Extracellular Proteolysis in Transgenic Mouse Models of Breast Cancer

Almholt, Kasper; Green, Kirsty Anne; Juncker-Jensen, Anna; Nielsen, Boye Schnack; Lund, Leif R.; Rømer, John

doi:10.1007/s10911-007-9040-x

Cited by 40 publications

(41 citation statements)

References 84 publications

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“…MSP is a serum protein, activated by a macrophage protease (MT-SP1 or matripase) that promotes macrophage as well as epithelial cell chemotaxis and is often overexpressed in breast tumors. MMTV-PyMT 634 tumor cells transduced with MSP, as well as tumors generated by a stem cell retrovirus expressing MT, had accelerated tumor growth and showed an increase in the frequency of metastasis at all sites (lung, lymph node, spleen, and liver (3,223,285). Proteases are involved in the process of metastasis, since metastases can be reduced by treatment with the general metalloproteinase inhibitor galardin (4) or knockout of urokinase (223).…”

Section: The Widely Used Transgenic Mmtv-pymtmentioning

confidence: 99%

Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

Fluck

Schaffhausen

2009

Microbiol Mol Biol Rev

142

156

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SUMMARY The small DNA tumor viruses have provided a very long-lived source of insights into many aspects of the life cycle of eukaryotic cells. In recent years, the emphasis has been on cancer-related signaling. Here we review murine polyomavirus middle T antigen, its mechanisms, and its downstream pathways of transformation. We concentrate on the MMTV-PyMT transgenic mouse, one of the most studied models of breast cancer, which permits the examination of in situ tumor progression from hyperplasia to metastasis.

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Section: The Widely Used Transgenic Mmtv-pymtmentioning

confidence: 99%

Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

Fluck

Schaffhausen

2009

Microbiol Mol Biol Rev

142

156

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“…The building blocks of this thick shield consist of layers of epithelial cells, myoepithelial cells, and basal membrane. The basal membrane consists of various proteins, fiber bundles (collagens), and ECM components early invasion (Almholt et al 2007). (See Fig.…”

Section: Introductionmentioning

confidence: 99%

A Hybrid Model of Tumor–Stromal Interactions in Breast Cancer

Kim

Othmer

2013

Bull Math Biol

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Ductal carcinoma in situ (DCIS) is an early stage noninvasive breast cancer that originates in the epithelial lining of the milk ducts, but it can evolve into comedo DCIS and ultimately, into the most common type of breast cancer, invasive ductal carcinoma. Understanding the progression and how to effectively intervene in it presents a major scientific challenge. The extracellular matrix (ECM) surrounding a duct contains several types of cells and several types of growth factors that are known to individually affect tumor growth, but at present the complex biochemical and mechanical interactions of these stromal cells and growth factors with tumor cells is poorly understood. Here we develop a mathematical model that incorporates the cross-talk between stromal and tumor cells, which can predict how perturbations of the local biochemical and mechanical state influence tumor evolution. We focus on the EGF and TGF-β signaling pathways and show how upor down-regulation of components in these pathways affects cell growth and proliferation. We then study a hybrid model for the interaction of cells with the tumor microenvironment (TME), in which epithelial cells (ECs) are modeled individually while the ECM is treated as a continuum, and show how these interactions affect the early development of tumors. Finally, we incorporate breakdown of the epithelium into the model and predict the early stages of tumor invasion into the stroma. Our results shed light on the interactions between growth factors, mechanical properties of the ECM, and feedback signaling loops between stromal and tumor cells, and suggest how epigenetic changes in transformed cells affect tumor progression.

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“…In the presence of a transgene-supplied oncogene, tumor development, growth, and metastasis are in most cases promoted by increased MMP activity and inhibited by decreased MMP activity (reviewed in ref. 15). A couple of examples, here limited to studies of transgenic breast cancer models, illustrate the general finding: (a) tumor onset is promoted by MMP-7 overexpression (16) and delayed by TIMP-2 overexpression (17), (b) tumor growth is reduced by overexpression of either TIMP-1 (18) or TIMP-2 (17), and (c) tumor metastasis is reduced by overexpressing TIMP-1 through a liver-specific transgene (18).…”

Section: Introductionmentioning

confidence: 99%

Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model

Almholt

Juncker-Jensen

Lærum

et al. 2008

Molecular Cancer Therapeutics

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Matrix metalloproteinases (MMP) have several roles that influence cancer progression and dissemination. However, low molecular weight metalloproteinase inhibitors (MPI) have not yet been tested in transgenic/spontaneous metastasis models. We have tested Galardin/GM6001, a potent MPI that reacts with most MMPs, in the MMTVPymT transgenic breast cancer model. We followed a cohort of 81 MMTV-PymT transgenic mice that received Galardin, placebo, or no treatment. Galardin treatment was started at age 6 weeks with 100 mg/kg/d, and all mice were killed at age 13.5 weeks. Galardin treatment significantly reduced primary tumor growth. Final tumor burden in Galardin-treated mice was 1.69 cm 3 compared with 3.29 cm 3 in placebo-treated mice (t test, P = 0.0014). We quantified the total lung metastasis volume in the same cohort of mice. The median metastasis volume was 0.003 mm 3 in Galardin-treated mice compared with 0.56 mm 3 in placebo-treated mice (t test, P < 0.0001). Thus, metastasis burden was reduced more than 100-fold, whereas primary tumor size was reduced only 2-fold. We also found that primary tumors from Galardin-treated mice exhibited a lower histopathologic tumor grade, increased collagen deposition, and increased MMP-2 activity. MMPs are known to have tumor-promoting and tumor-inhibitory effects, and several clinical trials of broad-spectrum MPIs have failed to show promising effects. The very potent antimetastatic effect of Galardin in the MMTV-PymT model does, however, show that it may be possible to find broad-spectrum MPIs with favorable inhibition profiles, or perhaps combinations of monospecific MPIs, for future clinical application. [Mol Cancer Ther 2008;7(9):2758 -67]

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Extracellular Proteolysis in Transgenic Mouse Models of Breast Cancer

Cited by 40 publications

References 84 publications

Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

A Hybrid Model of Tumor–Stromal Interactions in Breast Cancer

Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model

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