umer BA; Gao D; Johns C; Mattick JS; Wilton SD; Ferro V; McMillan NA; Swarbrick A; Mittal V; Mellick AS

2013-01-01

111

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF) and matrix metal...

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

112

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

UK PubMed Central (United Kingdom)

Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor ?-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression.

Mammoto T; Jiang A; Jiang E; Panigrahy D; Kieran MW; Mammoto A

2013-08-01

113

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

Science.gov (United States)

Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor ?-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID:23928381

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

2013-08-05

114

Acceleration of Mouse Mammary Tumor Virus-Induced Murine Mammary Tumorigenesis by a p53172H Transgene: Influence of FVB Background on Tumor Latency and Identification of Novel Sites of Proviral Insertion  

Digital Repository Infrastructure Vision for European Research (DRIVER)

We previously showed that a mammary-specific dominant-negative p53 transgene (WAP-p53172H) could accelerate ErbB2-induced mammary tumorigenesis in mice, but was not tumorigenic on its own. To identify other genes that cooperate with WAP-p53172H in tumorigenesis, we performed mouse mammary tumor viru...

Chatterjee, Gouri; Rosner, Andrea; Han, Yi; Zelazny, Edward T.; Li, Baolin; Cardiff, Robert D.; Perkins, Archibald S.

115

Tumor-associated soluble uPAR-directed endothelial cell motility and tumor angiogenesis.  

UK PubMed Central (United Kingdom)

The expression of urokinase-type plasminogen activator (uPA) receptor (uPAR) correlates with the malignant phenotype of various cancers. The soluble form of uPAR (s-uPAR) is present in the circulation of cancer patients, but the role of s-uPAR in endothelial cell migration is poorly understood. Therefore, we examined the role of tumor-associated s-uPAR on endothelial cell motility and angiogenesis. Here, we present evidence that tumor-associated s-uPAR augments the migration of human umbilical vein endothelial cells (HUVECs). When grown on tumor-conditioned medium, the membrane fraction of HUVECs had increased localization of s-uPAR onto its cell membrane. Colocalization studies for GM1 ganglioside receptor and uPAR further demonstrated s-uPAR recruitment onto lipid rafts of HUVECs. Immunoblot analysis for uPAR in lipid raft fractions confirmed s-uPAR recruiting onto HUVECs' membrane. Further, s-uPAR induced Rac1-mediated cell migration while either function-blocking uPAR antibodies or dominant-negative mutant Rac1 expression in HUVECs-mitigated s-uPAR-enhanced cell migration. In addition, orthotopic implantation of uPAR-overexpressing cells resulted in a significant increase in circulating s-uPAR in blood serum and invasive nature of tumor and tumor vasculature in mice. Collectively, this data provide insight into tumor-associated s-uPAR-directed migration of endothelial cells and its subsequent influence on tumor angiogenesis.

Rao JS; Gujrati M; Chetty C

2013-01-01

116

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

UK PubMed Central (United Kingdom)

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

Shin J; Lee J; Baek KH

2013-09-01

117

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

UK PubMed Central (United Kingdom)

The aim of this study was to evaluate MHC class I expression and prognosis using tumor tissues surgically removed from 9 dogs with mammary gland carcinomas and from 13 with complex mammary carcinomas. We assessed MHC class I expression and its correlation with tumor size, B2M expression, infiltration of lymphocytes, histological grade, and prognosis. Hematoxylin and eosin-stained sections were histologically graded using the Elston and Ellis grading method. MHC class I expression on tumor cells was evaluated using the avidin-biotin peroxidase complex method. Loss of MHC class I expression from canine mammary gland carcinomas was significantly correlated with poor prognosis (P<0.05). Loss of MHC class I expression showed no association with poor prognosis in canine mammary gland complex carcinomas because the data was not balanced. Only 1 of 13 (7.6%) canine mammary complex carcinomas showed loss of MHC class I expression. All 13 of these dogs showed good prognosis. Thus, the low frequency of MHC class I expression loss from canine mammary gland complex carcinomas may be associated with good prognosis. Taken together, these results suggest that loss of MHC class I expression may be associated with poor prognosis in canine mammary gland carcinomas.

Tanaka T; Shimada T; Akiyoshi H; Shimizu J; Zheng C; Yijyun L; Mie K; Hayashi A; Kuwamura M; Hoshi F; Ohashi F

2013-05-01

118

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models.  

UK PubMed Central (United Kingdom)

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.

Maione F; Molla F; Meda C; Latini R; Zentilin L; Giacca M; Seano G; Serini G; Bussolino F; Giraudo E

2009-11-01

119

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models.  

Science.gov (United States)

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature. PMID:19809158

Maione, Federica; Molla, Fabiola; Meda, Claudia; Latini, Roberto; Zentilin, Lorena; Giacca, Mauro; Seano, Giorgio; Serini, Guido; Bussolino, Federico; Giraudo, Enrico

2009-10-05

120

EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1? and NF?B, and VEGF expression  

Science.gov (United States)

The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1? and NF?B, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6?J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50–100?mg/kg/d in drinking water for 4?weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37?±?0.15 vs. 1.16?±?0.30?g; P?tumor CD (109?±?20 vs. 156?±?12 capillary #/mm^2; P?tumor VEGF expression (45.72?±?1.4 vs. 59.03?±?3.8?pg/mg; P?angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50??g/ml significantly inhibited the activation of HIF-1? and NF?B as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1? and NF?B activation as well as VEGF expression.

2013-01-01

 
 
 
 
121

EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1? and NF?B, and VEGF expression.  

UK PubMed Central (United Kingdom)

The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1? and NF?B, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6?J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50-100?mg/kg/d in drinking water for 4?weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37?±?0.15 vs. 1.16?±?0.30?g; P?tumor CD (109?±?20 vs. 156?±?12 capillary #/mm^2; P?tumor VEGF expression (45.72?±?1.4 vs. 59.03?±?3.8?pg/mg; P?angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50??g/ml significantly inhibited the activation of HIF-1? and NF?B as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1? and NF?B activation as well as VEGF expression.

Gu JW; Makey KL; Tucker KB; Chinchar E; Mao X; Pei I; Thomas EY; Miele L

2013-01-01

122

EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1? and NF?B, and VEGF expression.  

Science.gov (United States)

The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1? and NF?B, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6?J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50-100?mg/kg/d in drinking water for 4?weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37?±?0.15 vs. 1.16?±?0.30?g; P?tumor CD (109?±?20 vs. 156?±?12 capillary #/mm^2; P?tumor VEGF expression (45.72?±?1.4 vs. 59.03?±?3.8?pg/mg; P?angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50??g/ml significantly inhibited the activation of HIF-1? and NF?B as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1? and NF?B activation as well as VEGF expression. PMID:23638734

Gu, Jian-Wei; Makey, Kristina L; Tucker, Kevan B; Chinchar, Edmund; Mao, Xiaowen; Pei, Ivy; Thomas, Emily Y; Miele, Lucio

2013-05-02

123

Effects of Epigallocatechin-3-gallate (EGCG) on A549 Lung Cancer Tumor Growth and Angiogenesis.  

UK PubMed Central (United Kingdom)

Epigallocatechin 3-gallate (EGCG) has cytotoxic effects in many cancer cells. It has been reported that A549 lung cancer cells are markedly resistant to cell death induced by EGCG. In the present study, the effects of EGCG on A549 lung cancer cell growth and angiogenesis were studied. We found that EGCG dose-dependently suppressed A549 cell growth, while A549 cells were markedly resistant to cell death in vitro. Next we found that EGCG increased endostatin expression and suppressed vascular endothelial growth factor (VEGF) expression. We further studied to determine whether EGCG would suppress A549 tumor growth in nude mouse and angiogenesis. EGCG in drinking water significantly suppressed A549 tumor growth in nude mice. Histological analysis revealed that the number of CD34 positive vessels had a tendency to decrease in the tumor. In sum, EGCG had anti-proliferative effects of A549 on tumor growth and showed a tendency to suppress angiogenesis.

Sakamoto Y; Terashita N; Muraguchi T; Fukusato T; Kubota S

2013-09-01

124

Effects of Epigallocatechin-3-gallate (EGCG) on A549 Lung Cancer Tumor Growth and Angiogenesis.  

Science.gov (United States)

Epigallocatechin 3-gallate (EGCG) has cytotoxic effects in many cancer cells. It has been reported that A549 lung cancer cells are markedly resistant to cell death induced by EGCG. In the present study, the effects of EGCG on A549 lung cancer cell growth and angiogenesis were studied. We found that EGCG dose-dependently suppressed A549 cell growth, while A549 cells were markedly resistant to cell death in vitro. Next we found that EGCG increased endostatin expression and suppressed vascular endothelial growth factor (VEGF) expression. We further studied to determine whether EGCG would suppress A549 tumor growth in nude mouse and angiogenesis. EGCG in drinking water significantly suppressed A549 tumor growth in nude mice. Histological analysis revealed that the number of CD34 positive vessels had a tendency to decrease in the tumor. In sum, EGCG had anti-proliferative effects of A549 on tumor growth and showed a tendency to suppress angiogenesis. PMID:24018658

Sakamoto, Yuhi; Terashita, Nobuhiro; Muraguchi, Takashi; Fukusato, Toshio; Kubota, Shunichiro

2013-09-07

125

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

Science.gov (United States)

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 characterized for clonogenicity, self-renewal, and ability to differentiate in epithelial/myoepithelial cells of the mammary gland expressing basal and luminal cytokeratins and alpha-smooth muscle actin. In addition, tumor spheres were more resistant to doxorubicin compared with parental tumor cells. In the attempt to identify a selected marker for the sphere-generating cells, we found that Sca-1+ cells, present in tumors or enriched in mammospheres, and not CD24+ or CD29+ cells, were responsible for the sphere generation in vitro. Moreover, cells from the tumor spheres showed an increased tumor-generating ability in respect to the epithelial tumor cells. Sca-1+ sorted cells or clonal mammospheres derived from a Sca-1+ cell showed a superimposable tumor-initiating ability. The data of the present study indicate that a Sca-1+ population derived from mammary BALB-neuT tumors is responsible for sphere generation in culture and for initiating tumors in vivo.

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

2008-01-01

126

Sca-1 identifies the tumor-initiating cells in mammary tumors of BALB-neuT transgenic mice.  

Science.gov (United States)

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 characterized for clonogenicity, self-renewal, and ability to differentiate in epithelial/myoepithelial cells of the mammary gland expressing basal and luminal cytokeratins and alpha-smooth muscle actin. In addition, tumor spheres were more resistant to doxorubicin compared with parental tumor cells. In the attempt to identify a selected marker for the sphere-generating cells, we found that Sca-1(+) cells, present in tumors or enriched in mammospheres, and not CD24(+) or CD29(+) cells, were responsible for the sphere generation in vitro. Moreover, cells from the tumor spheres showed an increased tumor-generating ability in respect to the epithelial tumor cells. Sca-1(+) sorted cells or clonal mammospheres derived from a Sca-1(+) cell showed a superimposable tumor-initiating ability. The data of the present study indicate that a Sca-1(+) population derived from mammary BALB-neuT tumors is responsible for sphere generation in culture and for initiating tumors in vivo. PMID:19048122

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

2008-12-01

127

Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies.  

UK PubMed Central (United Kingdom)

Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, is one of the hallmarks of cancer that is pivotal for tumor growth and metastasis. Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Thus, the combination of angiogenesis inhibition and vessel normalization is a potential strategy for anticancer therapy. The solid tumor is composed of not only cancer cells, but also the nonmalignant resident stromal cells, such as bone-marrow-derived cells (BMDCs) and cancer-associated fibroblasts (CAFs). Tumor-associated macrophages (TAMs) are the most abundant cell components of BMDCs, which play a significant role in promoting tumor progression. Accumulating evidences from both patient biopsies and experimental animal models have shown that TAMs function in tumor angiogenesis and vessel abnormalization in a density- and phenotype-dependent manner. This chapter will discuss the evidence for the factors and signaling pathways that are involved in macrophage recruitment and polarization in the tumor microenvironment, and it summarizes the role and underlying molecular mechanisms of macrophage polarization in tumor angiogenesis and vessel normalization. In addition, an overview of the potential of targeting TAM polarization for anticancer therapy will be provided.

Chen P; Bonaldo P

2013-01-01

128

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 w...

Cianchi, Fabio; Cortesini, Camillo; Fantappiè, Ornella; Messerini, Luca; Schiavone, Nicola; Vannacci, Alfredo; Nistri, Silvia

129

Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors.  

UK PubMed Central (United Kingdom)

UNLABELLED: Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors. SIGNIFICANCE: In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.

Jaspers JE; Kersbergen A; Boon U; Sol W; van Deemter L; Zander SA; Drost R; Wientjens E; Ji J; Aly A; Doroshow JH; Cranston A; Martin NM; Lau A; O'Connor MJ; Ganesan S; Borst P; Jonkers J; Rottenberg S

2013-01-01

130

Inhibitory effects of Physalis angulata on tumor metastasis and angiogenesis.  

UK PubMed Central (United Kingdom)

UNLABELLED: ETHNOPHARMACOLOGICAL RELAVENCE: Physalis angulata is well-known in traditional Chinese medicine as a ingredient for various herbal formulation; also, it has been shown to exhibit anti-cancer and anti-inflammatory effects. In this study, the ability of P. angulata to inhibit tumor metastasis and angiogenesis was investigated. MATERIALS AND METHODS: Anti-proliferative activity of ethyl acetate extracts of P. angulata (PA extracts), was determined against human oral squamous carcinoma (HSC-3) and human umbilical vein endothelial cells (HUVECs) by trypan blue exclusion method. Wound-healing migration, trans-well invasion, Western blotting and chick chorioallantoic membrane assay were carried out to determine the anti-metastatic and anti-angiogenic effects of PA extracts in vitro and in vivo. RESULTS: We demonstrated that at sub-cytotoxic concentrations of PA extracts (5-15 ?g/mL) markedly inhibited the migration and invasion of highly metastatic HSC-3 cells as shown by wound-healing repair assay and trans-well assay. Gelatin zymography assay showed that PA extracts suppressed the activity of matrix metalloproteinase (MMP)-9 and -2, and urokinase plasminogen activator (u-PA) in HSC-3 cells. In addition, Western blot analysis confirmed that PA extracts significantly decreased MMP-2 and u-PA protein expression in HSC-3 cells. Notably, PA extracts significantly augmented the expression of their endogenous inhibitors, including tissue inhibitors of MMP (TIMP-1 and -2), and plasminogen activator inhibitors (PAI-1 and -2). Further investigations revealed that non-cytotoxic concentration of PA extracts (5-15 ?g/mL) inhibited vascular endothelial growth factor (VEGF)-induced proliferation, and migration/invasion of HUVECs in vitro. PA extracts also suppressed the activity of MMP-9, but not MMP-2, in HUVECs. Further, we observed, PA extracts strongly suppressed neovessel formation in the chorioallantoic membrane of chick embryos in vivo. CONCLUSIONS: These results strongly support an anti-metastatic and anti-angiogenic activity of P. angulata that may contribute to the development of better chemopreventive agent for cancer and inflammation.

Hseu YC; Wu CR; Chang HW; Kumar KJ; Lin MK; Chen CS; Cho HJ; Huang CY; Huang CY; Lee HZ; Hsieh WT; Chung JG; Wang HM; Yang HL

2011-06-01

131

An approach to malignant mammary phyllodes tumors detection  

Directory of Open Access Journals (Sweden)

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; Ran?elovi? Pavle; Ili? Ratko; Kati? Vuka; Milentijevi? Maja; Veli?kovi? Ljubinka; Krsti? Miljan

2009-01-01

132

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

UK PubMed Central (United Kingdom)

Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the MMTV promoter. However, the penetrance of the tumor phenotype became variable in FVB/C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3(-/-)/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3(-/-)/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors, and lung metastasis. Nevertheless, activation of ERK1/2 or AKT was reduced in ?20 week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of FAK, SRC and p38MAPK was similar to controls. All eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by Western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least ten galectins and seven MGAT GlcNAc-transferase genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identifying key galectins that promote mammary tumor progression in mouse is not straightforward because all eight galectin genes are expressed; and high levels of MGAT3, galectin-4, galectin-8, galectin-11, and galectin-14 transcripts correlate with better relapse-free survival in basal-like human breast cancer.

Miwa HE; Koba WR; Fine EJ; Giricz O; Kenny PA; Stanley P

2013-09-01

133

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

International Nuclear Information System (INIS)

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

1984-01-01

134

Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation.  

UK PubMed Central (United Kingdom)

PIK3CA, which codes for the p110? catalytic subunit of phosphatidylinositol 3-kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+);MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation.

Adams JR; Xu K; Liu JC; Agamez NM; Loch AJ; Wong RG; Wang W; Wright KL; Lane TF; Zacksenhaus E; Egan SE

2011-04-01

135

Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation.  

Science.gov (United States)

PIK3CA, which codes for the p110? catalytic subunit of phosphatidylinositol 3-kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+);MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation. PMID:21324922

Adams, Jessica R; Xu, Keli; Liu, Jeff C; Agamez, Natalia M Ruiz; Loch, Amanda J; Wong, Ruth G; Wang, Wei; Wright, Katherine L; Lane, Timothy F; Zacksenhaus, Eldad; Egan, Sean E

2011-02-15

136

Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis.  

Science.gov (United States)

Prostate cancer progression can be predicted in human tumor biopsies by abundant hyaluronan (HA) and its processing enzyme, the hyaluronidase HYAL1. Accumulation of HA is dictated by the balance between expression levels of HA synthases, the enzymes that produce HA polymers, and hyaluronidases, which process polymers to oligosaccharides. Aggressive prostate tumor cells express 20-fold higher levels of the hyaluronan synthase HAS3, but the mechanistic relevance of this correlation has not been determined. We stably overexpressed HAS3 in prostate tumor cells. Adhesion to extracellular matrix and cellular growth kinetics in vitro were significantly reduced. Slow growth in culture was restored either by exogenous addition of hyaluronidase or by stable HYAL1 coexpression. Coexpression did not improve comparably slow growth in mice, however, suggesting that excess hyaluronan production by HAS3 may alter the balance required for induced tumor growth. To address this, we used a tetracycline-inducible HAS3 expression system in which hyaluronan production could be experimentally controlled. Adjusting temporal parameters of hyaluronan production directly affected growth rate of the cells. Relief from growth suppression in vitro but not in vivo by enzymatic removal of HA effectively uncoupled the respective roles of hyaluronan in growth and angiogenesis, suggesting that growth mediation is less critical to establishment of the tumor than early vascular development. Collectively results also imply that HA processing by elevated HYAL1 expression in invasive prostate cancer is a requirement for progression. PMID:17502371

Bharadwaj, Alamelu G; Rector, Katherine; Simpson, Melanie A

2007-05-14

137

Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis.  

UK PubMed Central (United Kingdom)

Prostate cancer progression can be predicted in human tumor biopsies by abundant hyaluronan (HA) and its processing enzyme, the hyaluronidase HYAL1. Accumulation of HA is dictated by the balance between expression levels of HA synthases, the enzymes that produce HA polymers, and hyaluronidases, which process polymers to oligosaccharides. Aggressive prostate tumor cells express 20-fold higher levels of the hyaluronan synthase HAS3, but the mechanistic relevance of this correlation has not been determined. We stably overexpressed HAS3 in prostate tumor cells. Adhesion to extracellular matrix and cellular growth kinetics in vitro were significantly reduced. Slow growth in culture was restored either by exogenous addition of hyaluronidase or by stable HYAL1 coexpression. Coexpression did not improve comparably slow growth in mice, however, suggesting that excess hyaluronan production by HAS3 may alter the balance required for induced tumor growth. To address this, we used a tetracycline-inducible HAS3 expression system in which hyaluronan production could be experimentally controlled. Adjusting temporal parameters of hyaluronan production directly affected growth rate of the cells. Relief from growth suppression in vitro but not in vivo by enzymatic removal of HA effectively uncoupled the respective roles of hyaluronan in growth and angiogenesis, suggesting that growth mediation is less critical to establishment of the tumor than early vascular development. Collectively results also imply that HA processing by elevated HYAL1 expression in invasive prostate cancer is a requirement for progression.

Bharadwaj AG; Rector K; Simpson MA

2007-07-01

138

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

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 dr...

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

139

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

140

Characterization, chromosome assignment, and segregation analysis of endogenous proviral units of mouse mammary tumor virus.  

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In the course of analyzing sites of proviral integration in tumors induced by mouse mammary tumor virus (MMTV), we have isolated recombinant DNA clones corresponding to the 5' and 3' ends of four endogenous MMTV proviruses present in BALB/c and BR6 mice. This has permitted the structural characteriz...

Peters, G; Placzek, M; Brookes, S; Kozak, C; Smith, R; Dickson, C

 
 
 
 
141

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

Directory of Open Access Journals (Sweden)

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.

