Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

Abstract

Metastasis is a distinct stage of cancer progression that requires the development of angiogenic blood vessels serving as conduits for tumor cell dissemination. An accumulated body of evidence indicates that metastasis-supporting neovasculature should possess certain structural characteristics allowing for the process of tumor cell intravasation, an active entry of cancer cells into the vessel interior. It appears that the development of tumor vessels with lumens of a distinctive size and their structure supported by a discontinuous pericyte coverage, together constitute critical microarchitectural requirements to: (a) provide accessible points for vessel wall penetration by primary tumor cells; (b) provide enough lumen space for a tumor cell or cell aggregate upon intravasation; and (c) allow for sufficient rate of blood flow to carry away intravasated cells from the primary tumor to the next, proximal or distal site. This review will primarily focus on the functional roles of matrix metalloproteinases (MMPs), which catalytically trigger the development of an intravasation-sustaining neovasculature at the early stages of tumor growth and are also required for the maintenance of a metastasis-supporting state of blood vessels at later stages of cancer progression.

Brain infiltration by cancer cells: different roads to the same target?

“…[76] Among factors that stimulate vascular proliferation and vessel formation, MMP have been shown to promote endothelial cell migration and induce vascular endothelial growth factor (VEGF) release, leading to development of angiogenic vasculature. [77] In agreement with these findings, in lung carcinoma BM a correlation between MMP2 and angiogenesis was also found. [78] In this study tumors expressing MMP2 display a more proliferating vasculature at the tumor-brain interface compared to MMP2-negative tumors, suggesting that MMP2 expression may be a key player in this process by enhancing both invasion and vascularization.…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…Endorepellin is found in vivo, where it is proteolytically processed from perlecan (14) via matrix metalloproteinases, a family of enzymes involved in a multitude of biological processes (35)(36)(37)(38)(39). Although perlecan mRNA can undergo alternative splicing, no evidence exists for endorepellin production in vivo via this mechanism (14).…”

Experimental Dissection of Metalloproteinase Inhibition-Mediated and Toxic Effects of Phenanthroline on Zebrafish Development.

“…The effects of PhN on angiogenesis are also most parsimoniously explained as the result of metalloproteinase inhibition, as the sprouting, invasive protrusion and pathfinding activities of angioblasts all depend on metalloproteinases [58][59][60][61]. Thus, we conclude that the effects of PhN on angiogenesis, pigmentation and craniofacial development are most likely due to its inhibition of metalloproteinases, whereas tail curvature, pericardial and yolk-sac edema are likely manifestations of PAH-toxicity.…”