Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of the extracellular matrix is the sine qua non of tumor invasion and metastasis. Most of this degradation is mediated by matrix metalloproteinases (MMPs), a family of enzymes that, collectively, degrades the extracellular matrix. Although the basement membrane-degrading enzymes, MMP-2 and MMP-9, have been given considerable attention for their roles in invasion and metastasis, the interstitial collagenases, a subfamily of MMPs that cleaves the stromal collagens types I and III, have received relatively little recognition for their part in these processes. This subfamily is comprised of collagenase 1 (MMP-1), collagenase 3 (MMP-13), and the MT-MMPs, membrane-bound MMPs, and numerous reports over the last several years document the expression of these MMPs in a wide variety of advancing tumors. Of particular interest is a single nucleotide polymorphism in the MMP-1 promoter that increases the transcription of this gene and that is associated with melanoma and with ovarian and endometrial cancers. The collagenases can mediate tumor invasion through several mechanisms, which include constitutive production of enzyme by the tumor cells, induction of collagenase production in the neighboring stromal cells, and interactions between tumor/ stromal cells to induce collagenase production by one or both cell types. Thus, evidence indicates that elevated expression of the interstitial collagenases is associated with a poor prognosis in a variety of cancers, and therefore, these MMPs can serve as a marker of tumor progression.
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PMID:Interstitial collagenases as markers of tumor progression. 1115 41

S100A4(mts1) protein expression has been strongly associated with metastatic tumor progression. It has been suggested as a prognostic marker for a number of human cancers. It is proposed that extracellular S100A4 accelerates cancer progression by stimulating the motility of endothelial cells, thereby promoting angiogenesis. Here we show that in 3D culture mouse endothelial cells (SVEC 4-10) respond to recombinant S100A4 by stimulating invasive growth of capillary-like structures. The outgrowth is not dependent on the stimulation of cell proliferation, but rather correlates with the transcriptional modulation of genes involved in the proteolytic degradation of extracellular matrix (ECM). Treatment of SVEC 4-10 with the S100A4 protein leads to the transcriptional activation of collagenase 3 (MMP-13) mRNA followed by subsequent release of the protein from the cells. Beta-casein zymography demonstrates enhancement of proteolytic activity associated with MMP-13. This observation indicates that extracellular S100A4 stimulates the production of ECM degrading enzymes from endothelial cells, thereby stimulating the remodeling of ECM. This could explain the angiogenic and metastasis-stimulating activity of S100A4(mts1).
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PMID:Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. 1512 22

Matrix metalloproteinase (MMP) 13 (collagenase 3) is an extracellular matrix remodeling enzyme that is induced in myofibroblasts during the earliest invasive stages of human breast carcinoma, suggesting that it is involved in tumor progression. During progression of mammary carcinomas in the polyoma virus middle T oncogene mouse model (MMTV-PyMT), Mmp13 mRNA was strongly upregulated concurrently with the transition to invasive and metastatic carcinomas. As in human tumors, Mmp13 mRNA was found in myofibroblasts of invasive grade II and III carcinomas, but not in benign grade I and II mammary intraepithelial neoplasias. To determine if MMP13 plays a role in tumor progression, we crossed MMTV-PyMT mice with Mmp13 deficient mice. The absence of MMP13 did not influence tumor growth, vascularization, progression to more advanced tumor stages, or metastasis to the lungs, and the absence of MMP13 was not compensated for by expression of other MMPs or tissue inhibitor of metalloproteinases. However, an increased fraction of thin collagen fibrils was identified in MMTV-PyMT;Mmp13(-/-) compared to MMTV-PyMT;Mmp13(+/+) tumors, showing that collagen metabolism was altered in the absence of MMP13. We conclude that the expression pattern of Mmp13 mRNA in myofibroblasts of invasive carcinomas in the MMTV-PyMT breast cancer model recapitulates the expression pattern observed in human breast cancer. Our results suggest that MMP13 is a marker of carcinoma-associated myofibroblasts of invasive carcinoma, even though it does not make a major contribution to tumor progression in the MMTV-PyMT breast cancer model.
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PMID:Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression. 1869 13