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

2012-01-01

142

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

UK PubMed Central (United Kingdom)

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

Kim JW; Jung SY; Kwon YH; Lee JH; Lee YM; Lee BY; Kwon SM

2012-05-01

143

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

Science.gov (United States)

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

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

2012-05-01

144

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

UK PubMed Central (United Kingdom)

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

Schöniger S; Horn LC; Schoon HA

2013-07-01

145

Localization of murine mammary tumor virus polypeptides on the surface of tumor cells  

International Nuclear Information System (INIS)

Antisera raised in rabbits against purified components gp52, p28 and p12 of murine mammary tumor virus (MuMTV) were first characterised by means of immunodiffusion, immunoelectrophoresis and radioimmunoassay. No significant cross-reactivity could be detected. The three polypeptides were detected by means of three antisera in the cytoplasm of murine mammary tumor cell lines Mm5mt/cl and C3HMT/clll, as well as in the murine leukemia cell lines GRSL18 and L1210 by means of fixed cell immunofluoresence. The concentration of gp52 in the cytoplasm seems to be considerably lower than that of the two other polypeptides. By use of the membrane immunofluorescence assay, only gp52 proved to be localized on the cell surface. Humoral cyclotoxicity was only accomplished with anti-gp52 serum. No reaction was found in either fixed-cell or membrane immunofluorescence assay or the cyclotoxicity test with the control cell lines EMT-6 and BLAB/3T3 infected with Rauscher murine leukemia virus. (author).

1979-01-01

146

New MR analysis technique reveals brain tumor response to anti-angiogenesis therapy  

Science.gov (United States)

A new way of analyzing data acquired in MR imaging appears to be able to identify whether or not tumors are responding to anti-angiogenesis therapy, information that can help physicians determine the most appropriate treatments and discontinue ones that are ineffective. In their report receiving online publication in Nature Medicine, investigators from the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (a component of the Dana-Farber Cancer Institute), describe how their technique, called vessel architectural imaging (VAI), was able to identify changes in brain tumor blood vessels within days of the initiation of anti-angiogenesis therapy.

147

Effects of 4-nitroestrone 3-methyl ether on dimethylbenz(a)anthracene-induced mammary tumors.  

UK PubMed Central (United Kingdom)

4-Nitroestrone 3-methyl ether has been shown to be an effective growth inhibitor of certain dimethylbenz(a)anthracene-induced rat mammary tumors in intact or ovariectomized rats. When administered at optimum levels (24 mg/kg daily), this A-ring-substituted estrone displayed no toxicity, slight estrogenicity, and an antitumor activity which was comparable to that of tamoxifen and nafoxidine and was surpassed only by ovariectomy or pharmacological doses of 17 beta-estradiol 3-benzoate. In addition, the appearance of mammary tumors was prevented when this estrogen derivative was administered to rats just prior to or after dimethylbenz(a)anthracene intubation. Unique to the action of the methyl ether of 4-nitroestrone on mammary tumors was the destruction of adenocarcinomas while permitting the appearance of fibroadenomas. Systemically, 4-nitroestrone 3-methyl ether brought about focal atrophy within the pituitary and ovaries while causing moderate hypertrophy of the uterus. Plasma prolactin was unaffected.

Rozhin J; Ludwig EH; Corombos J; Odden D; Horwitz JP; Hughes R; Hughes DE; Wilson E; Brooks SC

1983-06-01

148

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

Energy Technology Data Exchange (ETDEWEB)

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

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

1985-10-01

149

Impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1-null mice  

Science.gov (United States)

Despite 2 decades of research, no clear function for annexin A1 (AnxA1) has been established. Using AnxA1-KO mice, we show that tumor growth and metastasis are significantly decreased, whereas rodent survival and tumor necrosis are greatly increased when tumors grow in AnxA1-KO mice. Systems analysis of gene expression in these tumors specifically implicates 2 related vascular functions, angiogenesis and wound healing, in this impairment. Both tumor vascular development and wound healing are greatly retarded in KO tissues. Aortic ring assays reveal induced AnxA1 expression on sprouting endothelial cells of normal mice whereas KO aortas exhibit impaired endothelial cell sprouting that is rescued by adenoviral expression of AnxA1. Key differences in specific gene regulation may define new molecular pathways mediating angiogenesis, including a reset profile of pro- versus anti-angiogenic factors, apparently distinct for physiological versus pathological angiogenesis. These studies establish novel pro-angiogenic functions for AnxA1 in vascular endothelial cell sprouting, wound healing, and tumor growth and metastasis, thereby uncovering a new functional target for repairing damaged tissue and treating diseases such as cancer. They also provide critical new evidence that the tumor stroma and its microenvironment can greatly affect tumor progression and metastasis.

Yi, Ming; Schnitzer, Jan E.

2009-01-01

150

Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion.  

UK PubMed Central (United Kingdom)

BACKGROUND: Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. AIM: To assess the prognostic significance of microvessel quantification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. PATIENTS/METHODS: Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 microns) were analyzed and endothelined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII). The microvessel count was performed from the identification of the area with increased microvessel density--hot spots--and results of the mean in five of these fields. RESULTS: The cut-off microvessel count was 14 microvessels/0.785 mm2, which divided the sample into hypovascular and hypervascular groups. While 2/8 (25%) tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73%) tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. CONCLUSIONS: The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.

Tarta C; Teixeira CR; Tanaka S; Haruma K; Chiele-Neto C; da Silva VD

2002-01-01

151

Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion  

Directory of Open Access Journals (Sweden)

Full Text Available Background - Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. Aim - To assess the prognostisc significance of microvessel quantification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. Patients/Methods - Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 µm) were analyzed and endothellined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII). The microvessel count was performed from the identification of the area with increased microvessel density - hot spots - and results of the mean in five of these fields. Results- The cut-off microvessel count was 14 microvessels/0,785 mm² , which divided the sample into hypovascular and hypervascular groups. While 2/8 (25%) tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73%) tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. Conclusions - The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.

TARTA Cláudio; TEIXEIRA Cláudio Rolim; TANAKA Shinji; HARUMA Ken; CHIELE-NETO César; SILVA Vinícius Duval da

2002-01-01

152

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

DEFF Research Database (Denmark)

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

153

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

154

Brief Report: Intravital Imaging of Cancer Stem Cell Plasticity in Mammary Tumors  

Science.gov (United States)

It is widely debated whether all tumor cells in mammary tumors have the same potential to propagate and maintain tumor growth or whether there is a hierarchical organization. Evidence for the latter theory is mainly based on the ability or failure of transplanted tumor cells to produce detectable tumors in mice with compromised immune systems; however, this assay has lately been disputed to accurately reflect cell behavior in unperturbed tumors. Lineage tracing experiments have recently shown the existence of a small population of cells, referred to as cancer stem cells (CSCs), that maintains and provides growth of squamous skin tumors and intestinal adenomas. However, the lineage tracing techniques used in these studies provide static images and lack the ability to study whether stem cell properties can be obtained or lost, a process referred to as stem cell plasticity. Here, by intravital lineage tracing, we report for the first time the existence of CSCs in unperturbed mammary tumors and demonstrate CSC plasticity. Our data indicate that existing CSCs disappear and new CSCs form during mammary tumor growth, illustrating the dynamic nature of these cells. Stem Cells 2013;31:602–606

Zomer, Anoek; Ellenbroek, Saskia Inge Johanna; Ritsma, Laila; Beerling, Evelyne; Vrisekoop, Nienke; Van Rheenen, Jacco

2013-01-01

155

Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway.  

Science.gov (United States)

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. PMID:23908598

Wang, Yugang; Ning, Yu; Alam, Goleeta N; Jankowski, Brandon M; Dong, Zhihong; Nör, Jacques E; Polverini, Peter J

2013-08-01

156

Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway1  

Science.gov (United States)

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.

Wang, Yugang; Ning, Yu; Alam, Goleeta N; Jankowski, Brandon M; Dong, Zhihong; Nor, Jacques E; Polverini, Peter J

2013-01-01

157

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

UK PubMed Central (United Kingdom)

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

Masuda T; Hattori N; Senoo T; Akita S; Ishikawa N; Fujitaka K; Haruta Y; Murai H; Kohno N

2013-08-01

158

Inhibition of the p110? isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis.  

Science.gov (United States)

Understanding the direct, tumor cell-intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell-extrinsic PI3K activity, mediated by the p110? isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110? led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110? in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110? in the tumor stroma is thus a regulator of vessel formation, with p110? inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor-centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110? may thus offer a new antiangiogenic therapeutic opportunity in cancer. PMID:24043760

Soler, Adriana; Serra, Helena; Pearce, Wayne; Angulo, Ana; Guillermet-Guibert, Julie; Friedman, Lori S; Viñals, Francesc; Gerhardt, Holger; Casanovas, Oriol; Graupera, Mariona; Vanhaesebroeck, Bart

2013-09-16

159

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine  

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AIM: To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1) isolated from an extract of herbal medicine Sorbaria sorbifolia. METHODS: Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM) method. Microvessel densit...

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

160

Rapid Analysis of Vessel Elements (RAVE): A Tool for Studying Physiologic, Pathologic and Tumor Angiogenesis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

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 measurement...

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

 
 
 
 
161

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

Science.gov (United States)

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.

2010-01-01

162

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

Directory of Open Access Journals (Sweden)

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.

Shibata Masa-Aki; Morimoto Junji; Shibata Eiko; Kurose Hitomi; Akamatsu Kanako; Li Zhong-Lian; Kusakabe Moriaki; Ohmichi Masahide; Otsuki Yoshinori

2010-01-01

163

In vitro angiogenesis induced by tumor-endothelial cell co-culture in bilayered, collagen I hydrogel bioengineered tumors.  

Science.gov (United States)

Although successful remission has been achieved when cancer is diagnosed and treated during its earliest stages of development, a tumor that has established neovascularization poses a significantly greater risk of mortality. The inability to recapitulate the complexities of a maturing in vivo tumor microenvironment in an in vitro setting has frustrated attempts to identify and test anti-angiogenesis therapies that are effective at permanently halting cancer progression. We have established an in vitro tumor angiogenesis model driven solely by paracrine signaling between MDA-MB-231 breast cancer cells and telomerase-immortalized human microvascular endothelial (TIME) cells co-cultured in a spatially relevant manner. The bilayered bioengineered tumor model consists of TIME cells cultured as an endothelium on the surface of an acellular collagen I hydrogel under which MDA-MB-231 cells are cultured in a separate collagen I hydrogel. Results showed that TIME cells co-cultured with the MDA-MB-231 cells demonstrated a significant increase in cell number, rapidly developed an elongated morphology, and invasively sprouted into the underlying acellular collagen I layer. Comparatively, bioengineered tumors cultured with less aggressive MCF7 breast cancer cells did not elicit an angiogenic response. Angiogenic sprouting was demonstrated by the formation of a complex capillary-like tubule network beneath the surface of a confluent endothelial monolayer with lumen formation and anastomosing branches. In vitro angiogenesis was dependent on vascular endothelial growth factor secretion, matrix concentration, and duration of co-culture. Basic fibroblast growth factor supplemented to the co-cultures augmented angiogenic sprouting. The development of improved preclinical tumor angiogenesis models, such as the one presented here, is critical for accurate evaluation and refinement of anti-angiogenesis therapies. PMID:23516987

Szot, Christopher S; Buchanan, Cara F; Freeman, Joseph W; Rylander, Marissa Nichole

2013-04-26

164

Involvement of angiogenesis in weight-loss in tumor-bearing and diet-restricted animals.  

UK PubMed Central (United Kingdom)

The body's weight loss mechanism while in a tumor-bearing state is still unclear. In this study, we investigated expressions of angiogenic factors in the adipose tissue of tumor-bearing and diet-restricted rabbits evaluating the differences between the two groups. We postulated that low nutrition induced vasculogenesis to transport nutrition in the adipose tissues of diet-restricted rabbits, unlike in tumor-bearing rabbits, and that vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were related to angiogenesis of the adipose tissues. Although we investigated the expressions of VEGF and PD-ECGF immunohistochemically in tumor-bearing and diet-restricted rabbits, there was no significant difference between the two groups. Whether angiogenesis of the adipose tissue in the diet-restricted animals may be observed during the nutritional recovery period should be investigated.

Sumi T; Ishiko O; Yoshida H; Hyun Y; Ogita S

2001-11-01

165

Involvement of angiogenesis in weight-loss in tumor-bearing and diet-restricted animals.  

Science.gov (United States)

The body's weight loss mechanism while in a tumor-bearing state is still unclear. In this study, we investigated expressions of angiogenic factors in the adipose tissue of tumor-bearing and diet-restricted rabbits evaluating the differences between the two groups. We postulated that low nutrition induced vasculogenesis to transport nutrition in the adipose tissues of diet-restricted rabbits, unlike in tumor-bearing rabbits, and that vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were related to angiogenesis of the adipose tissues. Although we investigated the expressions of VEGF and PD-ECGF immunohistochemically in tumor-bearing and diet-restricted rabbits, there was no significant difference between the two groups. Whether angiogenesis of the adipose tissue in the diet-restricted animals may be observed during the nutritional recovery period should be investigated. PMID:11605023

Sumi, T; Ishiko, O; Yoshida, H; Hyun, Y; Ogita, S

2001-11-01

166

Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells.  

UK PubMed Central (United Kingdom)

Stat1 is deficient or inactive in many types of human tumors whereas some tumors have activated Stat1. Whether Stat1 affects tumor growth and metastasis is unclear. In the present study, we used Stat1 knockout tumor cells to determine (1) whether Stat1 can regulate angiogenesis, growth, and metastasis of tumor cells; and (2) whether Stat1 is required for the inhibitory effect of IFN-beta on the expression of angiogenic factor bFGF. Highly tumorigenic and metastatic RAD-105 tumor cells derived from a fibrosarcoma of a Stat1 knockout mouse were reconstituted with a Stat1 expression vector. The reconstitution of Stat1 suppressed the tumorigenicity and metastasis of RAD-105 cells in nude mice which correlated with a decreased microvessel density and decreased expression of proangiogenic molecules bFGF, MMP-2, and MMP-9 in vivo. Moreover, noncytotoxic concentrations of IFN-beta significantly inhibited the in vitro expression of bFGF in the Stat1-reconstituted cells but not in the Stat1-deficient cells, which was consistent with decreased bFGF expression of Stat1-reconstituted tumors in vivo. Therefore, Stat1 is essential for IFN-mediated inhibition of bFGF production, suggesting that tumor-intrinsic Stat1 is an important mediator for antiangiogenic signals, such as IFN. Collectively, these data demonstrate that Stat1 expressed by tumor cells is a negative regulator of tumor angiogenesis and, hence, tumor growth and metastasis.

Huang S; Bucana CD; Van Arsdall M; Fidler IJ

2002-04-01

167

Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation.  

UK PubMed Central (United Kingdom)

Breast cancer developed in familial BRCA1 mutation carriers bears striking similarities to sporadic basal-like breast tumors. The mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that the deletion of p18(Ink4c) (p18), an inhibitor of G1 cyclin Ds-dependent CDK4 and CDK6, stimulates mammary luminal progenitor cell proliferation and leads to spontaneous luminal tumor development. We report here that germline mutation of Brca1 in p18-deficient mice blocks the increase of luminal progenitor cells, impairs luminal gene expression and promotes malignant transformation of mammary tumors. Instead of the luminal mammary tumors developed in p18 single-mutant mice, mammary tumors developed in the p18;Brca1 mice, similar to breast cancer developed in familial BRCA1 carriers, exhibited extensive basal-like features and lost the remaining wild-type allele of Brca1. These results reveal distinct functions of the RB and BRCA1 pathways in suppressing luminal and basal-like mammary tumors, respectively. These results also suggest a novel mechanism--causing luminal-to-basal transformation--for the development of basal-like breast cancer in familial BRCA1 carriers and establish a unique mouse model for developing therapeutic strategies to target both luminal and basal-like breast cancers.

Bai F; Smith MD; Chan HL; Pei XH

2013-05-01

168

Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation.  

Science.gov (United States)

Breast cancer developed in familial BRCA1 mutation carriers bears striking similarities to sporadic basal-like breast tumors. The mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that the deletion of p18(Ink4c) (p18), an inhibitor of G1 cyclin Ds-dependent CDK4 and CDK6, stimulates mammary luminal progenitor cell proliferation and leads to spontaneous luminal tumor development. We report here that germline mutation of Brca1 in p18-deficient mice blocks the increase of luminal progenitor cells, impairs luminal gene expression and promotes malignant transformation of mammary tumors. Instead of the luminal mammary tumors developed in p18 single-mutant mice, mammary tumors developed in the p18;Brca1 mice, similar to breast cancer developed in familial BRCA1 carriers, exhibited extensive basal-like features and lost the remaining wild-type allele of Brca1. These results reveal distinct functions of the RB and BRCA1 pathways in suppressing luminal and basal-like mammary tumors, respectively. These results also suggest a novel mechanism--causing luminal-to-basal transformation--for the development of basal-like breast cancer in familial BRCA1 carriers and establish a unique mouse model for developing therapeutic strategies to target both luminal and basal-like breast cancers. PMID:22777348

Bai, F; Smith, M D; Chan, H L; Pei, X-H

2012-07-09

169

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)

2008-01-01

170

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

171

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

UK PubMed Central (United Kingdom)

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.

Liu P; Li J; Zhang C; Xu LX

2013-06-01

172

Tissue factor regulates tumor angiogenesis of retinoblastoma via the extracellular signal-regulated kinase pathway.  

Science.gov (United States)

Retinoblastoma, a well-vascularized tumor that is dependent on a very robust angiogenic response, is the most common intraocular malignancy in children. Tissue factor (TF) is known to regulate tumor progression and in the present study we demonstrated that TF regulates tumor angiogenesis of retinoblastoma. In an orthotopic transplantation model of retinoblastoma, TF was selectively expressed in the proliferative area of retinoblastoma including tumor vessels as well as tumor cells, where TF expression was co-localized with endothelial cells of tumor vessels. TF expression progressively increased with fibroblast growth factor-2 (FGF-2)-induced proliferation of human umbilical vein endothelial cells (HUVECs), which was effectively inhibited by blockade of the TF pathway by TF pathway inhibitor (TFPI). In addition, FGF-2-induced angiogenic processes of migration and tube formation of vascular endothelial cells were also effectively suppressed by TFPI, which would be mediated by inhibition of extracellular signal-regulated kinase activation. Therefore, further to our previous report that TF is involved in tumor cell proliferation of retinoblastoma, our current data suggest that blockade of the TF pathway by TFPI could effectively inhibit tumor growth by suppressing tumor cell proliferation and tumor angiogenesis at the same time. PMID:23007470

Song, Hyun Beom; Park, Kyung Duk; Kim, Jin Hyoung; Kim, Dong Hun; Yu, Young Suk; Kim, Jeong Hun

2012-09-20

173

Tissue factor regulates tumor angiogenesis of retinoblastoma via the extracellular signal-regulated kinase pathway.  

UK PubMed Central (United Kingdom)

Retinoblastoma, a well-vascularized tumor that is dependent on a very robust angiogenic response, is the most common intraocular malignancy in children. Tissue factor (TF) is known to regulate tumor progression and in the present study we demonstrated that TF regulates tumor angiogenesis of retinoblastoma. In an orthotopic transplantation model of retinoblastoma, TF was selectively expressed in the proliferative area of retinoblastoma including tumor vessels as well as tumor cells, where TF expression was co-localized with endothelial cells of tumor vessels. TF expression progressively increased with fibroblast growth factor-2 (FGF-2)-induced proliferation of human umbilical vein endothelial cells (HUVECs), which was effectively inhibited by blockade of the TF pathway by TF pathway inhibitor (TFPI). In addition, FGF-2-induced angiogenic processes of migration and tube formation of vascular endothelial cells were also effectively suppressed by TFPI, which would be mediated by inhibition of extracellular signal-regulated kinase activation. Therefore, further to our previous report that TF is involved in tumor cell proliferation of retinoblastoma, our current data suggest that blockade of the TF pathway by TFPI could effectively inhibit tumor growth by suppressing tumor cell proliferation and tumor angiogenesis at the same time.

Song HB; Park KD; Kim JH; Kim DH; Yu YS; Kim JH

2012-12-01

174

Tumor Delivery of Chemotherapy Combined with Inhibitors of Angiogenesis and Vascular Targeting Agents.  

UK PubMed Central (United Kingdom)

Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most are used in polytherapy regimens. This review looks at recent progress and our own preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways, and vascular targeting agents with conventional chemotherapy, discussing the factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated with drug distribution and activity are reviewed. Modalities to improve drug delivery and strategies for optimizing combination therapy are examined.

Cesca M; Bizzaro F; Zucchetti M; Giavazzi R

2013-01-01

175

Immunochemical Characterization of Two Major Polypeptides from Murine Mammary Tumor Virus  

Digital Repository Infrastructure Vision for European Research (DRIVER)

A major murine mammary tumor viral (MMTV) antigen, sl, originally described by Nowinski et al. (1967, 1968, 1971), has been purified from RIII mouse milk MMTV by sequential ion-exchange and gel chromatography. The purified protein with sl antigenic reactivity contains carbohydrate, and has an appare...

Parks, Wade P.; Howk, Richard S.; Scolnick, Edward M.; Oroszlan, Steve; Gilden, Raymond V.

