Role of matrix metalloproteinases (MMPs) in colorectal cancer

Abstract

Considerable evidence has implicated matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, in the degradation of extracellular matrix (ECM) during the metastatic process. Most MMPs are secreted as inactive zymogens and are activated extracellularly. Over expression of MMP-1, -2, -3. -7, -9, -13, and MT1-MMP has been demonstrated in human colorectal cancers. The degree of over expression of some MMPs has been noted to correlate with stage of disease and/or prognosis. An unresolved debate has centered on whether MMPs are produced by the stromal cells surrounding a tumor or by the colorectal cancer cells themselves. MMP-7 is produced abundantly by colorectal cancer cells. The presence of a mutation in the APC gene results in nuclear accumulation of the beta-Catenin/TCF complex, which serves as a transcriptional factor that upregulates MMP-7 expression. Increased expression of MMP-3 in colorectal cancer correlates with low levels of microsatelite instability and poor prognosis. Increased levels of MMP-9 (produced primarily by inflammatory cells) have been demonstrated early in the transition from colon adenoma to adenocarcinoma. In contrast to other MMPs, overexpression of MMP-12 is associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis. Based on the assumption that MMPs were responsible for metastasis, several orally active, low molecular weight inhibitors of MMPs (MMPIs) have been developed. These MMPIs have been effective in controlling cancer progression in animals, but have failed to prolong survival in phase III clinical trials in patients with advanced cancer. MMPIs have not yet been evaluated in patients with colorectal cancer.

Molecular profiling of cervical cancer progression

“…Similar to AKT, MMP3 can also cause epithelial -mesenchymal transition in cancer (Radisky et al, 2005). Matrix metalloproteinase 9 plays a central role in connective tissue degradation, tumourinduced angiogenesis, cell proliferation/apoptosis and cell migration in various tumour types including cervical cancer (van Kempen and Coussens, 2002;Van Trappen et al, 2002;Zucker and Vacirca, 2004;Vazquez-Ortiz et al, 2005b). Recently, one study has shown that MMP9 forms a complex with the hyaluronan receptor CD44 on the surface of breast cancer cells and activates downstream TGF-b, facilitating tumour cell survival, invasion and metastasis (Yu and Stamenkovic, 2004).…”

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

“…1,2 Metalloproteinases are inhibited by tissue inhibitors (TIMPs) which are secreted proteins. These bioactive substances are specific inhibitors of MMPs that bind to enzymatically active MMPs at a 1:1 molar stoichiometry thus inhibiting proteolysis.…”

Antitumor Effects of Hyperthermic CO2Pneumoperitoneum on Human Gastric Cancer Cells

“…The tumor cell integrin binded to ECM ligands activating a form of intracellular signaling promoting cell invasion and metastasis; this type of adhesion molecules dependent intracellular signal transduction was generally called "outside-in signaling" (Giancotti et al, 1999). On the other hand, mold metalloproteinases (MMPs) were a family of zinc-dependent neutral endopeptidases that had a crucial role in the degradation of extracellular matrix, which were crucial for malignant tumor growth, invasion, and metastasis (Zucker et al, 2004). Ozgur Kemik et al investigated MMP-1 level in gastric cancer patients and compared them with a control group.…”