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

• MMPs are involved in angiogenesis-dependent intravasation and metastasis.
• Inflammatory cell MMP-9 triggers the onset of tumor neovascularization.
• IL-8-responding neutrophils are the major source of angiogenesis-inducing MMP-9.
• Neutrophil MMP-9 catalytically releases angiogenic factor VEGF from tumor matrix.
• MMP-9/VEGF axis regulates intravasation- and metastasis-sustaining neovasculature.

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 support of these vessels by a discontinuous pericyte coverage 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.