176

Combined effect of cyclocytidine and lentinan of spontaneous mammary tumors in mice.  

UK PubMed Central (United Kingdom)

Cytotoxic cytidine analog, cyclocytidine, and antitumor immunopotentiator, lentinan, offered an opportunity of testing the effect of combined modality of cytocidal agent and immunopotentiator on spontaneous mammary tumors of mice. Lentinan did not improve the therapeutic effect of cyclocytidine; it only prevented the early toxic death of mice due to cyclocytidine in one strain of mice but not in the other strain.

Tokuzen R; Okabe M; Nakahara LW

1976-04-01

177

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Mouse mammary tumor virus (MMTV) is a betaretrovirus that infects rodent cells and uses mouse transferrin receptor 1 for cell entry. To characterize the interaction of MMTV with its receptor, we aligned the MMTV envelope surface (SU) protein with that of Friend murine leukemia virus (F-MLV) and iden...

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

178

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

A fragment of the mouse mammary tumor virus (MMTV) promoter was reconstituted from pure histones into a dinucleosome with uniquely positioned octamer cores. Core boundaries for the in vitro-assembled dinucleosome corresponded to the observed in vivo phasing pattern for long terminal repeat nucleosom...

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

179

Requirements for Mouse Mammary Tumor Virus Rem Signal Peptide Processing and Function  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Mouse mammary tumor virus (MMTV) encodes a Rev-like protein, Rem, which is involved in the nuclear export and expression of viral RNA. Previous data have shown that all Rev-like functions are localized to the 98-amino-acid signal peptide (SP) at the N terminus of MMTV Rem or envelope proteins. MMTV-...

Byun, Hyewon; Halani, Nimita; Gou, Yongqiang; Nash, Andrea K.; Lozano, Mary M.; Dudley, Jaquelin P.

180

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

In this retrospective study, quantitative and qualitative analyses of argyrophil nucleolar organizer regions (AgNORs) in 54 malignant and 18 benign canine mammary gland tumors were made. Statistical analysis showed a significant difference in the mean number of AgNORs per cell between benign and mal...

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

 
 
 
 
181

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.  

UK PubMed Central (United Kingdom)

Placental growth factor (PlGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PlGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PlGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PlGF-induced vascular normalization. Thus, PlGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PlGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.

Yang X; Zhang Y; Yang Y; Lim S; Cao Z; Rak J; Cao Y

2013-08-01

182

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.  

Science.gov (United States)

Placental growth factor (PlGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PlGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PlGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PlGF-induced vascular normalization. Thus, PlGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PlGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy. PMID:23918367

Yang, Xiaojuan; Zhang, Yin; Yang, Yunlong; Lim, Sharon; Cao, Ziquan; Rak, Janusz; Cao, Yihai

2013-08-05

183

Scutellaria barbata D. Don Inhibits Tumor Angiogenesis via Suppression of Hedgehog Pathway in a Mouse Model of Colorectal Cancer  

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Full Text Available Angiogenesis, which plays a critical role during tumor development, is tightly regulated by the Sonic Hedgehog (SHH) pathway, which has been known to malfunction in many types of cancer. Therefore, inhibition of angiogenesis via modulation of the SHH signaling pathway has become very attractive for cancer chemotherapy. Scutellaria barbata D. Don (SB) has long been used in China to treat various cancers including colorectal cancer (CRC). Our published data suggested that the ethanol extract of SB (EESB) is able to induce apoptosis of colon cancer cells and inhibit angiogenesis in a chick embryo chorioallantoic membrane model. To further elucidate the precise mechanisms of its anti-tumor activity, in the present study we used a CRC mouse xenograft model to evaluate the effect of EESB on tumor growth and angiogenesis in vivo. Our current data indicated that EESB reduces tumor size without affecting on the body weight gain in CRC mice. In addition, EESB treatment suppresses the expression of key mediators of the SHH pathway in tumor tissues, which in turn resulted in the inhibition of tumor angiogenesis. Furthermore, EESB treatment inhibits the expression of vascular endothelial growth factor A (VEGF-A), an important target gene of SHH signaling and functioning as one of the strongest stimulators of angiogenesis. Our findings suggest that inhibition of tumor angiogenesis via suppression of the SHH pathway might be one of the mechanisms by which Scutellaria barbata D. Don can be effective in the treatment of cancers.

Lihui Wei; Jiumao Lin; Wei Xu; Qiaoyan Cai; Aling Shen; Zhenfeng Hong; Jun Peng

2012-01-01

184

Inhibiting effect of ascorbic acid on the growth of human mammary tumor xenografts.  

UK PubMed Central (United Kingdom)

The effect of ascorbic acid on the growth of a human mammary tumor in mice has been investigated using the 6-d subrenal capsule assay method. The results indicated that ascorbic acid administered in the drinking water significantly inhibited the growth of the tumor fragments implanted beneath the renal capsule of mice. Administration of a mixture of ascorbic acid and cupric sulfate orally or intraperitoneally significantly inhibited tumor growth in these mice, whereas neither alone was effective. These results support the hypothesis that certain oxidation or degradation products of ascorbic acid were active antineoplastic agents for the human mammary tumor studied. The activity of D-isoascorbic acid, an isomer of ascorbic acid, was similar to that of ascorbic acid. This suggests that the antitumor activity of ascorbic acid was not due to the metabolism of ascorbic acid as a vitamin, but due to its chemical properties.

Tsao CS

1991-12-01

185

Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice  

Science.gov (United States)

Tumor metastasis is the most common cause of death in cancer patients. Here, we show that two, fully synthetic migrastatin analogues, core macroketone and core macrolactam, are potent inhibitors of metastasis in a murine breast tumor model. Administration of these readily accessible compounds nearly completely inhibits lung metastasis of highly metastatic mammary carcinoma cells. Treatment of tumor cells with core macroketone and core macrolactam blocks Rac activation, lamellipodia formation, and cell migration, suggesting that these chemical compounds interfere with the invasion step of the metastatic process. These compounds also inhibit the migration of human metastatic breast cancer cells, prostate cancer cells, and colon cancer cells but not normal mammary-gland epithelial cells, fibroblasts, and leukocytes. These data demonstrate that the macroketone and macrolactam core structures are specific small-molecule inhibitors of tumor metastasis. These compounds or their analogues could potentially be used in cancer-therapy strategies.

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

2005-01-01

186

{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

187

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

International Nuclear Information System (INIS)

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

2004-01-01

188

Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors.  

UK PubMed Central (United Kingdom)

INTRODUCTION: Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. METHODS: Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. RESULTS: Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSCs-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs got consistent results. Compared with tumors induced by injection of tumor cells alone, blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells (HUVEC). When hBM-MSCs exposed to DU145 cells environment, the expression of markers associated with neovascularization (macrophage inflammatory protein-2 (MIP-2), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and interleukin-6 (IL6) were increased. CONCLUSIONS: These results indicate that BM-MSCs promote tumor growth and suggest that the crosstalk between tumor cells and BM-MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.

Zhang T; Lee YW; Rui YF; Cheng TY; Jiang XH; Li G

2013-06-01

189

Hyperspectral imaging system to discern malignant and benign canine mammary tumors  

Science.gov (United States)

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

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

2013-05-01

190

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

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

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

2012-01-01

191

CD133+ Renal Progenitor Cells Contribute to Tumor Angiogenesis  

Science.gov (United States)

In the present study, we tested the hypothesis that resident progenitor cells may contribute to tumor vascularization and growth. CD133+ cells were isolated from 30 human renal carcinomas and characterized as renal resident progenitor cells on the basis of the expression of renal embryonic and mesenchymal stem cell markers. CD133+ progenitors differentiated into endothelial and epithelial cells as the normal CD133+ counterpart present in renal tissue. In the presence of tumor-derived growth factors, these cells were committed to differentiate into endothelial cells able to form vessels in vivo in SCID mice. Undifferentiated CD133+ progenitors were unable to form tumors when transplanted alone in SCID mice. When co-transplanted with renal carcinoma cells, CD133+ progenitors significantly enhanced tumor development and growth. This effect was not attributable to the tumorigenic nature of CD133+ progenitor cells because the same results were obtained with CD133+ cells from normal kidney. CD133+ progenitors contributed to tumor vascularization as the majority of neoformed vessels present within the transplanted tumors were of human origin and derived from the co-transplanted CD133+ progenitors. In conclusion, these results indicate the presence of a renal progenitor cell population in renal carcinomas that may differentiate in endothelial cells and favor vascularization and tumor growth.

Bruno, Stefania; Bussolati, Benedetta; Grange, Cristina; Collino, Federica; Efrem Graziano, Manuela; Ferrando, Ugo; Camussi, Giovanni

2006-01-01

192

Mammary tumor development is directly inhibited by lifelong n-3 polyunsaturated fatty acids.  

UK PubMed Central (United Kingdom)

INTRODUCTION: Despite the advocacy that diet may be a significant contributor to cancer prevention, there is a lack of direct evidence from epidemiological and experimental studies to substantiate such claims. Experimental studies suggest that n-3 polyunsaturated fatty acids (n-3 PUFA) from marine oils may reduce breast cancer risk, however, findings are equivocal. Thus, in this study, novel transgenic mouse models were employed to provide, for the first time, direct evidence for an anti-cancer role of n-3 PUFA in mammary tumorigenesis. METHODS: fat-1 Mice, which are capable of endogenous n-3 PUFA synthesis, were bred with mouse mammary tumor virus (MMTV)-neu(ndl)-YD5 mice, an aggressive breast cancer model. The resultant offspring, including novel hybrid progeny, were assessed for tumor onset, size and multiplicity as well as n-3 PUFA composition in mammary gland and tumor tissue. A complementary group of MMTV-neu(ndl)-YD5 mice were fed n-3 PUFA in the diet. RESULTS: Mice expressing MMTV-neu(ndl)-YD5 and fat-1 displayed significant (P<.05) reductions in tumor volume (~30%) and multiplicity (~33%), as well as reduced n-6 PUFA and enriched n-3 PUFA in tumor phospholipids relative to MMTV-neu(ndl)-YD5 control mice. The effect observed in hybrid progeny was similarly observed in n-3 PUFA diet fed mice. CONCLUSION: Using complementary genetic and conventional dietary approaches we provide, for the first time, unequivocal experimental evidence that n-3 PUFA is causally linked to tumor prevention.

MacLennan MB; Clarke SE; Perez K; Wood GA; Muller WJ; Kang JX; Ma DW

2013-01-01

193

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

Directory of Open Access Journals (Sweden)

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

Indik Stanislav; Günzburg Walter H; Kulich Pavel; Salmons Brian; Rouault Francoise

2007-01-01

194

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

Directory of Open Access Journals (Sweden)

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

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

2004-01-01

195

Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis.  

UK PubMed Central (United Kingdom)

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

Nie D; Lamberti M; Zacharek A; Li L; Szekeres K; Tang K; Chen Y; Honn KV

2000-01-01

196

Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis.  

Science.gov (United States)

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis. PMID:10623605

Nie, D; Lamberti, M; Zacharek, A; Li, L; Szekeres, K; Tang, K; Chen, Y; Honn, K V

2000-01-01

197

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

Directory of Open Access Journals (Sweden)

Full Text Available In this retrospective study, quantitative and qualitative analyses of argyrophil nucleolar organizer regions (AgNORs) in 54 malignant and 18 benign canine mammary gland tumors were made. Statistical analysis showed a significant difference in the mean number of AgNORs per cell between benign and malignant tumors (p0.05), as well as between adenomas and benign mixed tumors (p>0.05). Six different patterns of AgNOR distribution were observed. Types I, II, III and in only two cases, type IV, were observed in benign tumors, while all six types were observed in malignant tumors. The predominant types in malignant tumors were III, IV, V and VI. Cell types II, III and IV were predominant in malignant tumors with 5.5-7 AgNORs per cell, while cell types V and VI were dominant in tumors with more than 7 AgNORs per cell.

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

2003-01-01

198

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

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Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissue, adipose tissue juxtaposed to implanted tumors exhibited reduced adipocyte size, extensive fibrosis, increased angiogenesis and a dense macrophage infiltrate. A mouse cytokine protein array revealed up-regulation of inflammatory mediators including IL-6, CXCL1, MCP-1, MIP-2 and TIMP-1 in peritumoral versus counterpart adipose tissues. CD11b(+) macrophages contributed strongly to the inflammatory activity. These macrophages were isolated from peritumoral adipose tissue and found to over-express ARG1, NOS2, CD301, CD163, MCP-1 and VEGF, which are indicative of both M1 and M2 polarization. Tumors implanted at a site distant from subcutaneous, anterior adipose tissue were strongly growth-delayed, had fewer blood vessels and were less populated by CD11b(+) macrophages. In contrast to normal adipose tissue, micro-dissected peritumoral adipose tissue explants launched numerous vascular sprouts when cultured in an ex vivo model. Thus, inflamed tumor-associated adipose tissue fuels the growth of malignant cells by acting as a proximate source for vascular endothelium and activated pro-inflammatory cells, in particular macrophages. PMID:22614697

Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge; Melero-Martin, Juan M; Lin, Ruei-Zeng; Klagsbrun, Michael; Dudley, Andrew C

2012-05-22

199

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

UK PubMed Central (United Kingdom)

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

Ning S; Liang N; Liu B; Chen X; Pang Q; Xin T

2013-02-01

200

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

Science.gov (United States)

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 into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.

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

 
 
 
 
201

Contrast-enhanced color Doppler US in breast cancer: Tumoral vascularity correlated with angiogenesis  

International Nuclear Information System (INIS)

To evaluate the effects of contrast-enhanced color Doppler ultrasonography (CDUS) on the depiction of vascularity and flow pattern in breast cancer and to determine the relationship between tumoral vascularity and angiogenesis. Twenty-one patients with breast cancer were prospectively evaluated with CDUS before and after injection of the contrast agent (SH U 508A, 2.5g, 300 mg/ml ). The tumoral vascularity was expressed as percentage of color Doppler area, which was measured quantitatively by a computerized program (Ultrasonic Imaging Tool; Soongsil University, Seoul, Korea). The flow pattern (four-patterns; spotty, linear, branching, marginal) of the vascularity was analyzed. After surgery, tumor angiogenesis was assessed by microvessel density. The relationship between the vascularity on CDUS and microvessel density was statistically analyzed. At unenhanced CDUS, tumoral flow signals were detected in 12 lesions (48%); at contrast-enhanced CDUS, 18 lesions (86%). All These 18 lesions showed increased signals, compared with those at unenhanced CDUS. The percentage color Doppler area was 1.86 ± 0.48% at unenhanced CDUS and 5.23 ± 1.18% at contrast-enhanced CDUS. The flow patterns before contrast injection were spotty pattern in 11 tumors and linear pattern in one; after contrast injection, spotty in 8, linear in 4, branching in 5, and marginal in one. The tumoral vascularity at contrast-enhanced CDUS showed no significant correlation with microvessel density. Contrast-enhanced CDUS seems to be a valuable tool in the depiction of vascularity and characterization of flow pattern in breast cancer. However, tumoral vascularity on CDUS may not reflect tumoral angiogenesis.

2000-01-01

202

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.  

UK PubMed Central (United Kingdom)

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes--or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

Otto B; Streichert T; Wegwitz F; Gevensleben H; Klätschke K; Wagener C; Deppert W; Tolstonog GV

2013-03-01

203

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.  

Science.gov (United States)

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes--or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis. PMID:23161608

Otto, Benjamin; Streichert, Thomas; Wegwitz, Florian; Gevensleben, Heidrun; Klätschke, Kristin; Wagener, Christoph; Deppert, Wolfgang; Tolstonog, Genrich V

2012-12-13

204

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

International Nuclear Information System (INIS)

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

2007-03-01

205

Potential role of SC1, a cell adhesion molecule, in mammary gland tumors.  

UK PubMed Central (United Kingdom)

SC1, an immunoglobulin superfamily cell adhesion molecule, is expressed in embryonic tissues and plays an important role in development through its cell adhesive activity. SC1 is also found in a variety of tumors and its expression is associated with a poor prognosis. The expressional patterns of SC1 were examined in sporadic cases of canine mammary gland tumors and it was found that this molecule is enriched in adenocarcinomas and is weaker in benign mixed tumors. SC1 might therefore be involved in the malignancy and progression of canine mammary gland tumors. To confirm this paradigm, the mammary gland cell line JYG-B was used as the recipient of SC1 cDNA. The resulting SC1-transfected cells were subsequently analyzed using a convenient in vitro model system. The self-aggregation activity of SC1-transfected cells was significantly increased and was blocked by an anti-SC1 antibody generated by hyper-immunized ostrich yolk. In addition, cell locomotion assays revealed an enhanced migration activity of SC1-transfected cells on SC1-coated transwell chambers. The in vivo activities of the cells were examined by subcutaneous implantation into nude mice. Tumor growth was significantly promoted in the mice after implantation with SC1-transfected cells, in comparison to parental- and mock-transfectants. This growth was inhibited by oral administration of gold-ion water. The invasion of SC1-transfectants into the surrounding muscular and adipose tissues was rigorously enhanced. These findings suggest that SC1 might promote the progression of mammary gland tumor cells by increasing cell adhesion.

Adachi K; Hagimori K; Kato H; Fukuda K; Kikuta M; Tsukamoto Y

2008-03-01

206

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

UK PubMed Central (United Kingdom)

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.

Prats AC; 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

207

p73 Overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis.  

Science.gov (United States)

Tumor neovascularization is controlled by a balance between positive and negative effectors, whose production can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate whether the angiogenic potential of tumors could also be controlled by p73, a gene homologous to the tumor suppressor p53, whose involvement in tumor angiogenesis is known. We have studied the production of proangiogenic (VEGF, FGF-2, PIGF and PDGF) and antiangiogenic (TSP-1) factors in two p73 overexpressing clones obtained from the human ovarian carcinoma cells A2780. TSP-1 was downregulated in both clones compared to mock transfected cells, both at mRNA and protein level. Conversely, both clones showed an increased production of VEGF mRNA and protein. For both TSP-1 and VEGF, regulation of expression was partially due to modulation of the promoter activity, and was dependent on p53 status. Production of the other angiogenic factors FGF-2, PIGF and PDGF-B was also increased in p73 overexpressing clones. The two clones were more angiogenic than parental cells, as shown in vitro by their increased chemotactic activity for endothelial cells, and in vivo by the generation of more vascularized tumors. These findings suggest a potential role of p73 in tumor angiogenesis. PMID:11704858

Vikhanskaya, F; Bani, M R; Borsotti, P; Ghilardi, C; Ceruti, R; Ghisleni, G; Marabese, M; Giavazzi, R; Broggini, M; Taraboletti, G

2001-11-01

208

Suppression of Tumor Growth and Angiogenesis in Vivo by a Truncated Form of 24-kd Fibroblast Growth Factor (FGF)-2  

Science.gov (United States)

Efforts to treat tumors have routinely depended on disruption of cell proliferation by a variety of methods, many involving stimulation of apoptosis. We have previously shown that a truncated form of 24-kd basic fibroblast growth factor consisting of the amino terminal 86 amino acids inhibits migration of tumor and endothelial cells in vitro. In the present study, this peptide was tested for its ability to suppress angiogenesis and tumor growth using the murine dorsal skin-fold chamber model in vivo. Treatment of MCF-7 breast carcinoma tumor spheroids with this peptide resulted in cessation of the angiogenic response and a significant reduction in tumor size. Blood vessels that did form were poorly developed. In addition to inhibiting angiogenesis, the peptide also inhibited migration of Lewis lung carcinoma cells away from the tumor core before onset of angiogenesis indicating that the peptide-mediated inhibition of migration affects both angiogenesis and tumor growth independently. Despite inhibition of tumor cell migration, the peptide had no effect on neutrophil or eosinophil chemotaxis. This study demonstrates that the truncated form of 24-kd basic fibroblast growth factor is effective in suppressing tumor development in vivo through inhibition of angiogenesis as well as inhibition of tumor cell migration without compromising other homeostatic events.

Levin, Eugene G.; Sikora, Lyudmila; Ding, Lan; Rao, Savita P.; Sriramarao, P.

2004-01-01

209

MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth.  

UK PubMed Central (United Kingdom)

FGF2 and VEGFA are the two most potent angiogenic factors. Here we report that miR-503 can simultaneously down-regulate FGF2 and VEGFA. The expression of miR-503 is repressed in HCC cells and primary tumors due to a potential epigenetic mechanism. Overexpression of miR-503 reduced tumor angiogenesis in vitro and in vivo. We also found that miR-503 expression was down-regulated by hypoxia through HIF1?. These results identify a miRNA that targets both FGF2 and VEGFA in cancers, demonstrate the anti-angiogenesis role of miR-503 in tumorigenesis, and provide a novel mechanism for hypoxia-induced FGF2 and VEGFA through HIF1?-mediated inhibition of miR-503.

Zhou B; Ma R; Si W; Li S; Xu Y; Tu X; Wang Q

2013-06-01

210

A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis.  

