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Matrix metalloproteinase (MMP) degradation of extracellular matrix is thought to play an important role in invasion, angiogenesis, tumor growth, and metastasis. Several studies have demonstrated that CD147/ extracellular MMP inducer, a membrane-spanning molecule highly expressed in tumor cells, may be involved in the progression of malignancies by regulating expression of MMP in peritumoral stromal cells. In the present study we show that CD147 is expressed in microvesicles derived from epithelial ovarian cancer cells and that CD147-positive vesicles may promote an angiogenic phenotype in endothelial cells in vitro. Vesicles shed by human ovarian carcinoma cell lines OVCAR3, SKOV3, and A2780 expressed different levels of CD147 and stimulated proangiogenic activities of human umbilical vein endothelial cells (HUVECs) in a CD147-dependent fashion (OVCAR3 > SKOV3 > A2780). Moreover, vesicles shed by ovarian carcinoma cell line CABA I with low CD147 expression had no significant effect on the development of angiogenic phenotype in HUVECs. The treatment of OVCAR3 cells with small interfering RNA against CD147 suppressed the angiogenic potential of OVCAR3-derived microvesicles. However, transfection of CD147 cDNA into the CABA I cell line enabled CABA I-derived vesicles to induce angiogenesis and to promote MMP genes expression in HUVECs. We therefore conclude that vesicles shed by ovarian cancer cells may induce proangiogenic activities of HUVECs by a CD147-mediated mechanism.

Publisher Summary Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) are involved in numerous physiologic and pathologic processes. Considerable interest has evolved over the past decade in the measurement of MMPs and TIMPs in blood and urine as an aid in the diagnosis and prognosis of disease. The goal of this chapter is to provide a comprehensive review of the subject with the focus on potential future developments and applications of the technology. The chapter also discusses involvement of MMPs and TIMPs in pathophysiology of disease such as cancer, inflammatory diseases, liver disease, cardiovascular disease, lung diseases, central nervous system disease, shock syndromes, chronic wounds and inflammation of the skin, and oral cavity. Several assays for measurement of MMPs and TIMPs in body fluids such as pitfalls in measurement and origin of MMPs and TIMPs in blood are also discussed in this chapter. Based on research implicating MMPs in various pathologic processes, this chapter has described the measurement of MMPs and TIMPs in the blood and urine of patients with various diseases. Another consideration is whether measurement of blood and urinary levels of MMPs and TIMPs have potential utility in general screening for disease in periodic health examinations. In this chapter, comparisons to baseline MMP measurements for single individuals might be useful in detecting development of disease over protracted periods of time, for example, progressive development of cardiovascular disease.

Publisher Summary Matrix metalloproteinases (MMPs) belong to the family of zinc endopeptidases collectively referred to as metzincins. The metzincin superfamily is distinguished by a highly conserved motif containing three histidines that bind zinc at the catalytic site and a conserved methionine that sits beneath the active site. The metzincins are subdivided into four multigene families: serralysins, astacins, ADAMs/adamalysins, and MMPs. Once activated, MMPs degrade a variety of extracellular matrix components and assorted other proteins including growth factors, growth factor binding proteins, and protease inhibitors. The ability to degrade extracellular matrix proteins is essential for any cell to interact properly with its immediate surroundings and for multicellular organisms to develop and function normally. MMPs also generate matrix protein fragments, which have functional activity of their own. These various functions of MMPs modulate cell invasion and metastasis, cell migration, apoptosis, and angiogenesis. The belief that an MMP is involved in a given biologic/pathologic process is often based on the strength of its association with that process and the existence of plausible mechanisms that can be tested by experimental approaches. Because of extensive redundancy of MMP function in animals, it has been difficult to appreciate the role of individual genes in various experimental models. The multiplicity of MMPs with distinct but somewhat overlapping functions appears to act as a safeguard against loss of regulatory control. The known MMP genes have been divided into four subfamilies based on gene structure. Group I consists of the collagenase subfamily. Group 2 consists of the gelatinases/modular alteration (fimodular a-like domains) subfamily. Group 3 consists of the variant hemopexin exon subfamily. Group 4 consists of the variant catalytic exon and unique 3′-end exon (plasma membrane and cytoplasmic domains) subfamily, which consists of the membrane type-matrix metalloproteinases (MT-MMPs).

Cancer progression is a multistage process in which cancer cells undergo genetic changes that lead to phenotypic alterations, including the capacity to metastasize. An overwhelming amount of experimental evidence has been accumulated to implicate matrix metalloproteinases (MMPs) and plasminogen activators (PAs) in invasion and metastasis. However, specific MMPs appear to have different functions depending on the experimental model and the stage of cancer. The fact that most MMPs and PAs in human cancers are produced by reactive stromal cells, such as fibroblasts, endothelial cells, and inflammatory cells surrounding the tumor rather than cancer cells themselves needs to be better understood. Proteases may be good anticancer targets in that they appear to be required for the stromal tissue remodeling associated with angiogenesis and tumor metastasis. However, true clinical efficacy may require combination therapy with cytotoxic agents, as well as long-term administration, possibly at earlier stages of cancer. Numerous highly effective hydroxamic acid-based MMP inhibitors (MMPIs) have been developed, three of which are in clinical trials on patients with advanced cancer. An exciting new approach in the development of more specific MMPIs involves the use of phage display random peptide libraries to isolate selective enzyme inhibitors. The prototype synthetic peptide inhibited the migration of human endothelial cells and tumor cells, prevented tumor growth and invasion in animal models, targeted angiogenic blood vessels in vivo, and improved survival of mice bearing human tumors.