Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions

Abstract

A number of extensive reviews are available discussing the roles of MMPs in various aspects of cancer progression from benign tumor formation to overt cancer present with deadly metastases. This review will focus specifically on the evidence functionally linking the MMPs and tumor-induced angiogenesis in various in vivo models. Emphasis has been placed on the cellular origin of the MMPs in tumor tissue, the requirement of proMMP activation and the resulting proteolytic activity for the induction and progression of tumor angiogenesis, and the pleiotropic roles for some of the MMPs. The functional mechanisms of the angiogenic MMPs are discussed as well as their catalytic detection in complex biological systems. In addition, the contribution of active MMPs to metastatic spread and establishment of secondary metastasis will be discussed in view of the findings indicating that MMPs are involved in the preparation of pre-metastatic niches. Finally, the most recent evidence, indicating the pro-metastatic consequences of anti-angiogenic therapies employing MMP inhibitors will be presented as examples highlighting possible outcomes of interfering with the pleiotropic nature of the MMP functionality.

Figure 1. MMP-9 is a powerful proangiogenic factor acting via release of ECM-sequestered VEGF and FGF-2

MMP-9 is produced as a zymogen and requires activation before exerting its angiogenic activity. Upon activation, MMP-9 enzyme is capable of releasing pro-angiogenic factors such as VEGF and FGF-2, which are sequestered in the ECM. Bioavailable VEGF and FGF-2 bind to the endothelial cells expressing corresponding receptors for the angiogenic factors. Complex formation between angiogenic factors and their tyrosine kinases receptors triggers signal transduction, which in turn leads to the angiogenic switch, involving endothelial cell reorganization and matrix and tissue remodeling.

Figure 2. Efficient and rapid activation of neutrophil proMMP-9 due to its unique TIMP-free status

Neutrophils synthesize and store MMP-9 in their secretory granules, readily available for release on demand. Since TIMP-1 production in neutrophils is very low or even undetectable, MMP-9 zymogen is released in the TIMP-free form, immediately accessible to proteolytic activation. Therefore, activation of TIMP-free neutrophil MMP-9 is relatively rapid and activated MMP-9 enzyme becomes readily available to trigger the angiogenic switch. In contrast to neutrophils, stimulated monocytes/macrophages and tumors cells synthesize MMP-9 de novo. Usually, induction of MMP-9 is concomitant with an increased expression of TIMP-1 and therefore, MMP-9 zymogen at least partially is complexed with TIMP-1. Complexing with TIMP-1 slows activation of MMP-9 zymogen and makes it relatively inefficient as compared with activation rates of TIMP-free MMP-9. This delayed activation, might make monocyte and tumor-derived MMP-9 less efficient in the induction of angiogenesis.