UK PubMed Central (United Kingdom)

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185(BCR-ABL+) B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16(INK4a) and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16(INK4a), providing an internal safeguard. However, in the absence of p16(INK4a), CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16(INK4a).

Kollmann K; Heller G; Schneckenleithner C; Warsch W; Scheicher R; Ott RG; Schäfer M; Fajmann S; Schlederer M; Schiefer AI; Reichart U; Mayerhofer M; Hoeller C; Zöchbauer-Müller S; Kerjaschki D; Bock C; Kenner L; Hoefler G; Freissmuth M; Green AR; Moriggl R; Busslinger M; Malumbres M; Sexl V

2013-08-01

211

A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis.  

Science.gov (United States)

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185(BCR-ABL+) B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16(INK4a) and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16(INK4a), providing an internal safeguard. However, in the absence of p16(INK4a), CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16(INK4a). PMID:23948297

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

2013-08-12

212

TRAF6 upregulates expression of HIF-1? and promotes tumor angiogenesis.  

UK PubMed Central (United Kingdom)

TNF receptor (TNFR)-associated factor TRAF6 is a key activator of NF-?B, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses. TRAF6 interactions determine receptor-induced cell death versus survival. TRAF6 has been implicated in cancer but its contributions have not been investigated deeply. In this study, we show that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)-1?. TRAF6 affects HIF-1? protein levels but has little effect on mRNA level. TRAF6 increases HIF-1? protein independent of oxygen. We found that TRAF6 binds HIF-1? and mediates its K63-linked polyubiquitination. The E3 ligase activity of TRAF6 was required to increase HIF-1? protein levels. Finally, we showed that TRAF6 promoted tumor angiogenesis and growth. Our results reveal how TRAF6 functions to upregulate HIF-1? expression and promote tumor angiogenesis.

Sun H; Li XB; Meng Y; Fan L; Li M; Fang J

2013-08-01

213

CD133+ Renal Progenitor Cells Contribute to Tumor Angiogenesis  

Digital Repository Infrastructure Vision for European Research (DRIVER)

In the present study, we tested the hypothesis that resident progenitor cells may contribute to tumor vascularization and growth. CD133+ cells were isolated from 30 human renal carcinomas and characterized as renal resident progenitor cells on the basis of the expression of renal embryonic and mesen...

Bruno, Stefania; Bussolati, Benedetta; Grange, Cristina; Collino, Federica; Efrem Graziano, Manuela; Ferrando, Ugo

214

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

DEFF Research Database (Denmark)

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

Willmann, Jürgen K; Cheng, Zhen

2008-01-01

215

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

UK PubMed Central (United Kingdom)

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

Staudt ND; Jo M; Hu J; Bristow JM; Pizzo DP; Gaultier A; VandenBerg SR; Gonias SL

2013-07-01

216

G protein-coupled receptor kinase 6 deficiency promotes angiogenesis, tumor progression, and metastasis.  

UK PubMed Central (United Kingdom)

G protein-coupled receptor kinases (GRKs) phosphorylate the activated form of G protein-coupled receptors leading to receptor desensitization and downregulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis, and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6(-/-)) exhibited a significant increase in Lewis lung cancer growth and metastasis relative to control littermates (GRK6(+/+)). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor, but upregulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs, and microvessel density. Because ?-arrestin-2-deficient (?arr2(-/-)) mice exhibited increased Lewis lung cancer growth and metastasis similar to that of GRK6(-/-), we developed a double GRK6(-/-)/?arr2(-/-) mouse model. Surprisingly, GRK6(-/-)/?arr2(-/-) mice exhibited faster tumor growth relative to GRK6(-/-) or ?arr2(-/-) mice. Treatment of the mice with anti-CXCR2 Ab inhibited tumor growth in both GRK6(-/-) and GRK6(-/-)/?arr2(-/-) animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression, and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment, thereby promoting angiogenesis and metastasis. Because GRK6(-/-)/?arr2(-/-) showed greater tumor growth relative to GRK6(-/-) or ?arr2(-/-) mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis.

Raghuwanshi SK; Smith N; Rivers EJ; Thomas AJ; Sutton N; Hu Y; Mukhopadhyay S; Chen XL; Leung T; Richardson RM

2013-05-01

217

Notch signaling regulates tumor-induced angiogenesis in SPARC-overexpressed neuroblastoma.  

Science.gov (United States)

Despite existing aggressive treatment modalities, the prognosis for advanced stage neuroblastoma remains poor with significant long-term illness in disease survivors. Advance stage disease features are associated with tumor vascularity, and as such, angiogenesis inhibitors may prove useful along with current therapies. The matricellular protein, secreted protein acidic and rich in cysteine (SPARC), is known to inhibit proliferation and migration of endothelial cells stimulated by growth factors. Here, we sought to determine the effect of SPARC on neuroblastoma tumor cell-induced angiogenesis and to decipher the molecular mechanisms involved in angiogenesis inhibition. Conditioned medium from SPARC-overexpressed neuroblastoma cells (pSPARC-CM) inhibited endothelial tube formation, cell proliferation, induced programmed cell death and suppressed expression of pro-angiogenic molecules such as VEGF, FGF, PDGF, and MMP-9 in endothelial cells. Further analyses revealed that pSPARC-CM-suppressed expression of growth factors was mediated by inhibition of the Notch signaling pathway, and cells cultured on conditioned medium from tumor cells that overexpress both Notch intracellular domain (NICD-CM) and SPARC resumed the pSPARC-CM-suppressed capillary tube formation and growth factor expression in vitro. Further, SPARC overexpression in neuroblastoma cells inhibited neo-vascularization in vivo in a mouse dorsal air sac model. Furthermore, SPARC overexpression-induced endothelial cell death was observed by co-localization studies with TUNEL assay and an endothelial marker, CD31, in xenograft tumor sections from SPARC-overexpressed mice. Our data collectively suggest that SPARC overexpression induces endothelial cell apoptosis and inhibits angiogenesis both in vitro and in vivo. PMID:22956186

Gorantla, Bharathi; Bhoopathi, Praveen; Chetty, Chandramu; Gogineni, Venkateswara Rao; Sailaja, G S; Gondi, Christopher S; Rao, Jasti S

2012-09-06

218

Notch signaling regulates tumor-induced angiogenesis in SPARC-overexpressed neuroblastoma.  

UK PubMed Central (United Kingdom)

Despite existing aggressive treatment modalities, the prognosis for advanced stage neuroblastoma remains poor with significant long-term illness in disease survivors. Advance stage disease features are associated with tumor vascularity, and as such, angiogenesis inhibitors may prove useful along with current therapies. The matricellular protein, secreted protein acidic and rich in cysteine (SPARC), is known to inhibit proliferation and migration of endothelial cells stimulated by growth factors. Here, we sought to determine the effect of SPARC on neuroblastoma tumor cell-induced angiogenesis and to decipher the molecular mechanisms involved in angiogenesis inhibition. Conditioned medium from SPARC-overexpressed neuroblastoma cells (pSPARC-CM) inhibited endothelial tube formation, cell proliferation, induced programmed cell death and suppressed expression of pro-angiogenic molecules such as VEGF, FGF, PDGF, and MMP-9 in endothelial cells. Further analyses revealed that pSPARC-CM-suppressed expression of growth factors was mediated by inhibition of the Notch signaling pathway, and cells cultured on conditioned medium from tumor cells that overexpress both Notch intracellular domain (NICD-CM) and SPARC resumed the pSPARC-CM-suppressed capillary tube formation and growth factor expression in vitro. Further, SPARC overexpression in neuroblastoma cells inhibited neo-vascularization in vivo in a mouse dorsal air sac model. Furthermore, SPARC overexpression-induced endothelial cell death was observed by co-localization studies with TUNEL assay and an endothelial marker, CD31, in xenograft tumor sections from SPARC-overexpressed mice. Our data collectively suggest that SPARC overexpression induces endothelial cell apoptosis and inhibits angiogenesis both in vitro and in vivo.

Gorantla B; Bhoopathi P; Chetty C; Gogineni VR; Sailaja GS; Gondi CS; Rao JS

2013-01-01

219

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

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 ...

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

220

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

2013-06-05

 
 
 
 
221

The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis  

Science.gov (United States)

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.

Wertheim, Gerald B. W.; Yang, Thomas W.; Pan, Tien-chi; Ramne, Anna; Liu, Zhandong; Gardner, Heather P.; Dugan, Katherine D.; Kristel, Petra; Kreike, Bas; van de Vijver, Marc J.; Cardiff, Robert D.; Reynolds, Carol; Chodosh, Lewis A.

2009-01-01

222

Effects of a high molecular mass Convolvulus arvensis extract on tumor growth and angiogenesis.  

UK PubMed Central (United Kingdom)

BACKGROUND: Plant materials represent promising sources of anti-cancer agents. We developed and tested a novel extract from the ubiquitous plant Convolvulus arvensis. MATERIALS AND METHODS: Convolvulus arvensis components were extracted in boiling water, and small molecules were removed by high-pressure filtration. The extract's biological activity was assessed by measuring its effects on S-180 fibrosarcoma growth in Kun Ming mice and on heparin-induced angiogenesis in chick embryos. We also examined the extract's effects on lymphocytes ex vivo and tumor cell growth in vitro. RESULTS: The extract (primarily proteins and polysaccharides) inhibited tumor growth in a dose-dependent fashion when administered orally. At the highest dose tested, 200 mg/kg/day, tumor growth was inhibited by roughly seventy percent. Subcutaneous or intraperitoneal administration at 50 mg/kg/day also inhibited tumor growth by over seventy percent. The extract's acute LD50 in Kun Ming mice was 500 mg/kg/day when injected, indicating that tumor growth inhibition occurred at non-toxic doses. It inhibited angiogenesis in chick embryos, improved lymphocyte survival ex vivo, and enhanced yeast phagocytosis, but did not kill tumor cells in culture. CONCLUSION: High molecular mass extract deserves further study as an anti-cancer agent.

Meng XL; Riordan NH; Casciari JJ; Zhu Y; Zhong J; González MJ; Miranda-Massari JR; Riordan HD

2002-12-01

223

Numerical simulation of the inhibitory effect of angiostatin on metastatic tumor angiogenesis and microenvironment.  

UK PubMed Central (United Kingdom)

The present work formulates and analyzes the inhibitory effect of anti-angiogenic factor angiostatin excreted by the primary tumor on metastatic tumor angiogenesis, blood perfusion, and interstitial fluid flow in the tumor microenvironment by means of a numerical experiment. The simulation results demonstrate that angiostatin has an obvious impact on the morphology, growth rate, and the number of branches of microvascular network inside and outside the metastatic tumor, and angiostatin has the capacity to regulate and inhibit the formation of new blood vessels. Heterogeneous blood perfusion, widespread interstitial hypertension, and low convection within the metastatic tumor have obviously improved under the inhibitory effect of angiostatin, which are consistent with physiological observed facts. The simulation results may provide beneficial information and theoretical models for clinical research of anti-angiogenic therapy strategies.

Zhao G; Yan W; Chen E; Yu X; Cai W

2013-02-01

224

Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice.  

UK PubMed Central (United Kingdom)

BACKGROUND: Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis. METHODS: Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1(-/-) or Akt2(-/-) mice. Tumor onset, growth rate, and metastasis were determined. RESULTS: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors. CONCLUSIONS: Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer.

Watson KL; Moorehead RA

2013-01-01

225

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...

Murata, Takahisa; Lin, Michelle I.; Aritake, Kosuke; Matsumoto, Shigeko; Narumiya, Shu; Ozaki, Hiroshi; Urade, Yoshihiro

226

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal ...

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

227

Antiangiogenesis therapy using a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay  

International Nuclear Information System (INIS)

The present study investigated whether treatment with anginex, a novel antiangiogenic peptide, could block re-vascularization after radiation treatment. A squamous cell (SCCVII) xenograft tumor mouse model was employed to assess the effects of anginex given post-radiation on tumor growth, microvessel density (MVD), and oxygen levels. The oxygen status was determined by the partial pressure of O2. Tumors in untreated mice increased threefold in 7.0 days, anginex-treated tumors (10 mg/kg intraperitoneal, twice) required 7.3±0.9 days, and tumors exposed to 8-Gy radiation increased threefold over 11 days. Combination treatment of anginex and radiation caused the tumors to grow threefold in 16.1±1.6 days, a delay which was significant and deemed supra-additive. Oxygen levels in tumors treated by stand-alone or combination therapies were significantly reduced; for example from 19.5±4.9 mmHg in controls to 9.7±1.9 mmHg in combination-treated, size-matched tumors. In addition, immunohistochemistry showed a decrease in MVD in the tumors treated with anginex, radiation, or the combination. These results suggest that a combination of anginex and radiation can greatly affect the amount of functional vasculature in tumors and prolong radiation-induced tumor regression. Antiangiogenesis therapy with anginex, in addition to radiotherapy, will be useful by blocking angiogenesis-dependent regrowth of vessels. (author)

2007-01-01

228

Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis.  

UK PubMed Central (United Kingdom)

BACKGROUND: Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix and basement membrane. Expression of the heparanase gene is associated with the invasive, angiogenic, and metastatic potential of diverse malignant tumors and cell lines. We used gene-silencing strategies to evaluate the role of heparanase in malignancy and to explore the therapeutic potential of its specific targeting. METHODS: We designed plasmid vectors to express hammerhead ribozymes or small interfering RNAs (siRNAs) directed against the human or mouse heparanase mRNAs. Human breast carcinoma (MDA-MB-435) and mouse lymphoma (Eb) and melanoma (B16-BL6) tumor cell lines, which have naturally high levels of endogenous heparanase or have been genetically engineered to overexpress heparanase, were transfected with anti-heparanase ribozyme or siRNA. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and measurements of enzymatic activity were used to confirm the efficient silencing of heparanase gene expression. Cells transfected with the anti-heparanase ribozyme and siRNA vectors were tested for invasiveness in vitro and metastatic dissemination in animal models of experimental and spontaneous metastasis. RESULTS: Compared with cells transfected with control constructs, cells transfected with the anti-heparanase ribozyme or siRNA vectors had profoundly reduced invasion and adhesion in vitro, regardless of cell type, and expressed less heparanase. In vivo, tumors produced by cells transfected with the anti-heparanase ribozyme and siRNA vectors were less vascularized and less metastatic than tumors produced by cells transfected with the control vectors. Mice injected with cells transfected with the anti-heparanase ribozyme and siRNA vectors lived longer than mice injected with control cells. CONCLUSIONS: The association of reduced levels of heparanase and altered tumorigenic properties in cells with anti-heparanase ribozyme- or siRNA-mediated gene-silencing vectors suggests that heparanase is important in cancer progression. Heparanase gene silencing has potential use as a target for anticancer drug development.

Edovitsky E; Elkin M; Zcharia E; Peretz T; Vlodavsky I

2004-08-01

229

Prognostic significance of tumor angio-genesis in advanced breast carcinoma: And Indian experience  

International Nuclear Information System (INIS)

Angio-genesis is essential for tumor growth and metastasis. In the present study we investigated the prognostic significance of microvessels (MV) density using immunohisto-localization of factor VIII antigen i 51 breast cancer patients. We counted microvessels per 200 x field in the most active areas of neovasculilarization by staining factor VIII related antigen and correlated with stage, LN involvement and histologic grade. Patient who subsequently developed metastases had significantly high MV counts than patients without metastatic disease (p25 MV per 200 x field had tumor recurrence faster as compared with patients having

1997-01-01

230

Prepn process and application of kringle variant protein for inhibiting angiogenesis, tumorigenesis and tumor metastasis  

UK PubMed Central (United Kingdom)

The present invention belongs to the field of applying genetic engineering technology for producing protein medicine in biomedicine preparing domain. The present invention discloses the preparation process and application of one new kind of prourokinase Kringle structure domain variant protein mUKK capable of inhibiting angiogensis, tumorigenesis and tumor metastasis. The preparation process includes constituting mUKK expressing recombinant plasmid, realizing the efficient expression of the recombinant plasmid in colibacillus, and separating and purifying to obtain the protein medicine with high purity. The protein medicine may be applied in the treatment of tumor, obesity, diabetes, cardiac and cerebral vascular diseases and other abnormal angiogenesis related diseases.

LIU JIANNING ZHANG

231

Segregation patterns of endogenous mouse mammary tumor viruses in five recombinant inbred strain sets.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

We identified mouse mammary tumor proviral loci in the AKR/J, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, and SWR/J inbred mouse strains and determined their segregation patterns in the AKXD, AKXL, BXD, BXH, and SWXL recombinant inbred strain sets. Two new Mtv loci, Mtv-29 and Mtv-30, were identified. Mtv-30...

Lee, B K; Eicher, E M

232

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

Directory of Open Access Journals (Sweden)

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

Jovi? Slavoljub; Magaš V.; Aleksi?-Kova?evi? Sanja

2007-01-01

233

Anti-Gb3 monoclonal antibody inhibits angiogenesis and tumor development.  

UK PubMed Central (United Kingdom)

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

Desselle A; Chaumette T; Gaugler MH; Cochonneau D; Fleurence J; Dubois N; Hulin P; Aubry J; Birklé S; Paris F

2012-01-01

234

In vivo imaging of tumor angiogenesis using fluorescence confocal videomicroscopy.  

Science.gov (United States)

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

2013-09-11

235

In vivo Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy.  

UK PubMed Central (United Kingdom)

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.

Fitoussi V; Faye N; Chamming's F; Clement O; Cuenod CA; Fournier LS

2013-01-01

236

Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors.  

Science.gov (United States)

Inhibitors of angiogenesis are an important addition to conventional chemotherapy. Among different "druggable" angiogenic factors, fibroblast growth factor-2 (FGF-2) is an attractive target for novel therapies because of its intricated involvement in tumor neovascularization, tumor cell proliferation and migration, and the acquisition of resistance to antiangiogenic therapies. FGF-2 bioavailability and activity is affected by several natural ligands, including the endogenous inhibitor of angiogenesis thrombospondin-1 (TSP-1). We hypothesized that the FGF-2-binding sequence of TSP-1 might serve as a template for the development of non-peptide inhibitors of angiogenesis. Computational biology and nuclear magnetic resonance spectroscopy approaches, major investigative tools in the characterizations of protein-protein interaction (PPI), were used to map the residues at the TSP-1/FGF-2 interface. The translation of this three-dimensional information into a pharmacophore model allowed screening a small molecule databases, identifying three FGF-2-binding, antiangiogenic small molecules, mimetic of TSP-1. Pharmacophore-based approaches are thus feasible tools to exploit naturally occurring PPI, by generating a set of lead compounds mimetic of endogenous proteins, as a starting point for the development of novel therapeutic agents. PMID:21317461

Taraboletti, Giulia; Rusnati, Marco; Ragona, Laura; Colombo, Giorgio

2010-11-01

237

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

Directory of Open Access Journals (Sweden)

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

Gurzov Esteban N; Nabha Sanaa M; Yamamoto Hamilto; Meng Hong; Scharovsky O Graciela; Bonfil R Daniel

2007-01-01

238

Bioavailability and efficacy of a gap junction enhancer (PQ7) in a mouse mammary tumor model.  

Science.gov (United States)

The loss of gap junctional intercellular communication is characteristic of neoplastic cells, suggesting that the restoration with a gap junction enhancer may be a new therapeutic treatment option with less detrimental effects than traditional antineoplastic drugs. A gap junction enhancer, 6-methoxy-8-[(2-furanylmethyl) amino]-4-methyl-5-(3-trifluoromethylphenyloxy) quinoline (PQ7), on the normal tissue was evaluated in healthy C57BL/6J mice in a systemic drug distribution study. Immunoblot analysis of the vital organs indicates a reduction in Cx43 expression in PQ7-treated animals with no observable change in morphology. Next the transgenic strain FVB/N-Tg(MMTV-PyVT) 634Mul/J (also known as PyVT) was used as a spontaneous mammary tumor mouse model to determine the biological and histological effects of PQ7 on tumorigenesis and metastasis at three stages of development: Pre tumor, Early tumor, and Late tumor formation. PQ7 was assessed to have a low toxicity through intraperitoneal administration, with the majority of the compound being detected in the heart, liver, and lungs six hours post injection. The treatment of tumor bearing animals with PQ7 had a 98% reduction in tumor growth, while also decreasing the total tumor burden compared to control mice during the Pre stage of development. PQ7 treatment increased Cx43 expression in the neoplastic tissue during Pre-tumor formation; however, this effect was not observed in Late stage tumor formation. This study shows that the gap junction enhancer, PQ7, has low toxicity to normal tissue in healthy C57BL/6J mice, while having clinical efficacy in the treatment of spontaneous mammary tumors of PyVT mice. Additionally, gap junctional intercellular communication and neoplastic cellular growth are shown to be inversely related, while treatment with PQ7 inhibits tumor growth through targeting gap junction expression. PMID:23776708

Shishido, Stephanie N; Prasain, Keshar; Beck, Amanda; Nguyen, Thi D T; Hua, Duy H; Nguyen, Thu Annelise

2013-06-12

239

Bioavailability and efficacy of a gap junction enhancer (PQ7) in a mouse mammary tumor model.  

