Matrix metalloproteinase (MMP)-7, also known as matrilysin, is a "minimal domain MMP" that exhibits proteolytic activity against components of the extracellular matrix (ECM). Matrilysin is frequently overexpressed in human cancer tissues and is associated with cancer progression. Tumorigenesis is a multistep process involving cell growth, invasion, metastasis, and angiogenesis. Matrilysin has been shown to play important roles not only in degradation of ECM proteins, but also in the regulation of several biochemical processes such as activation, degradation, and shedding of non-ECM proteins. This minire-view provides a summary of the current literature on the roles of matrilysin in tumorigenesis with a focus on the roles of modifications of non-ECM proteins by matrilysin and other related MMPs in tumorigenesis. Proteolysis of insulin-like growth factor binding protein by matrilysin results in increased bioavailability of insulin-like growth factors and enhanced cellular proliferation. Matrilysin has also been implicated in the ectodomain shedding of several cell surface molecules. Heparin-binding epidermal growth factor precursor (proHB-EGF) is cleaved by matrilysin into mature HB-EGF, which promotes cellular proliferation. Membrane-bound Fas ligand (FasL) is cleaved into soluble FasL, which increases apoptosis of cells adjacent to tumor cells. E-cadherin is converted to soluble E-cadherin to promote invasion. Tumor necrosis factor (TNF)-alpha precursor is cleaved to release soluble TNF-alpha to increase apoptosis. We propose that these matrilysin-mediated pathways provide the necessary and logical mechanisms to promote cancer progression.

BACKGROUND: Insulin‐like growth factor (IGF)‐I receptor (IGF‐IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant‐negative IGF‐IR (IGF‐IR/dn). In addition, it has been demonstrated that IGF‐IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF‐IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer. METHODS: The impact of IGF signals on the expression of VEGF‐A and VEGF‐C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF‐IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed. RESULTS: IGFs induced the expression of VEGF ligands and up‐regulated in vitro vascular vessel formation. IGF‐IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen‐activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF‐IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF‐IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF‐IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis. CONCLUSIONS: The current results indicated that IGF‐IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF‐IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy. Cancer 2011. © 2011 American Cancer Society.

Purpose: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.Experimental Design: We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.Results Conclusions: IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations. Clin Cancer Res; 17(15); 5048-59. Ó2011 AACR.