UK PubMed Central (United Kingdom)

The loss of gap junctional intercellular communication is characteristic of neoplastic cells, suggesting that the restoration with a gap junction enhancer may be a new therapeutic treatment option with less detrimental effects than traditional antineoplastic drugs. A gap junction enhancer, 6-methoxy-8-[(2-furanylmethyl) amino]-4-methyl-5-(3-trifluoromethylphenyloxy) quinoline (PQ7), on the normal tissue was evaluated in healthy C57BL/6J mice in a systemic drug distribution study. Immunoblot analysis of the vital organs indicates a reduction in Cx43 expression in PQ7-treated animals with no observable change in morphology. Next the transgenic strain FVB/N-Tg(MMTV-PyVT) 634Mul/J (also known as PyVT) was used as a spontaneous mammary tumor mouse model to determine the biological and histological effects of PQ7 on tumorigenesis and metastasis at three stages of development: Pre tumor, Early tumor, and Late tumor formation. PQ7 was assessed to have a low toxicity through intraperitoneal administration, with the majority of the compound being detected in the heart, liver, and lungs six hours post injection. The treatment of tumor bearing animals with PQ7 had a 98% reduction in tumor growth, while also decreasing the total tumor burden compared to control mice during the Pre stage of development. PQ7 treatment increased Cx43 expression in the neoplastic tissue during Pre-tumor formation; however, this effect was not observed in Late stage tumor formation. This study shows that the gap junction enhancer, PQ7, has low toxicity to normal tissue in healthy C57BL/6J mice, while having clinical efficacy in the treatment of spontaneous mammary tumors of PyVT mice. Additionally, gap junctional intercellular communication and neoplastic cellular growth are shown to be inversely related, while treatment with PQ7 inhibits tumor growth through targeting gap junction expression.

Shishido SN; Prasain K; Beck A; Nguyen TD; Hua DH; Nguyen TA

2013-01-01

240

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

UK PubMed Central (United Kingdom)

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(hi)/CD49f(hi)/CD24(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 RB; Wang Q; Khillan JS

2013-07-01

 
 
 
 
241

Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis?  

Science.gov (United States)

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1?/?) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1?/? mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1?/? tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1?/? tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.

Ma, Zhefu; Gibson, Shannon L.; Byrne, Maura A.; Zhang, Junran; White, Morris F.; Shaw, Leslie M.

2006-01-01

242

Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis.  

UK PubMed Central (United Kingdom)

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1(-/-)) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1(-/-) mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1(-/-) tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1(-/-) tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.

Ma Z; Gibson SL; Byrne MA; Zhang J; White MF; Shaw LM

2006-12-01

243

Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis.  

Science.gov (United States)

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1(-/-)) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1(-/-) mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1(-/-) tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1(-/-) tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer. PMID:17030605

Ma, Zhefu; Gibson, Shannon L; Byrne, Maura A; Zhang, Junran; White, Morris F; Shaw, Leslie M

2006-10-09

244

Expression of pigment epithelium-derived factor and tumor necrosis factor-? is correlated in bladder tumor and is related to tumor angiogenesis.  

UK PubMed Central (United Kingdom)

OBJECTIVE: Angiogenesis is a pivotal process on which solid tumor growth is substantially dependent. Pigment epithelium-derived factor (PEDF) is the most potent natural anti-angiogenic factor, which has seldom been studied in bladder tumor, and whose functioning pathway remains unclear. We have thus investigated PEDF expression in relation to tumor necrosis factor-? (TNF-?) and microvessel density (MVD) with immunohistochemistry. METHODS: Antibodies of PEDF and TNF-? were examined by Western blotting before immunohistochemistry. Sixty-four urothelial tumor sections and 23 normal controls were stained and expression of PEDF, TNF-?, and MVD were studied. RESULTS: Decreased PEDF expression and increased TNF-? expression was noticed in tumorous tissue compared with healthy urothelium. Lower PEDF expression was related to higher tumor grade but stage. Increased TNF-? expression was noticed in recurrent, larger tumors as well as in tumors with progression in grade and stage. Expression of PEDF and TNF-? was correlated in bladder tumor. PEDF or TNF-? was correlated with MVD negatively or positively, respectively, in cancerous tissue and tumorous grouping without correlation in papillary urothelial neoplasm of low malignant potential. CONCLUSION: Expressional change of PEDF and TNF-? is in relation to angiogenesis of bladder tumor, especially in bladder cancer development.

Feng CC; Wang PH; Ding Q; Guan M; Zhang YF; Jiang HW; Wen H; Wu Z

2013-02-01

245

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

UK PubMed Central (United Kingdom)

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

Wang FL; Sun JY; Wang Y; Mu YL; Liang YJ; Chong ZZ; Qin SH; Yao QQ

2013-01-01

246

Luteolin Supplementation Modulates Mammary Tumor Growth in C3H Mice Fed Diet with High- and Low-Fat Content.  

UK PubMed Central (United Kingdom)

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

Song MJ; Lee EJ; Yang Y; Sung MK

2013-09-01

247

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

Directory of Open Access Journals (Sweden)

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; Rubenstein Marvin; Guinan Patrick

2005-01-01

248

A low molecular weight polysaccharide isolated from Agaricus blazei suppresses tumor growth and angiogenesis in vivo.  

UK PubMed Central (United Kingdom)

Previous studies indicated that the low molecular weight polysaccharide extracts from Agaricus blazei are potential antitumor agents or adjuvant in tumor treatment. In this study, we investigated the antitumor activity of LMPAB, a low molecular weight polysaccharide isolated from Agaricus blazei, and the molecular mechanisms of its antitumor activity. The antitumor effect of LMPAB was examined using mouse sarcoma 180 (S180) xenograft models. Antiangiogenic effect of LMPAB was determined by chicken embryo chorioallantoic membrane (CAM) angiogenesis and Matrigel-induced neovascularization in vivo models. The mRNA and protein levels of vascular endothelial growth factor (VEGF) were assessed using real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assays. Tumor inhibitory rates in the S180 xenograft models were 9.7, 23.9, and 33.0%, respectively, after administration of LMPAB at dose of 50, 100, and 200 mg/kg/day for 2 weeks. LMPAB also inhibited angiogenesis in the CAM model and Matrigel-induced neovascularization in C57BL/6 mice. The mRNA and protein levels of VEGF in tumor tissues were significantly down-regulated in the BALB/c mice received LMPAB treatment. Furthermore, significant down-regulation of serum VEGF levels was also observed in the mice. Our data suggest that LMPAB might be a promising agent for tumor therapy, and the antitumor and antiangiogenic effects of LMPAB may be related with down-regulation of VEGF.

Niu YC; Liu JC; Zhao XM; Wu XX

2009-01-01

249

A low molecular weight polysaccharide isolated from Agaricus blazei suppresses tumor growth and angiogenesis in vivo.  

Science.gov (United States)

Previous studies indicated that the low molecular weight polysaccharide extracts from Agaricus blazei are potential antitumor agents or adjuvant in tumor treatment. In this study, we investigated the antitumor activity of LMPAB, a low molecular weight polysaccharide isolated from Agaricus blazei, and the molecular mechanisms of its antitumor activity. The antitumor effect of LMPAB was examined using mouse sarcoma 180 (S180) xenograft models. Antiangiogenic effect of LMPAB was determined by chicken embryo chorioallantoic membrane (CAM) angiogenesis and Matrigel-induced neovascularization in vivo models. The mRNA and protein levels of vascular endothelial growth factor (VEGF) were assessed using real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assays. Tumor inhibitory rates in the S180 xenograft models were 9.7, 23.9, and 33.0%, respectively, after administration of LMPAB at dose of 50, 100, and 200 mg/kg/day for 2 weeks. LMPAB also inhibited angiogenesis in the CAM model and Matrigel-induced neovascularization in C57BL/6 mice. The mRNA and protein levels of VEGF in tumor tissues were significantly down-regulated in the BALB/c mice received LMPAB treatment. Furthermore, significant down-regulation of serum VEGF levels was also observed in the mice. Our data suggest that LMPAB might be a promising agent for tumor therapy, and the antitumor and antiangiogenic effects of LMPAB may be related with down-regulation of VEGF. PMID:19082455

Niu, Y C; Liu, J C; Zhao, X M; Wu, X X

2009-01-01

250

"Click" conjugation of peptide on the surface of polymeric nanoparticles for targeting tumor angiogenesis.  

UK PubMed Central (United Kingdom)

PURPOSE: Angiogenesis plays a critical role in tumor growth. This phenomena is regulated by numerous mediators such as vascular endothelial growth factor (VEGF). CBO-P11, a cyclo-peptide, has proven to specifically bind to receptors of VEGF and may be used as targeting ligand for tumor angiogenesis. We herein report the design of novel nanoparticles conjugated to CBO-P11 in order to specifically target tumor site. METHODS: The conjugation of CBO-P11 on the surface of poly(vinylidene fluoride) (PVDF) nanoparticles was investigated using the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition known as "click" reaction. CBO-P11 was modified with a near-infrared cyanine dye bearing an alkyne function, allowing both "click" coupling on azido-modified nanoparticles and fluorescence labelling. Each step of this nanodevice construction was judiciously performed in aqueous solution and successfully characterized. The cytotoxicity of nanoparticles was evaluated in human brain endothelial cell line and their affinity for VEGF receptors was determined via fluorescence-based uptake assays on porcine aortic endothelial cell line. RESULTS: Nanoparticles were found to be spherical, dense, monodisperse and stable. No cytotoxicity was observed after four days of incubation demonstrating the biocompatibility of nanoparticles. Fluorescence highlighted the specific interaction of these functionalized nanoparticles for VEGF receptors, suggesting that the targeting peptide bioactivity was retained. CONCLUSIONS: These results demonstrate the potential of these functionalized nanoparticles for targeting tumor angiogenesis and their possible use as multifunctional platform for cancer treatment if coupled with therapeutic agents.

Deshayes S; Maurizot V; Clochard MC; Baudin C; Berthelot T; Esnouf S; Lairez D; Moenner M; Déléris G

2011-07-01

251

Estrogen receptor isoforms and progestin hormone dependence in a mouse mammary tumor model.  

Science.gov (United States)

The close interaction between receptors and other transcription factors suggests that their corresponding transducing signals can trigger functional and structural changes in other related molecules. The effect of a progestinic agent, medroxyprogesterone acetate (MPA), on some of the estrogen-receptor (ER) parameters was studied in 2 murine mammary tumor sublines with different progestin hormone dependence for their respective growth. The relative binding affinity of estradiol and tamoxifen for the ER, the receptor content and the ER isoforms studied by HPLC were determined in the hormone-autonomous (HA) and the hormone-dependent (HD) tumor sublines. In the HA subline administration of MPA did not modify the tumor growth rate, whereas this was accelerated in the HD subline. The ER content was clearly increased in the HD tumor subline, but not in the HA subline, compared with the untreated controls. In contrast, the E2 and tamoxifen relative binding affinity for the ER and the isoform profiles were affected by MPA treatment in the HA, but not in the HD tumor subline. The functional change (decrease in relative binding affinity) can be attributed to the appearance of a lower-molecular-size ER isoform under the progestinic treatment. Modifications in one receptor molecule by the action of ligands corresponding to another type of receptor show the interconection between transcription factors and the necessity of broadening conventional concepts regarding hormone dependence in mammary tumorigenesis. PMID:8077051

Actis, A M; Caruso, S P; Levin, E

1994-09-01

252

Estrogen receptor isoforms and progestin hormone dependence in a mouse mammary tumor model.  

UK PubMed Central (United Kingdom)

The close interaction between receptors and other transcription factors suggests that their corresponding transducing signals can trigger functional and structural changes in other related molecules. The effect of a progestinic agent, medroxyprogesterone acetate (MPA), on some of the estrogen-receptor (ER) parameters was studied in 2 murine mammary tumor sublines with different progestin hormone dependence for their respective growth. The relative binding affinity of estradiol and tamoxifen for the ER, the receptor content and the ER isoforms studied by HPLC were determined in the hormone-autonomous (HA) and the hormone-dependent (HD) tumor sublines. In the HA subline administration of MPA did not modify the tumor growth rate, whereas this was accelerated in the HD subline. The ER content was clearly increased in the HD tumor subline, but not in the HA subline, compared with the untreated controls. In contrast, the E2 and tamoxifen relative binding affinity for the ER and the isoform profiles were affected by MPA treatment in the HA, but not in the HD tumor subline. The functional change (decrease in relative binding affinity) can be attributed to the appearance of a lower-molecular-size ER isoform under the progestinic treatment. Modifications in one receptor molecule by the action of ligands corresponding to another type of receptor show the interconection between transcription factors and the necessity of broadening conventional concepts regarding hormone dependence in mammary tumorigenesis.

Actis AM; Caruso SP; Levin E

1994-09-01

253

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

International Nuclear Information System (INIS)

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

1987-01-01

254

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

Directory of Open Access Journals (Sweden)

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

2010-01-01

255

Revisiting a role for a mammary tumor retrovirus in human breast cancer.  

UK PubMed Central (United Kingdom)

There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum.

Salmons B; Gunzburg WH

2013-10-01

256

Revisiting a role for a mammary tumor retrovirus in human breast cancer.  

Science.gov (United States)

There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum. PMID:23580334

Salmons, Brian; Gunzburg, Walter H

2013-05-15

257

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

UK PubMed Central (United Kingdom)

PURPOSE: 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 IC(50) 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 × 10(7) cells/200 ?L) 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 IC(50) 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.

Mahasiripanth T; Hokputsa S; Niruthisard S; Bhattarakosol P; Patumraj S

2012-01-01

258

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] 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)

2006-01-01

259

Human tumor cells induce angiogenesis through positive feedback between CD147 and insulin-like growth factor-I.  

UK PubMed Central (United Kingdom)

Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). In this study, we made a three-dimensional (3D) tumor angiogenesis model using a co-culture system of human hepatocellular carcinoma cells SMMC-7721 and humanumbilical vein endothelial cells (HUVECs) in vitro. We found that CD147-expressing cancer cells could promote HUVECs to form net-like structures resembling the neo-vasculature, whereas the ability of proliferation, migration and tube formation of HUVECs was significantly decreased in tumor conditioned medium (TCM) of SMMC-7721 cells transfected with specific CD147-siRNA. Furthermore, by assaying the change of pro-angiogenic factors in TCM, we found that the inhibition of CD147 expression led to significant decrease of VEGF and insulin-like growth factor-I (IGF-I) secretion. Interestingly, we also found that IGF-I up-regulated the expression of CD147 in both tumor cells and HUVECs. These findings suggest that there is a positive feedback between CD147 and IGF-I at the tumor-endothelial interface and CD147 initiates the formation of an angiogenesis niche.

Chen Y; Gou X; Ke X; Cui H; Chen Z

2012-01-01

260

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

Energy Technology Data Exchange (ETDEWEB)

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

Janssens, J.P.; Wittevrongel, C.; Van Dam, J.; Goddeeris, P.; Lauwerijns, J.M.; De Loecker, W.

1981-02-01

 
 
 
 
261

Expression of DLL4 and VEGF in Lung Adenocarcinoma and their Relationship with Angiogenesis in Tumor  

Directory of Open Access Journals (Sweden)

Full Text Available Background and objective Angiogenesis depends on the interaction of a variety of promoting factors and inhibiting factors. Vascular endothelial growth factor (VEGF) and Notch signaling pathway take part in this process. This experiment investigates the expression of Notch ligand DLL4 and VEGF in lung adenocarcinoma and theirrelationship with angiogenesis in tumor. Methods Immunohistochemical method was used to detect DLL4, VEGF and CD34 protein expression in 80 cases of lung adenocarcinoma (including bronchioloalveolar carcinoma and common lung adenocarcinoma) paraffin section tissues. Results The expression of DLL4 and VEGF was closely related to tumordiameter, clinical stage, histological grade and lymph node metastasis, the VEGF expression rate in DLL4 positive expression cases was significantly more than the DLL4 negative cases, the correlation between microvascular density and DLL4, VEGF co-expression was more significant, the expression of DLL4 in common lung adenocarcinoma was significantly higher than that in bronchioloalveolar carcinoma. Conclusion The prognosis of lung adenocarcinoma is significant correlated with the angiogenesis, high expression of DLL4 is closely related to the metastasis and the prognosis.

Xiaoping LI; Qingfu ZHANG; Bin LU; Xueshan QIU; Yang LUO; Weidong ZHANG; Shun XU

2009-01-01

262

Animal model for mammary tumor growth in the bone microenvironment.  

UK PubMed Central (United Kingdom)

Advanced breast cancer commonly spreads to the bones, lungs, liver or brain, and bone is the most common site of breast cancer metastasis. Nearly all patients with advanced breast cancer develop bone metastasis and suffer from serious bone metastasis-associated complications, including chronic pain, fracture, spinal cord compression and hypercalcemia. Metastasis formation in the bone is a complex process that requires cooperative reciprocal interactions between tumor cells and the cellular environment of the bone, which includes osteoclasts and osteoblasts. We have developed a murine bone invasion model of breast cancer, which required a simple surgical technique and mimics the biology of the disease. Osteolytic and/or osteoblastic lesions induced in the tumor-bone interface allowed us to explore cellular and molecular interactions between malignant cells and skeletal tissue in a syngeneic setting. In this review, we will discuss a different animal model that provides a consistent and reproducible platform for investigating the molecular mechanisms underlying tumor-bone interaction and breast cancer-induced osteolytic changes.

Futakuchi M; Singh RK

2013-07-01

263

Animal model for mammary tumor growth in the bone microenvironment.  

Science.gov (United States)

Advanced breast cancer commonly spreads to the bones, lungs, liver or brain, and bone is the most common site of breast cancer metastasis. Nearly all patients with advanced breast cancer develop bone metastasis and suffer from serious bone metastasis-associated complications, including chronic pain, fracture, spinal cord compression and hypercalcemia. Metastasis formation in the bone is a complex process that requires cooperative reciprocal interactions between tumor cells and the cellular environment of the bone, which includes osteoclasts and osteoblasts. We have developed a murine bone invasion model of breast cancer, which required a simple surgical technique and mimics the biology of the disease. Osteolytic and/or osteoblastic lesions induced in the tumor-bone interface allowed us to explore cellular and molecular interactions between malignant cells and skeletal tissue in a syngeneic setting. In this review, we will discuss a different animal model that provides a consistent and reproducible platform for investigating the molecular mechanisms underlying tumor-bone interaction and breast cancer-induced osteolytic changes. PMID:23335063

Futakuchi, Mitsuru; Singh, Rakesh K

2013-01-19

264

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

Directory of Open Access Journals (Sweden)

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

Krzysztof Fink; Janusz Boraty?ski

2012-01-01

265

Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61.  

Science.gov (United States)

Oncolytic viral therapy is under evaluation for toxicity and efficacy in clinical trials relating to several different tumors. We report a significant increase in the angiogenic index of oncolytic virus (OV)-treated glioma-matrigel implants (2.83-fold, P < 0.02). In a rat intracranial glioma model, large tumors from OV-treated animals were significantly more angiogenic than the phosphate-buffered saline (PBS)-treated control tumors (OV: 101 +/- 21.6; PBS: 19.8 +/- 10; P = 0.0037). Transcript profiling of OV-treated tumors revealed dysregulation of several transcripts involved in glioma angiogenesis. OV-mediated induction of CYR61 gene expression (8.94-fold, P = 0.001) correlated significantly with the presence of OV in tumor tissue in vivo (R = 0.7, P < 0.001). Further, induction of CYR61 mRNA and protein were confirmed in multiple human cancer cell lines and primary human tumor-derived cells in vitro, and in tumor lysate and cerebrospinal fluid (CSF) in vivo. Finally, we show that treatment of glioma cells with Cilengitide, known to counter CYR61-induced integrin activation, significantly suppressed the proangiogenic effect of OV treatment of gliomas (P < 0.05). PMID:18545226

Kurozumi, Kazuhiko; Hardcastle, Jayson; Thakur, Roopa; Shroll, Joshua; Nowicki, Michal; Otsuki, Akihiro; Chiocca, E Antonio; Kaur, Balveen

2008-06-10

266

The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells.  

Science.gov (United States)

Stem-like cells may be integral to the development and maintenance of human cancers. Direct proof is still lacking, mainly because of our poor understanding of the biological differences between normal and cancer stem cells (SCs). Using the ErbB2 transgenic model of breast cancer, we found that self-renewing divisions of cancer SCs are more frequent than their normal counterparts, unlimited and symmetric, thus contributing to increasing numbers of SCs in tumoral tissues. SCs with targeted mutation of the tumor suppressor p53 possess the same self-renewal properties as cancer SCs, and their number increases progressively in the p53 null premalignant mammary gland. Pharmacological reactivation of p53 correlates with restoration of asymmetric divisions in cancer SCs and tumor growth reduction, without significant effects on additional cancer cells. These data demonstrate that p53 regulates polarity of cell division in mammary SCs and suggest that loss of p53 favors symmetric divisions of cancer SCs, contributing to tumor growth. PMID:19766563

Cicalese, Angelo; Bonizzi, Giuseppina; Pasi, Cristina E; Faretta, Mario; Ronzoni, Simona; Giulini, Barbara; Brisken, Cathrin; Minucci, Saverio; Di Fiore, Pier Paolo; Pelicci, Pier Giuseppe

2009-09-18

267

The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells.  

UK PubMed Central (United Kingdom)

Stem-like cells may be integral to the development and maintenance of human cancers. Direct proof is still lacking, mainly because of our poor understanding of the biological differences between normal and cancer stem cells (SCs). Using the ErbB2 transgenic model of breast cancer, we found that self-renewing divisions of cancer SCs are more frequent than their normal counterparts, unlimited and symmetric, thus contributing to increasing numbers of SCs in tumoral tissues. SCs with targeted mutation of the tumor suppressor p53 possess the same self-renewal properties as cancer SCs, and their number increases progressively in the p53 null premalignant mammary gland. Pharmacological reactivation of p53 correlates with restoration of asymmetric divisions in cancer SCs and tumor growth reduction, without significant effects on additional cancer cells. These data demonstrate that p53 regulates polarity of cell division in mammary SCs and suggest that loss of p53 favors symmetric divisions of cancer SCs, contributing to tumor growth.

Cicalese A; Bonizzi G; Pasi CE; Faretta M; Ronzoni S; Giulini B; Brisken C; Minucci S; Di Fiore PP; Pelicci PG

2009-09-01

268

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

International Nuclear Information System (INIS)

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

2005-01-01

269

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.

Maisin, H.; Anckaert, M.A.; De Coster, B. (Centre des Tumeurs, Bruxelles (Belgium))

1983-01-01

270

Protocol for the anatomopathological examination of canine mammary tumors  

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Full Text Available Foi elaborado um protocolo para exame anatomopatológico de tumores de mama em cães, constituído de três partes: requisição, exame clínico e laudo histopatológico. O exame clínico contém dados sobre a descrição macroscópica da lesão. O laudo histopatológico constituiu-se de campos para descrição microscópica pormenorizada das lesões e classificação da principal lesão observada. A elaboração do protocolo tem como objetivo estabelecer critérios para estudos e pesquisas sobre neoplasias mamárias em animais e auxiliar no diagnóstico e prognóstico de lesões mamárias.

Ferreira E.; Bregunci G.C.; Schmitt F.C.; Cassali G.D.

2003-01-01

271

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

Science.gov (United States)

Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3?oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2(+) breast cancer. PMID:22619689

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

2012-04-26

272

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

UK PubMed Central (United Kingdom)

Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3?oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2(+) breast cancer.

Clafshenkel WP; King TL; Kotlarczyk MP; Cline JM; Foster WG; Davis VL; Witt-Enderby PA

2012-01-01

273

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

International Nuclear Information System (INIS)

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

274

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

Energy Technology Data Exchange (ETDEWEB)

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

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

2009-04-15

275

Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice.  

UK PubMed Central (United Kingdom)

Tocotrienols (T3), the lesser known isomers of vitamin E, have been reported to possess anticancer activity both in in vitro and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of dietary supplementation with annatto-T3 (90% ?-T3 and 10% ?-T3) on the spontaneous development of mammary tumors in HER-2/neu transgenic mice. Underlying mechanisms of the antitumor effect were evaluated by studying apoptosis, senescent-like growth arrest, immune modulation, oxidative effect and the expression of HER-2/neu in tumoral mammary glands of transgenic mice and in vitro in human and mice tumor cell lines. Annatto-T3 supplementation delayed the development of mammary tumors, reducing the number and size of mammary tumor masses and those of lung metastases. In annatto-T3-supplemented mice, both apoptosis and senescent-like growth arrest of tumor cells were increased in mammary glands while no immune modulation was observed. In vitro, a dose-dependent inhibition of cell growth, increased apoptosis and senescent-like growth arrest and a time-dependent accumulation of reactive oxygen species were observed in tumor cells treated with annatto-T3 or purified ?-T3. Annatto-T3 reduced both HER-2/neu mRNA and p185(HER-2/neu) protein in tumors and in tumor cell lines. The results show that the antitumor effect of annatto-T3 supplementation in HER-2/neu transgenic mice is mainly related to the direct induction of oxidative stress, senescent-like growth arrest and apoptosis of tumor cells rather than to an immune modulation.

Pierpaoli E; Viola V; Barucca A; Orlando F; Galli F; Provinciali M

2013-06-01

276

A novel radiofluorinated agouti-related protein for tumor angiogenesis imaging.  

Science.gov (United States)

A novel protein scaffold based on the cystine knot domain of the agouti-related protein (AgRP) has been used to engineer mutants that can bind to the ?(v)?(3) integrin receptor with high affinity and specificity. In the current study, an (18)F-labeled AgRP mutant (7C) was prepared and evaluated as a positron emission tomography (PET) probe for imaging tumor angiogenesis. AgRP-7C was synthesized by solid phase peptide synthesis and site-specifically conjugated with 4-nitrophenyl 2-(18/19)F-fluoropropionate ((18/19)F-NFP) to produce the fluorinated peptide, (18/19)F-FP-AgRP-7C. Competition binding assays were used to measure the relative affinities of AgRP-7C and (19)F-FP-AgRP-7C to human glioblastoma U87MG cells that overexpress ?(v)?(3) integrin. In addition, biodistribution, metabolic stability, and small animal PET imaging studies were conducted with (18)F-FP-AgRP-7C using U87MG tumor-bearing mice. Both AgRP-7C and (19)F-FP-AgRP-7C specifically competed with (125)I-echistatin for binding to U87MG cells with half maximal inhibitory concentration (IC(50)) values of 9.40 and 8.37 nM, respectively. Non-invasive small animal PET imaging revealed that (18)F-FP-AgRP-7C exhibited rapid and good tumor uptake (3.24 percentage injected dose per gram [% ID/g] at 0.5 h post injection [p.i.]). The probe was rapidly cleared from the blood and from most organs, resulting in excellent tumor-to-normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Furthermore, co-injection of (18)F-FP-AgRP-7C with a large molar excess of blocking peptide c(RGDyK) significantly inhibited tumor uptake in U87MG xenograft models, demonstrating the integrin-targeting specificity of the probe. Metabolite assays showed that the probe had high stability, making it suitable for in vivo applications. (18)F-FP-AgRP-7C exhibits promising in vivo properties such as rapid tumor targeting, good tumor uptake, and excellent tumor-to-normal tissue ratios, and warrants further investigation as a novel PET probe for imaging tumor angiogenesis. PMID:22945905

Jiang, Han; Moore, Sarah J; Liu, Shuanglong; Liu, Hongguang; Miao, Zheng; Cochran, Frank V; Liu, Yang; Tian, Mei; Cochran, Jennifer R; Zhang, Hong; Cheng, Zhen

2012-09-04

277

A novel radiofluorinated agouti-related protein for tumor angiogenesis imaging.  

UK PubMed Central (United Kingdom)

A novel protein scaffold based on the cystine knot domain of the agouti-related protein (AgRP) has been used to engineer mutants that can bind to the ?(v)?(3) integrin receptor with high affinity and specificity. In the current study, an (18)F-labeled AgRP mutant (7C) was prepared and evaluated as a positron emission tomography (PET) probe for imaging tumor angiogenesis. AgRP-7C was synthesized by solid phase peptide synthesis and site-specifically conjugated with 4-nitrophenyl 2-(18/19)F-fluoropropionate ((18/19)F-NFP) to produce the fluorinated peptide, (18/19)F-FP-AgRP-7C. Competition binding assays were used to measure the relative affinities of AgRP-7C and (19)F-FP-AgRP-7C to human glioblastoma U87MG cells that overexpress ?(v)?(3) integrin. In addition, biodistribution, metabolic stability, and small animal PET imaging studies were conducted with (18)F-FP-AgRP-7C using U87MG tumor-bearing mice. Both AgRP-7C and (19)F-FP-AgRP-7C specifically competed with (125)I-echistatin for binding to U87MG cells with half maximal inhibitory concentration (IC(50)) values of 9.40 and 8.37 nM, respectively. Non-invasive small animal PET imaging revealed that (18)F-FP-AgRP-7C exhibited rapid and good tumor uptake (3.24 percentage injected dose per gram [% ID/g] at 0.5 h post injection [p.i.]). The probe was rapidly cleared from the blood and from most organs, resulting in excellent tumor-to-normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Furthermore, co-injection of (18)F-FP-AgRP-7C with a large molar excess of blocking peptide c(RGDyK) significantly inhibited tumor uptake in U87MG xenograft models, demonstrating the integrin-targeting specificity of the probe. Metabolite assays showed that the probe had high stability, making it suitable for in vivo applications. (18)F-FP-AgRP-7C exhibits promising in vivo properties such as rapid tumor targeting, good tumor uptake, and excellent tumor-to-normal tissue ratios, and warrants further investigation as a novel PET probe for imaging tumor angiogenesis.

Jiang H; Moore SJ; Liu S; Liu H; Miao Z; Cochran FV; Liu Y; Tian M; Cochran JR; Zhang H; Cheng Z

2013-02-01

278

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

Directory of Open Access Journals (Sweden)

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

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

2009-01-01

279

Inflammatory angiogenesis and the tumor microenvironment as targets for cancer therapy and prevention.  

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In addition to aberrant transformed cells, tumors are tissues that contain host components, including stromal cells, vascular cells (ECs) and their precursors, and immune cells. All these constituents interact with each other at the cellular and molecular levels, resulting in the production of an intricate and heterogeneous complex of cells and matrix defined as the tumor microenvironment. Several pathways involved in these interactions have been investigated both in pathological and physiological scenarios, and diverse molecules are currently targets of chemotherapeutic and preventive drugs. Many phytochemicals and their derivatives show the ability to inhibit tumor progression, angiogenesis, and metastasis, exerting effects on the tumor microenvironment. In this review, we will outline the principal players and mechanisms involved in the tumor microenvironment network and we will discuss some interesting compounds aimed at interrupting these interactions and blocking tumor insurgence and progression. The considerations provided will be crucial for the design of new preventive approaches to the reduction in cancer risk that need to be applied to large populations composed of apparently healthy individuals.

Bruno A; Pagani A; Magnani E; Rossi T; Noonan DM; Cantelmo AR; Albini A

2014-01-01

280

Inflammatory Angiogenesis and the Tumor Microenvironment as Targets for Cancer Therapy and Prevention.  

UK PubMed Central (United Kingdom)

In addition to aberrant transformed cells, tumors are tissues that contain host components, including stromal cells, vascular cells (ECs) and their precursors, and immune cells. All these constituents interact with each other at the cellular and molecular levels, resulting in the production of an intricate and heterogeneous complex of cells and matrix defined as the tumor microenvironment. Several pathways involved in these interactions have been investigated both in pathological and physiological scenarios, and diverse molecules are currently targets of chemotherapeutic and preventive drugs. Many phytochemicals and their derivatives show the ability to inhibit tumor progression, angiogenesis, and metastasis, exerting effects on the tumor microenvironment. In this review, we will outline the principal players and mechanisms involved in the tumor microenvironment network and we will discuss some interesting compounds aimed at interrupting these interactions and blocking tumor insurgence and progression. The considerations provided will be crucial for the design of new preventive approaches to the reduction in cancer risk that need to be applied to large populations composed of apparently healthy individuals.

Bruno A; Pagani A; Magnani E; Rossi T; Noonan DM; Cantelmo AR; Albini A

2014-01-01

 
 
 
 
281

Effect of deoxyribozymes targeting c-Jun on solid tumor growth and angiogenesis in rodents.  

UK PubMed Central (United Kingdom)

BACKGROUND: The basic region-leucine zipper protein c-Jun has been linked to cell proliferation, transformation, and apoptosis. However, a direct role for c-Jun in angiogenesis has not been shown. METHODS: We used human microvascular endothelial cells (HMEC-1) transfected with a DNAzyme targeting the c-Jun mRNA (Dz13), related oligonucleotides, or vehicle in in vitro models of microvascular endothelial cell proliferation, migration, chemoinvasion, and tubule formation, a rat model of corneal neovascularization, and a mouse model of solid tumor growth and vascular endothelial growth factor (VEGF)-induced angiogenesis. All statistical tests were two-sided. RESULTS: Compared with mock-transfected cells, HMEC-1 cells transfected with Dz13 expressed less c-Jun protein and possessed lower DNA-binding activity. Dz13 blocked endothelial cell proliferation, migration, chemoinvasion, and tubule formation. Dz13 inhibited the endothelial cell expression and proteolytic activity of MMP-2, a c-Jun-dependent gene. Dz13 inhibited VEGF-induced neovascularization in the rat cornea compared with vehicle control (Dz13 versus vehicle: 4.0 neovessels versus 30.7 neovessels, difference = 26.7 neovessels; P =.004; area occupied by new blood vessels for Dz13 versus vehicle: 0.35 mm2 versus 1.52 mm2, difference = 1.17 mm2; P =.005) as well as solid melanoma growth in mice (Dz13 versus vehicle at 14 days: 108 mm3 versus 283 mm3, difference = 175 mm3; P =.006) with greatly reduced vascular density (Dz13 versus vehicle: 30% versus 100%, difference = 70%; P<.001). CONCLUSION: DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.

Zhang G; Dass CR; Sumithran E; Di Girolamo N; Sun LQ; Khachigian LM

2004-05-01

282

A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.  

UK PubMed Central (United Kingdom)

Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

Bhattacharjee PS; Huq TS; Mandal TK; Graves RA; Muniruzzaman S; Clement C; McFerrin HE; Hill JM

2011-01-01

283

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; Karlsson Sara; Partheen Karolina; Nilsson Staffan; Szpirer Claude; Behboudi Afrouz

2012-01-01

284

Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands.  

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The objective of this study was to evaluate the ability of troglitazone (a thiazolidinedione) and Wy-14,643 (a clofibrate) to inhibit progression of non-detectable and detectable mammary tumors in rats induced by 7,12 dimethylbenz(a)anthracene (DMBA) when compared to those receiving no treatment or tamoxifen. Although not as effective as tamoxifen in decreasing overall tumor incidence, Wy-14,643 reduced the percentage and number of malignant tumors that developed when compared to both troglitazone and control. Treatment of detectable tumors with either Wy-14,643 or troglitazone induced regression or stasis of total tumor volume in 40-50% of the animals, compared to only 10% in control and 65% in tamoxifen treated animals. Moreover, each PPAR ligand was as effective as tamoxifen in preventing additional tumor development. In summary, both PPAR ligands were more effective than no treatment in preventing tumor progression once detected. However, only the PPAR-alpha activator, Wy-14,643 was able to reduce the development of malignant tumors when administered prior to detection. PMID:11396171

Pighetti, G M; Novosad, W; Nicholson, C; Hitt, D C; Hansens, C; Hollingsworth, A B; Lerner, M L; Brackett, D; Lightfoot, S A; Gimble, J M

285

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

UK PubMed Central (United Kingdom)

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 14d in ascitic and 100mg/kg bw in solid tumor for 30d. On day 15, blood samples were collected for hematological assessment of hemoglobin (Hb%), RBCs, WBCs and PCV. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF, iNOS, CD31, caspase-3 and Bax were also performed. UA significantly inhibited tumor growth, cell viability, in both ascites and solid tumor model in vivo (p<0·001). The anti-angiogenic effects were accompanied with decreased VEGF, iNOS, TNF-? and increased IL-12 levels. UA at 100mg/kg bw dose significantly increased SOD and CAT activity (p<0.01). GSH and TBARS were increased as compared to control group (p<0.001). Furthermore, UA increased total RBCs, WBCs as well as Hb% significantly (p<0.05) compared to cyclophosphamide (CP). Histopathological examination of tumor cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. Decreased peritoneal angiogenesis showed the anti-angiogenic potential. UA downregulated VEGF & iNOS expression whereas bax and caspase-3 expressions were upregulated suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3 and downregulation of VEGF. The present study sheds light on the potent antitumor property of the UA and can be extended further to develop therapeutic protocols for treatment of cancer.

Saraswati S; Agrawal SS; Alhaider AA

2013-09-01

286

Firefly luciferase-based dynamic bioluminescence imaging: a noninvasive technique to assess tumor angiogenesis.  

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OBJECTIVE: Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth. METHODS: With the use of stereotactic technique, 10 firefly luciferase-transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80). After intraperitoneal injection of D-luciferin (150 mg/kg), serial dynamic BLI was performed at 1-minute intervals (30 seconds exposure) every 2 to 3 days until death of the animals. The maximum intensity was used as an indirect measurement of tumor growth. The adjusted slope of initial intensity (I90/Im) was used as a proxy to monitor the flow rate of blood into the vascular tree. Using a modified Evans blue perfusion protocol, we calculated the relative permeability of the vascular tree at various time points. RESULTS: Daily maximum intensity correlated strongly with tumor volume. At postinjection day 23, histology and BLI demonstrated an exponential growth of the tumor mass. Slopes were calculated to reflect the flow in the vessels feeding the tumor (adjusted slope = I90/Im). The increase in BLI intensity was correlated with a decrease in adjusted slope, reflecting a decrease in the rate of blood flow as tumor volume increased (y = 93.8e-0.49, R2 = 0.63). Examination of calculated slopes revealed a peak in permeability around postinjection day 20 (n = 42, P < .02 by 1-way analysis of variance) and showed a downward trend in relation to both postinjection day and maximum intensity observed; as angiogenesis progressed, tumor vessel caliber increased dramatically, resulting in sluggish but increased flow. This trend was correlated with Evans blue histology, revealing an increase in Evans blue dye uptake into the tumor, as slope calculated by BLI increases. CONCLUSION: Dynamic BLI is a practical, noninvasive technique that can semiquantitatively monitor changes in vascular permeability and therefore facilitate the study of tumor angiogenesis in animal models of disease.

Sun A; Hou L; Prugpichailers T; Dunkel J; Kalani MA; Chen X; Kalani MY; Tse V

2010-04-01

287

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; Hokputsa S; Niruthisard S; Bhattarakosol P; Patumraj S

2012-01-01

288

ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression.  

UK PubMed Central (United Kingdom)

The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non-targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis.

Montalvo J; Spencer C; Hackathorn A; Masterjohn K; Perkins A; Doty C; Arumugam A; Ongusaha PP; Lakshmanaswamy R; Liao JK; Mitchell DC; Bryan BA

2013-01-01

289

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

UK PubMed Central (United Kingdom)

Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of acacetin in inhibiting VEGF expression, we showed that acacetin inhibited HIF-1? expression and AKT activation. Over-expression of HIF-1? or AKT restored acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of acacetin for inhibiting VEGF expression in the cells. Moreover, acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1? and VEGF expression. Acacetin did not change HIF-1? mRNA level, but inhibited HIF-1? protein level through increasing its degradation and decreasing its stability. These results indicate that acacetin may be a useful natural compound for ovarian cancer prevention and treatment.

Liu LZ; Jing Y; Jiang LL; Jiang XE; Jiang Y; Rojanasakul Y; Jiang BH

2011-09-01

290

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

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Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of acacetin in inhibiting VEGF expression, we showed that acacetin inhibited HIF-1? expression and AKT activation. Over-expression of HIF-1? or AKT restored acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of acacetin for inhibiting VEGF expression in the cells. Moreover, acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1? and VEGF expression. Acacetin did not change HIF-1? mRNA level, but inhibited HIF-1? protein level through increasing its degradation and decreasing its stability. These results indicate that acacetin may be a useful natural compound for ovarian cancer prevention and treatment. PMID:21893035

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

2011-08-27

291

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

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Acacetin (5,7-dihydroxy-4?-methoxyflavone) is a flavone compound, some of which have anti-cancerous effects. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and tumor growth. In this study, we found that acacetin decreased the steady level of VEGF mRNA level and inhibited VEGF transcriptional activation. To further determine the potential mechanism of acacetin in inhibiting VEGF expression, we showed that acacetin inhibited HIF-1? expression and AKT activation. Over-expression of HIF-1? or AKT restored acacetin-decreasing VEGF transcriptional activation, indicating that AKT and HIF-1 are the essential downstream targets of acacetin for inhibiting VEGF expression in the cells. Moreover, acacetin significantly inhibited ovarian cancer cell-induced angiogenesis and tumor growth in vivo through inhibiting HIF-1? and VEGF expression. Acacetin did not change HIF-1? mRNA level, but inhibited HIF-1? protein level through increasing its degradation and decreasing its stability. These results indicate that acacetin may be a useful natural compound for ovarian cancer prevention and treatment.

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

2011-01-01

292

Biological significance of interstitial collagenase in DMBA-induced mammary tumors of the rat.  

UK PubMed Central (United Kingdom)

In this review the production of interstitial collagenase in DMBA-induced mammary tumors of the rat has been examined. Cell sorting and cell cultures have given us the opportunity to relate the release of collagenase to a specific cell type. By means of FITC-fluorescence and monospecific antibodies (S. Sakamoto, Harvard University, Boston) it was further possible to localize collagenase in vitro and in vivo. The most outstanding characteristic is that collagenase is produced both by cuboidal, epithelial cell and by macrophages in vitro but not by myoepithelial-like cells. On the other hand, synthesis of collagenase in vivo was detected in some stromal cells, possibly macrophages, but not in neoplastic cuboidal cells. This observation has been related to the inability of cuboidal cells to interact with stromal, fibrillar collagen in vivo since tumor cells are arranged in glandular-like structures bordered by myoepithelial cells and a basement membrane. In vitro, fibrillar rat tail tendon collagen was found to be a potent stimulator of collagenase production by cuboidal cells. Collagenase stimulation by interstitial collagen therefore suggests a plausible mechanism for the degradation of collagen fibrils during local invasion by mammary tumor cells.

Wirl G

1984-01-01

293

?-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.

Shibata Masa-Aki; Iinuma Munekazu; Morimoto Junji; Kurose Hitomi; Akamatsu Kanako; Okuno Yasushi; Akao Yukihiro; Otsuki Yoshinori

2011-01-01

294

The influence of angiogenesis inhibitor AGM-1470 on immune system status and tumor growth in vitro.  

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The synthetic angiogenesis modulator-1470 O-(chloroacetyl-carbamoyl, AGM-1470) is a potent inhibitor of neovascularization. We have investigated the potential influence of this inhibitor in tumor immunobiology using both in vivo and in vitro models. Mice given a single tail-vein injection of tumor cells were later treated wtih AGM-1470 by s.c. injection. After tumor injection, the lungs were evaluated for macroscopic tumor nodules. AGM-1470 significantly reduced the development of macroscopic pulmonary disease but did not eliminate disease. However, tumor-bearing mice treated with AGM-1470 had significantly reduced spleen weight compared to controls. To determine if the observed decrease in spleen weight in the treated animals was associated with immunosuppression, we studied the possible immunomodulatory effects of AGM-1470. AGM-1470 induced no changes in spleen-cell viability compared to controls. However, addition of angioinhibin at the beginning of IL-2-induced spleen-cell activation significantly inhibited the development of NK-mediated tumor-cell killing. Similarly, splenic T-cell proliferation induced by a mitogenic monoclonal antibody to murine T cells was significantly inhibited when activated in the presence of AGM-1470. The in vitro studies were extended by evaluation of immune system status in tumor-bearing mice treated with AGM-1470. In vivo therapy with AGM-1470 did not significantly change the mean splenic lymphocyte counts and CD4/CD8 ratios from control values. In addition, the induction of splenic NK-mediated tumor killing with IL-2 as well as mitogen-induced T-cell activation was not significantly different from control values. These results suggest that AGM-1470 inhibits tumor growth by blocking neovascularization and may, under certain conditions of drug administration, inhibit immune system function. PMID:7691763

Schoof, D D; Obando, J A; Cusack, J C; Goedegebuure, P S; Brem, H; Eberlein, T J

1993-10-21

295

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

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

Castillo-Pichardo Linette; Cubano Luis A; Dharmawardhane Suranganie

2013-01-01

296

Effects of hydroxy safflower yellow-A on tumor capillary angiogenesis in transplanted human gastric adenocarcinoma BGC-823 tumors in nude mice.  

UK PubMed Central (United Kingdom)

OBJECTIVE: To study the effects of hydroxy safflower yellow A (HSYA) on tumor capillary angiogenesis in transplanted human gastric adenocarcinoma BGC-823 tumors in nude mice. METHODS: BGC-823 cells were injected subcutaneously into the right anterior armpit of nude mice to establish an animal model of transplanted tumors. After 24 h, 18 nude mice injected with tumor cells were randomized into model, control, and HSYA 0.028 g/L groups, with six mice in each group. Transplanted tumors were excised on day 20. Tumor inhibition ratios were calculated for the transplanted tumors. Pathological changes and capillary angiogenesis in the tumors were observed by light microscopy. RESULTS: Tumors in the model group grew more quickly than those in the control and HSYA groups, with inhibition ratios of 48% and 30%, respectively. The microvessel count in the HSYA group was lower than in the model group (P < 0.01), and microvessel density was also lower in the HSYA group (P < 0.05). Pathological changes were more obvious in tumors in the model group compared to the HSYA group. CONCLUSION: HSYA inhibits the growth of transplanted BGC-823 tumors, and its effects on tumor capillary angiogenesis may represent one of the mechanisms responsible for this antineoplastic effect.

Xi SY; Zhang Q; Liu CY; Xie H; Yue LF; Gao XM

2012-06-01

297

Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer.  

Science.gov (United States)

microRNAs (miRNAs) have been reported to play a crucial role in regulating a variety of genes pivotal for tumor metastasis. miR-126 is well known as one of the angiogenesis regulatory miRNAs. Recent studies have reported controversial roles of miR-126 in tumor progression. In this study, we sought to investigate the potential roles of miR-126 in colorectal cancer (CRC). By real-time PCR, miR-126 was shown to be downregulated in primary CRC tissues and cell lines. Restoration of miR-126 in CRC cells inhibited cell growth, migration and invasion. Using both in silico prediction and immunoblotting, we found that vascular endothelial growth factor (VEGF) was a target of miR-126. The interaction of miR-126 on the 3'UTR of VEGF mRNA was validated by luciferase reporter assay. Mechanistically, we found that the silencing of miR-126 was induced by promoter methyl-ation of its host gene, EGFL7. Treatment with 5-aza-CdR restored miR-126 expression and thereby led to a decline in VEGF expression. Functionally, due to suppression of VEGF, enhanced miR-126 expression inhibited tumor neovasculature triggered by CRC cells. In conclusion, our findings suggest that DNA methylation-induced silencing of miR-126 contributes, at least in part, to tumor invasion and angiogenesis in CRC, through upregulation of VEGF expression. miR-126 may be a potential target for the therapeutic strategy against CRC. PMID:23900443

Zhang, Yu; Wang, Xinying; Xu, Binghong; Wang, Baocai; Wang, Zhongqiu; Liang, Yan; Zhou, Jieqiong; Hu, Jingjing; Jiang, Bo

2013-07-23

298

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

UK PubMed Central (United Kingdom)

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

Wang LH; Zhang ZH; Zhao L; Zhu CM; Zhao LS; Hao CL

2013-02-01

299

Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer.  

UK PubMed Central (United Kingdom)

microRNAs (miRNAs) have been reported to play a crucial role in regulating a variety of genes pivotal for tumor metastasis. miR-126 is well known as one of the angiogenesis regulatory miRNAs. Recent studies have reported controversial roles of miR-126 in tumor progression. In this study, we sought to investigate the potential roles of miR-126 in colorectal cancer (CRC). By real-time PCR, miR-126 was shown to be downregulated in primary CRC tissues and cell lines. Restoration of miR-126 in CRC cells inhibited cell growth, migration and invasion. Using both in silico prediction and immunoblotting, we found that vascular endothelial growth factor (VEGF) was a target of miR-126. The interaction of miR-126 on the 3'UTR of VEGF mRNA was validated by luciferase reporter assay. Mechanistically, we found that the silencing of miR-126 was induced by promoter methyl-ation of its host gene, EGFL7. Treatment with 5-aza-CdR restored miR-126 expression and thereby led to a decline in VEGF expression. Functionally, due to suppression of VEGF, enhanced miR-126 expression inhibited tumor neovasculature triggered by CRC cells. In conclusion, our findings suggest that DNA methylation-induced silencing of miR-126 contributes, at least in part, to tumor invasion and angiogenesis in CRC, through upregulation of VEGF expression. miR-126 may be a potential target for the therapeutic strategy against CRC.

Zhang Y; Wang X; Xu B; Wang B; Wang Z; Liang Y; Zhou J; Hu J; Jiang B

2013-10-01

300

A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice.  

Science.gov (United States)

Mice carrying the MMTV-cmyc transgene develop mammary tumors at 9 to 12 months of age. Little is known about karyotypic changes in this model of human breast cancer. We have developed and applied molecular cytogenetic techniques to study chromosomal aberrations that occur in these tumors, namely, comparative genomic hybridization and spectral karyotyping. Cell lines from eight tumors were established and analyzed, four of which carried a heterozygous p53 mutation. All of the tumor cell lines revealed increases in ploidy and/or multiple numerical and structural chromosomal aberrations. No consistent differences were observed between cmyc/p53+/+ and cmyc/p53+/- tumors, suggesting that cmyc induces karyotype instability independent of p53 status. Loss of whole chromosome (Chr) 4 was detected in five of the eight tumors. Parts of Chr 4 are syntenic to human 1p31-p36, a region that is also deleted in human breast carcinomas. Four tumors carried translocations involving the distal portion of Chr 11 (syntenic to human chromosome arm 17q), including two translocations T(X;11), with cytogenetically identical breakpoints. We compare the pattern of chromosomal aberrations with human breast cancers, find similarities in several syntenic regions, and discuss the potential of an interspecies cytogenetic map of chromosomal gains and losses. PMID:10379871

Weaver, Z A; McCormack, S J; Liyanage, M; du Manoir, S; Coleman, A; Schröck, E; Dickson, R B; Ried, T

1999-07-01

 
 
 
 
301

A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice.  

UK PubMed Central (United Kingdom)

Mice carrying the MMTV-cmyc transgene develop mammary tumors at 9 to 12 months of age. Little is known about karyotypic changes in this model of human breast cancer. We have developed and applied molecular cytogenetic techniques to study chromosomal aberrations that occur in these tumors, namely, comparative genomic hybridization and spectral karyotyping. Cell lines from eight tumors were established and analyzed, four of which carried a heterozygous p53 mutation. All of the tumor cell lines revealed increases in ploidy and/or multiple numerical and structural chromosomal aberrations. No consistent differences were observed between cmyc/p53+/+ and cmyc/p53+/- tumors, suggesting that cmyc induces karyotype instability independent of p53 status. Loss of whole chromosome (Chr) 4 was detected in five of the eight tumors. Parts of Chr 4 are syntenic to human 1p31-p36, a region that is also deleted in human breast carcinomas. Four tumors carried translocations involving the distal portion of Chr 11 (syntenic to human chromosome arm 17q), including two translocations T(X;11), with cytogenetically identical breakpoints. We compare the pattern of chromosomal aberrations with human breast cancers, find similarities in several syntenic regions, and discuss the potential of an interspecies cytogenetic map of chromosomal gains and losses.

Weaver ZA; McCormack SJ; Liyanage M; du Manoir S; Coleman A; Schröck E; Dickson RB; Ried T

1999-07-01

302

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

UK PubMed Central (United Kingdom)

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 MA; Prosperi JR; Goss KH

2013-01-01

303

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

Directory of Open Access Journals (Sweden)

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; Prosperi Jenifer R; Goss Kathleen H

2013-01-01

304

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..mu..Ci/20..mu..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.

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

1984-01-01

305

Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-?/VEGF/Rho-GTPases: pivotal role of STAT-3.  

UK PubMed Central (United Kingdom)

Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cells in a dose dependant manner. Moreover, secretion of VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both VEGF and MMP-2 play a critical role in angiogenesis and metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of VEGFR-2 (Tyr-1175), and expression of HIF-?. Rho-GTPases, which are regulated by VEGF play a crucial role in pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB. STAT-3 over-expression or IL-6 treatment significantly induced HIF-1? and VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1? and VEGF expression. Finally, in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC, indicating reduced tumor angiogenesis. Immunoblotting of BITC treated tumors show reduced expression of STAT-3 phosphorylation (Tyr-705), HIF-?, VEGFR-2, VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through STAT-3-dependant pathway.

Boreddy SR; Sahu RP; Srivastava SK

2011-01-01

306

Dietary soy modulation of biochemical parameters in DMBA-induced mammary tumors.  

UK PubMed Central (United Kingdom)

The aim of this study was to extend our previous observations on the soy modulation of biochemical parameters in 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors, by simultaneously investigating the expression of estrogen receptor-alpha (ERalpha), estrogen receptor-beta (ERbeta), progesterone receptor (PR), apoptosis, neu, and markers of cell proliferation, such as proliferating cell nuclear antigen (PCNA) by immunohistochemistry. The percentage of ERalpha positive tumors was 65.8% in masses from control animals, and significantly dropped to 36.8% in tumors from soy treated rats (P=0.010). The percentage of ERbeta positive tumors was 70.3% in masses from control animals vs. 50.0% in tumors from soy exposed animals (P=0.066). Moreover, the percentage of cases which were both ERalpha and ERbeta positive was significantly lower (17.6%) in soy treated than in control animals (51.3%) (P=0.006). The percentage of PR positive tumors was 34.2% in control animals vs. 2.6% in tumors from soy treated rats (P=0.0006). There were no statistically significant differences in the percentage of tumors positively stained for neu, apoptosis, or PCNA, in control vs. soy treated rats. However, when analyzing the reciprocal correlation among the different biochemical parameters we showed that, in treated animals, the majority of ERalpha positive tumors (91.7%) were also PCNA positive (P=0.036). The median percentage of PCNA positivity was significantly higher in ERalpha positive than in ERalpha negative tumors (25 vs. 5%) (P=0.0031). Moreover, an association was found between PCNA and neu status since all neu positive tumors were also PCNA positive (P=0.011).

Gallo D; Ferrandina G; Giacomelli S; Fruscella E; Zannoni G; Morazzoni P; Riva A; Bombardelli E; Mancuso S; Scambia G

2002-12-01

307

Clonal selection within metastatic SP1 mouse mammary tumors is independent of metastatic potential.  

Science.gov (United States)

Our previous studies using randomly integrated plasmid DNA as unique clonotypic markers of SPI mouse mammary tumor cells transplanted into syngeneic CBA/J or nude mice demonstrated reproducible selection and eventual overgrowth of the primary transplant tumors by genotypically distinct metastatic subclones. Two independent metastatic SPI clones, neo5 and ras1, were shown to exhibit "clonal dominance" relative to the non-metastatic SPI tumor-cell population. These results suggested that the capacity for preferential growth within the tumors may be related to cellular properties associated with metastatic ability. To investigate the clonal interactions of metastatic SPI clones present within the same tumor mass, we have analyzed tumors composed of paired mixtures of neo5 and ras1. The tumors were monitored for the relative proportion of each clone by Southern blot analysis. The ras1 clone was found to dominate over the neo5 clone in the majority of tumors examined, even when present as 1% of the mixed inoculum. This represents a 20- to 50-fold enrichment of ras1, while the proportion of neo5 within the tumors was reduced at least 5-fold. No evidence for selection of either clone was seen during co-culture in vitro. Neo5 and ras1 are indistinguishable with respect to tumorigenic and metastatic potential when inoculated separately into different mice, suggesting that clonal dominance is independent of metastatic ability. Analysis of the metastases resulting from mixed inocula indicates that it is possible for a subpopulation representing less than 1% of the primary tumor mass to give rise to metastases. This also suggests that the process of metastasis within metastatic tumors is independent of clonal dominance. PMID:2004857

Samiei, M; Waghorne, C G

1991-03-12

308

Clonal selection within metastatic SP1 mouse mammary tumors is independent of metastatic potential.  

UK PubMed Central (United Kingdom)

Our previous studies using randomly integrated plasmid DNA as unique clonotypic markers of SPI mouse mammary tumor cells transplanted into syngeneic CBA/J or nude mice demonstrated reproducible selection and eventual overgrowth of the primary transplant tumors by genotypically distinct metastatic subclones. Two independent metastatic SPI clones, neo5 and ras1, were shown to exhibit "clonal dominance" relative to the non-metastatic SPI tumor-cell population. These results suggested that the capacity for preferential growth within the tumors may be related to cellular properties associated with metastatic ability. To investigate the clonal interactions of metastatic SPI clones present within the same tumor mass, we have analyzed tumors composed of paired mixtures of neo5 and ras1. The tumors were monitored for the relative proportion of each clone by Southern blot analysis. The ras1 clone was found to dominate over the neo5 clone in the majority of tumors examined, even when present as 1% of the mixed inoculum. This represents a 20- to 50-fold enrichment of ras1, while the proportion of neo5 within the tumors was reduced at least 5-fold. No evidence for selection of either clone was seen during co-culture in vitro. Neo5 and ras1 are indistinguishable with respect to tumorigenic and metastatic potential when inoculated separately into different mice, suggesting that clonal dominance is independent of metastatic ability. Analysis of the metastases resulting from mixed inocula indicates that it is possible for a subpopulation representing less than 1% of the primary tumor mass to give rise to metastases. This also suggests that the process of metastasis within metastatic tumors is independent of clonal dominance.

Samiei M; Waghorne CG

1991-03-01

309

Gap junction enhancer increases efficacy of cisplatin to attenuate mammary tumor growth.  

Science.gov (United States)

Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs) acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increase in efficacy of antineoplastic drugs via the enhancement of gap junctions. Mice were implanted with estradiol-17ß (1.7 mg/pellet) before the injection of 1×10? T47D breast cancer cells subcutaneously into the inguinal region of mammary fat pad. Animals were treated intraperitoneally with DMSO (control), cisplatin (3.5 mg/kg), PQ (25 mg/kg), or a combining treatment of cisplatin and PQ. Cisplatin alone decreased mammary tumor growth by 85% while combinational treatment of cisplatin and PQ1 or PQ7 showed an additional reduction of 77% and 22% of tumor growth after 7 treatments at every 2 days, respectively. Histological results showed a significant increase of gap junction proteins, Cx43 and Cx26, in PQ-treated tissues compared to control or cisplatin. Furthermore, evidence of highly stained caspase 3 in tumors of combinational treatment (PQ and cisplatin) was seen compared to cisplatin alone. We have showed for the first time an increase in the efficacy of antineoplastic drugs through a combinational treatment with PQs, a specific class of gap junction enhancers. PMID:23028705

Shishido, Stephanie N; Nguyen, Thu A

2012-09-13

310

Gap junction enhancer increases efficacy of cisplatin to attenuate mammary tumor growth.  

UK PubMed Central (United Kingdom)

Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs) acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increase in efficacy of antineoplastic drugs via the enhancement of gap junctions. Mice were implanted with estradiol-17ß (1.7 mg/pellet) before the injection of 1×10? T47D breast cancer cells subcutaneously into the inguinal region of mammary fat pad. Animals were treated intraperitoneally with DMSO (control), cisplatin (3.5 mg/kg), PQ (25 mg/kg), or a combining treatment of cisplatin and PQ. Cisplatin alone decreased mammary tumor growth by 85% while combinational treatment of cisplatin and PQ1 or PQ7 showed an additional reduction of 77% and 22% of tumor growth after 7 treatments at every 2 days, respectively. Histological results showed a significant increase of gap junction proteins, Cx43 and Cx26, in PQ-treated tissues compared to control or cisplatin. Furthermore, evidence of highly stained caspase 3 in tumors of combinational treatment (PQ and cisplatin) was seen compared to cisplatin alone. We have showed for the first time an increase in the efficacy of antineoplastic drugs through a combinational treatment with PQs, a specific class of gap junction enhancers.

Shishido SN; Nguyen TA

2012-01-01

311

Expression of Pax2 in Human Renal Tumor-Derived Endothelial Cells Sustains Apoptosis Resistance and Angiogenesis  

Science.gov (United States)

The transcription factor Pax2 is known to play a key role during renal development and to act as an oncogene favoring renal tumor growth. We recently showed that endothelial cells derived from human renal carcinomas display abnormal characteristics of survival and angiogenic properties. In the present study we found that renal tumor-derived endothelial cells, but not normal endothelial cells, expressed Pax2 protein and mRNA. To down-regulate Pax2 expression, we transfected tumor-derived endothelial cells with an anti-sense PAX2 vector whereas we transfected normal human microvascular endothelial cells with a sense PAX2 vector to induce Pax2 expression. The inhibition of Pax2 expression in tumor-derived endothelial cells induced an increase in tumor suppressor PTEN expression and a decrease in Akt phosphorylation. In addition, decreased apoptosis resistance, adhesion, invasion, and in vitro and in vivo angiogenesis were observed. Conversely, Pax2 induction in normal endothelial cells conferred to these cells a proinvasive, proangiogenic phenotype similar to that of tumor-derived endothelial cells. These results indicate that Pax2 is involved in renal tumor angiogenesis and its expression may antagonize that of the PTEN tumor suppressor gene, affecting the Akt-survival pathway and promoting angiogenesis.

Fonsato, Valentina; Buttiglieri, Stefano; Deregibus, Maria Chiara; Puntorieri, Valeria; Bussolati, Benedetta; Camussi, Giovanni

2006-01-01

312

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

UK PubMed Central (United Kingdom)

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.

Walsh EM; Kim R; Del Valle L; Weaver M; Sheffield J; Lazarovici P; Marcinkiewicz C

2012-07-01

313

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine  

Directory of Open Access Journals (Sweden)

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

2011-01-01

314

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

UK PubMed Central (United Kingdom)

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.

Liu C; Li XW; Cui LM; Li LC; Chen LY; Zhang XW

2011-11-01

315

Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors.  

UK PubMed Central (United Kingdom)

Studies in laboratory animals and epidemiological surveys suggest a relationship between the type and amount of dietary fat and mammary cancer. One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX). Until recently there have been no studies which have examined COX gene expression in human breast or rodent mammary tissues. In this study we have demonstrated the presence of two immunoreactive isoforms of cyclooxygenase (COX-1 and -2), and the modulating effects of n-3 fatty acids on their expression, in N-nitrosomethylurea (NMU)-induced rat mammary tumors. Three different high fat diets were compared namely, corn oil (CO) 23%; CO 18% menhaden oil (MO) 5%; CO, 5%/MO 18%; low fat corn oil (5%) served as a control. It was found that immunoreactive COX-2 protein levels were approximately 3x higher than COX-1 levels in NMU-induced mammary tumors. Moreover, the high menhaden oil diet (rich in n-3 fatty acids) significantly suppressed both COX-1 (-28%) and COX-2 (-36%) protein levels when compared to the high corn oil diet. No differences were found among the other treatment groups when compared pair-wise or with low-fat control. The mechanism(s) by which n-3 fatty acids suppress COX-1 and COX-2 remain to be determined.

Hamid R; Singh J; Reddy BS; Cohen LA

1999-03-01

316

Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors.  

Science.gov (United States)

Studies in laboratory animals and epidemiological surveys suggest a relationship between the type and amount of dietary fat and mammary cancer. One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX). Until recently there have been no studies which have examined COX gene expression in human breast or rodent mammary tissues. In this study we have demonstrated the presence of two immunoreactive isoforms of cyclooxygenase (COX-1 and -2), and the modulating effects of n-3 fatty acids on their expression, in N-nitrosomethylurea (NMU)-induced rat mammary tumors. Three different high fat diets were compared namely, corn oil (CO) 23%; CO 18% menhaden oil (MO) 5%; CO, 5%/MO 18%; low fat corn oil (5%) served as a control. It was found that immunoreactive COX-2 protein levels were approximately 3x higher than COX-1 levels in NMU-induced mammary tumors. Moreover, the high menhaden oil diet (rich in n-3 fatty acids) significantly suppressed both COX-1 (-28%) and COX-2 (-36%) protein levels when compared to the high corn oil diet. No differences were found among the other treatment groups when compared pair-wise or with low-fat control. The mechanism(s) by which n-3 fatty acids suppress COX-1 and COX-2 remain to be determined. PMID:10024686

Hamid, R; Singh, J; Reddy, B S; Cohen, L A

1999-03-01

317

A tumor suppressor role for srGAP3 in mammary epithelial cells.  

UK PubMed Central (United Kingdom)

srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs. Re-expression of srGAP3 in a subset of these cell lines inhibits both anchorage-independent growth and cell invasion in a GAP-dependent manner, and this is accompanied by an increase in phosphorylation of the ezrin/radixin/moesin (ERM) family proteins and myosin light chain 2 (MLC2). Inhibition of the Rho regulated kinase, ROCK, reduces ERM and MLC2 phosphorylation and restores invasion. We conclude that srGAP3 has tumor suppressor-like activity in HMECs, likely through its activity as a negative regulator of Rac1.Oncogene advance online publication, 29 October 2012; doi:10.1038/onc.2012.489.

Lahoz A; Hall A

2012-10-01

318

A tumor suppressor role for srGAP3 in mammary epithelial cells.  

Science.gov (United States)

srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs. Re-expression of srGAP3 in a subset of these cell lines inhibits both anchorage-independent growth and cell invasion in a GAP-dependent manner, and this is accompanied by an increase in phosphorylation of the ezrin/radixin/moesin (ERM) family proteins and myosin light chain 2 (MLC2). Inhibition of the Rho regulated kinase, ROCK, reduces ERM and MLC2 phosphorylation and restores invasion. We conclude that srGAP3 has tumor suppressor-like activity in HMECs, likely through its activity as a negative regulator of Rac1.Oncogene advance online publication, 29 October 2012; doi:10.1038/onc.2012.489. PMID:23108406

Lahoz, A; Hall, A

2012-10-29

319

Mouse mammary tumor virus integration site selection in human and mouse genomes.  

Science.gov (United States)

Based on integration site preferences, retroviruses can be placed into three groups. Viruses that comprise the first group, murine leukemia virus and foamy virus, integrate preferentially near transcription start sites. The second group, notably human immunodeficiency virus and simian immunodeficiency virus, preferentially targets transcription units. Avian sarcoma-leukosis virus (ASLV) and human T-cell leukemia virus (HTLV), forming the third group, show little preference for any genomic feature. We have previously shown that some human cells sustain mouse mammary tumor virus (MMTV) infection; therefore, we infected a susceptible human breast cell line, Hs578T, and, without introducing a species-specific bias, compared the MMTV integration profile to those of other retroviruses. Additionally, we infected a mouse cell line, NMuMG, and thus we could compare MMTV integration site selection in human and mouse cells. In total, we examined 468 unique MMTV integration sites. Irrespective of whether human or mouse cells were infected, no integration bias favoring transcription start sites was detected, a profile that is reminiscent of that of ASLV and HTLV. However, in contrast to ASLV and HTLV, not even a modest tendency in favor of integration within genes was observed. Similarly, repetitive sequences and genes that are frequently tagged by MMTV in mammary tumors were not preferentially targeted in cell culture either in mouse or in human cells; hence, we conclude that MMTV displays the most random dispersion of integration sites among retroviruses determined so far. PMID:18032509

Faschinger, Alexander; Rouault, Francoise; Sollner, Johannes; Lukas, Arno; Salmons, Brian; Günzburg, Walter H; Indik, Stanislav

2007-11-21

320

Expression of autophagy-related protein beclin-1 in malignant canine mammary tumors  

Science.gov (United States)

Background Autophagy is a self-catabolic mechanism that degrades unnecessary cellular components through lysosomal enzymes. Beclin-1, an autophagy-related protein, establishes the first connection between autophagy and tumorigenesis. The purpose of this study is to assess the Beclin-1 expression pattern and to determine its prognostic significance in patients with malignant canine mammary tumor (CMT). Results We examined Beclin-1 expression in 70 cases of malignant CMTs by immunohistochemistry. Cytoplasmic Beclin-1 expression was significantly weaker in cancer cells than in nearby normal mammary glands (p?tumor progression of malignant CMTs.

2013-01-01

 
 
 
 
321

The effect of antineoplastic drugs in a male spontaneous mammary tumor model.  

UK PubMed Central (United Kingdom)

Male breast cancer is a rare disease. The limited number of clinical cases has led to the primary treatments for men being derived from female breast cancer studies. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden and drug sensitivity of the antineoplastic drugs tamoxifen, cisplatin, and paclitaxel on tumorigenesis at an early stage of mammary carcinoma development in a male mouse model. Cisplatin treatment significantly reduced tumor volume, while paclitaxel and tamoxifen did not attenuate tumor growth. Cisplatin treatment was shown to induce apoptosis, grossly observed by reduced tumor formation, through reduced Bcl-2 and survivin protein expression levels with an increase in caspase 3 expression compared to control tumors. Tamoxifen treatment significantly altered the hormone receptor expression levels of the tumor, while additionally upregulating Bcl-2 and Cyclin D1. This suggests an importance in hormonal signaling in male breast cancer pathogenesis. The results of this study provide valuable information toward the better understanding of male breast cancer and may help guide treatment decisions.

Shishido SN; Faulkner EB; Beck A; Nguyen TA

2013-01-01

322

The effect of antineoplastic drugs in a male spontaneous mammary tumor model.  

Science.gov (United States)

Male breast cancer is a rare disease. The limited number of clinical cases has led to the primary treatments for men being derived from female breast cancer studies. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden and drug sensitivity of the antineoplastic drugs tamoxifen, cisplatin, and paclitaxel on tumorigenesis at an early stage of mammary carcinoma development in a male mouse model. Cisplatin treatment significantly reduced tumor volume, while paclitaxel and tamoxifen did not attenuate tumor growth. Cisplatin treatment was shown to induce apoptosis, grossly observed by reduced tumor formation, through reduced Bcl-2 and survivin protein expression levels with an increase in caspase 3 expression compared to control tumors. Tamoxifen treatment significantly altered the hormone receptor expression levels of the tumor, while additionally upregulating Bcl-2 and Cyclin D1. This suggests an importance in hormonal signaling in male breast cancer pathogenesis. The results of this study provide valuable information toward the better understanding of male breast cancer and may help guide treatment decisions. PMID:23755153

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

2013-06-03

323

Autoantibodies against muscarinic receptors in breast cancer: their role in tumor angiogenesis.  

UK PubMed Central (United Kingdom)

The presence of autoantibodies in cancer has become relevant in recent years. We demonstrated that autoantibodies purified from the sera of breast cancer patients activate muscarinic acetylcholine receptors in tumor cells. Immunoglobulin G (IgG) from breast cancer patients in T1N0Mx stage (tumor size?2 cm, without lymph node metastasis) mimics the action of the muscarinic agonist carbachol stimulating MCF-7 cell proliferation, migration and invasion. Angiogenesis is a central step in tumor progression because it promotes tumor invasion and metastatic spread. Vascular endothelial growth factor-A (VEGF-A) is the main angiogenic mediator, and its levels have been correlated with poor prognosis in cancer. The aim of the present work was to investigate the effect of T1N0Mx-IgG on the expression of VEGF-A, and the in vivo neovascular response triggered by MCF-7 cells, via muscarinic receptor activation. We demonstrated that T1N0Mx-IgG (10(-8) M) and carbachol (10(-9) M) increased the constitutive expression of VEGF-A in tumor cells, effect that was reverted by the muscarinic antagonist atropine. We also observed that T1N0Mx-IgG and carbachol enhanced the neovascular response produced by MCF-7 cells in the skin of NUDE mice. The action of IgG or carbachol was reduced in the presence of atropine. In conclusion, T1N0Mx-IgG and carbachol may promote VEGF-A production and neovascularization induced by breast tumor cells via muscarinic receptors activation. These effects may be accelerating breast tumor progression.

Lombardi MG; Negroni MP; Pelegrina LT; Castro ME; Fiszman GL; Azar ME; Morgado CC; Sales ME

2013-01-01

324

Autoantibodies against muscarinic receptors in breast cancer: their role in tumor angiogenesis.  

Science.gov (United States)

The presence of autoantibodies in cancer has become relevant in recent years. We demonstrated that autoantibodies purified from the sera of breast cancer patients activate muscarinic acetylcholine receptors in tumor cells. Immunoglobulin G (IgG) from breast cancer patients in T1N0Mx stage (tumor size?2 cm, without lymph node metastasis) mimics the action of the muscarinic agonist carbachol stimulating MCF-7 cell proliferation, migration and invasion. Angiogenesis is a central step in tumor progression because it promotes tumor invasion and metastatic spread. Vascular endothelial growth factor-A (VEGF-A) is the main angiogenic mediator, and its levels have been correlated with poor prognosis in cancer. The aim of the present work was to investigate the effect of T1N0Mx-IgG on the expression of VEGF-A, and the in vivo neovascular response triggered by MCF-7 cells, via muscarinic receptor activation. We demonstrated that T1N0Mx-IgG (10(-8) M) and carbachol (10(-9) M) increased the constitutive expression of VEGF-A in tumor cells, effect that was reverted by the muscarinic antagonist atropine. We also observed that T1N0Mx-IgG and carbachol enhanced the neovascular response produced by MCF-7 cells in the skin of NUDE mice. The action of IgG or carbachol was reduced in the presence of atropine. In conclusion, T1N0Mx-IgG and carbachol may promote VEGF-A production and neovascularization induced by breast tumor cells via muscarinic receptors activation. These effects may be accelerating breast tumor progression. PMID:23460876

Lombardi, María Gabriela; Negroni, María Pía; Pelegrina, Laura Tatiana; Castro, María Ester; Fiszman, Gabriel L; Azar, María Eugenia; Morgado, Carlos Cresta; Sales, María Elena

2013-02-27

325

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

Directory of Open Access Journals (Sweden)

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.

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

2007-01-01

326

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

Directory of Open Access Journals (Sweden)

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; Radhika S; Motiwale Leena; Rao KVK

2006-01-01

327

Lack of association of mouse mammary tumor virus-like sequences in Iranian breast cancer patients.  

UK PubMed Central (United Kingdom)

OBJECTIVE: The present study aimed to detect mouse mammary tumor virus (MMTV)-like sequences in Iranian breast cancer patients in the city of Shiraz, located in southwest Iran. SUBJECTS AND METHODS: We searched for two MMTV genetic regions in the peripheral blood leukocytes of 300 women with breast cancer, 300 age-matched healthy control subjects, and 50 breast tumor tissues. Two regions of MMTV, 660 bp and 250 bp, were searched by nested polymerase chain reactions. RESULTS: None of the above two regions were detected. There were no differences between the control group and the breast cancer group. CONCLUSION: Our findings did not show any association of MMTV-like sequences with breast cancer development in Iranian patients in Shiraz.

Motamedifar M; Saki M; Ghaderi A

2012-01-01

328

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 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 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 (more) 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 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 (more) 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.

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

2009-02-01

329

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

Directory of Open Access Journals (Sweden)

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; 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

2009-01-01

330

Visualization of rodent brain tumor angiogenesis and effects of antiangiogenic treatment using 3D ?R2-?MRA.  

Science.gov (United States)

Understanding of structural and functional characteristics of the vascular microenvironment in gliomas and the impact of antiangiogenic treatments is essential for developing better therapeutic strategies. Although a number of methods exist in which this process can be studied experimentally, no single noninvasive test has the capacity to provide information concerning both microvascular function and morphology. The purpose of present study is to demonstrate the feasibility of using a novel three-dimensional ?R2-based microscopic magnetic resonance angiography (3D ?R2-?MRA) technique for longitudinal imaging of tumor angiogenesis and monitoring the effects of antiangiogenic treatment in rodent brain tumor models. Using 3D ?R2-?MRA, a generally consistent early pattern of vascular development in gliomas was revealed, in which a single feeding vessel was visualized first (arteriogenesis), followed by sprouting angiogenesis. Considerable variability of the tumor-associated vasculature was then noted at later stages of tumor evolution. ?R2-?MRA revealed that anti-vascular endothelial growth factor treatment induced a rapid and significant alteration of the intratumoral angiogenic phenotype. In summary, 3D ?R2-?MRA enables high-resolution visualization of tumor-associated vessels while simultaneously providing functional information on the tumor microvasculature. It can serve as a useful tool for monitoring both the temporal evolution of tumor angiogenesis and the impact of antiangiogenic therapies. PMID:23736837

Lin, Chien-Yuan; Siow, Tiing Yee; Lin, Ming-Huang; Hsu, Yi-Hua; Tung, Yu-Yin; Jang, Taichang; Recht, Lawrence; Chang, Chen

2013-06-05

331

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

UK PubMed Central (United Kingdom)

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

Kaimal R; Aljumaily R; Tressel SL; Pradhan RV; Covic L; Kuliopulos A; Zarwan C; Kim YB; Sharifi S; Agarwal A

2013-04-01

332

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

Energy Technology Data Exchange (ETDEWEB)

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

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

1984-01-01

333

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

Digital Repository Infrastructure Vision for European Research (DRIVER)

Yajie Liu, Yi Yang, Chunfu Zhang School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Abstract: Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification ...

Liu Y; Yang Y; Zhang C

334

Dual Inhibition of Plasminogen Kringle 5 on Angiogenesis and Chemotaxis Suppresses Tumor Metastasis by Targeting HIF-1? Pathway  

Digital Repository Infrastructure Vision for European Research (DRIVER)

We had demonstrated that plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibited retinal neovascularization and hepatocellular carcinoma growth by anti-angiogenesis. The current study investigated the effects and the underlying mechanisms of K5 on both tumor growth and spontaneous pulmo...

Cai, Wei-Bin; Zhang, Yang; Cheng, Rui; Wang, Zheng; Fang, Shu-Huan; Xu, Zu-Min; Yang, Xia; Yang, Zhong-Han; Ma, Jian-Xing

335

Effect of melatonin and pineal extracts on human ovarian and mammary tumor cells in a chemosensitivity assay.  

Science.gov (United States)

Pinealectomy enhances tumor growth and metastatic spread in experimental animals. This effect is only in part due to melatonin since melatonin-free pineal extracts containing yet unidentified pineal substances have also shown tumor inhibiting activity. Despite numerous reports suggesting melatonin as a potential anti-cancer agent there have not been sufficient clinical trials to define the actual therapeutic potential of melatonin for the treatment of human cancers. To help fill this gap, we used a chemosensitivity assay designed to test the sensitivity of tumors from individual patients towards chemotherapeutic drugs for assessing the effect of melatonin and pineal extracts on primary human tumor cells. Primary cell cultures from seven ovarian and six mammary tumors were incubated with melatonin, the pineal extract YC05R (containing substances between 500 and 1000 daltons) and chemotherapeutic drugs. The pineal extract YC05R inhibited growth of all tumors in a dose-dependent manner. Physiological concentrations of melatonin (10(-8)-10(-10) M) inhibited the growth of one out of six mammary carcinomas in a dose-dependent manner. Primary cell cultures from three ovarian tumors were affected by melatonin in different ways, i.e., two were inhibited and one was slightly stimulated. There was no correlation between sensitivity towards melatonin and sex steroid receptor status, stage or grade of the tumor. It is concluded that, 1), melatonin may be an inhibitor of human mammary and ovarian carcinoma in individual cases and, 2), the pineal gland contains very active anti-tumor substances inhibiting both, the mammary and ovarian tumors, tested. These substances require chemical and biological identification. PMID:11133007

Bartsch, H; Buchberger, A; Franz, H; Bartsch, C; Maidonis, I; Mecke, D; Bayer, E

2000-11-01

336

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN.  

Science.gov (United States)

Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin) is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNF? (1 ng/ml). Membranal EMMPRIN expression was increased in the co-cultures (by 3-4-folds, p < 0.01), as was the secretion of MMP-9 and VEGF (by 2-5-folds for both MMP-9 and VEGF, p < 0.01), relative to the single cultures with TNF?. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2-3-folds, p < 0.05, only in the A498 co-culture) via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway. PMID:23874303

Amit-Cohen, Bat-Chen; Rahat, Maya M; Rahat, Michal A

2013-07-12

337

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN.  

UK PubMed Central (United Kingdom)

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

Amit-Cohen BC; Rahat MM; Rahat MA

2013-01-01

338

Characterization of fatty acid synthase in cell lines derived from experimental mammary tumors.  

UK PubMed Central (United Kingdom)

The lipogenic enzyme fatty acid synthase (FAS) is elevated in various human primary cancers and certain human cancer cell lines. FAS overexpression in human neoplasia has clinical relevance because of its association with tumor aggression and potential chemotherapeutic intervention. Here, we surveyed FAS in cell lines established from normal murine mammary epithelium (NMuMG) and from mammary tumors induced by either rodent polyoma (Py) virus or murine mammary tumor virus (MMTV). Western blotting revealed greater content of FAS in Py-transformed A1-1 and T1 than NMuMG or MMTV-transformed Mm5MT, RIIIMT and MMT060562. These data suggest that signaling events mediated by Py transformation may increase cellular amounts of FAS. Although FAS content was elevated to similar levels in A1-1 and T1, specific activities were significantly different as enzyme activity in T1 was 3-fold higher than A1-1. Likewise, FAS activity in NMuMG was about 0.5-fold higher than the MMTV-transformed lines, even though enzyme content was similar. Immunoprecipitation studies employing anti-phosphoamino acid antibodies followed by immunoblot analysis with anti-FAS antisera (and vice versa) were used to characterize the constitutive phosphorylation state of the enzyme. Phosphoserine and phosphothreonine residues were detected in the more active FAS from T1 and NMuMG, but not in the less active FAS from Mm5MT or A1-1. Discovery of phosphorylated FAS suggests that the enzyme may have more immediate control over lipogenesis than previously thought. High-dose (10-4 M) dexamethasone induced FAS content and activity in NMuMG and MMTV-transformed lines but not Py-transformed cells. Lower concentrations (10-8, 10-6 M) of dexamethasone also activated FAS but without concomitant elevation of its protein content, which was consistent with a phosphorylated form of FAS. Finally, cell lines were treated with the FAS inhibitor cerulenin: almost all breast cancer lines were growth inhibited at significantly lower amounts of drug than normal cell lineages, suggesting that FAS plays a greater role in viability of tumor cells than normal cells. Pretreatment with palmitate (a primary end-product of FAS) prior to cerulenin rescued A1-1 cells only slightly from growth inhibition, whereas pretreatment with oleate (a monounsaturated fatty acid synthesized from palmitate) synergized cerulenin's cytotoxic effects.

Hennigar RA; Pochet M; Hunt DA; Lukacher AE; Venema VJ; Seal E; Marrero MB

1998-05-01

339

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

International Nuclear Information System (INIS)

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

2005-06-24

340

Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis.  

Science.gov (United States)

Development of metastasis in peripheral tissues is a major problem in the fight to cure breast cancer. Although it is becoming evident that chronic inflammation can contribute to tumor progression and metastasis, the effect of acute inflammation in primary tumor is less known. Using mouse models for breast cancer here we show that biopsy of mammary tumors increases the frequency of lung metastases. This effect is associated with the recruitment of inflammatory cells to the lung and elevated