A catalytic role for proangiogenic marrow-derived cells in tumor neovascularization

Abstract

Small numbers of proangiogenic bone marrow-derived cells (BMDCs) can play pivotal roles in tumor progression. In this issue of Cancer Cell, two papers, utilizing different tumor angiogenesis models, both find that activated MMP-9 delivered by BMDCs modulates neovessel remodeling, thereby promoting tumor growth. The changes in microvascular anatomy induced by MMP-9-expressing BMDCs are strikingly different between the preirradiated tumor vascular bed model employed by Ahn and Brown and the invasive glioblastoma model utilized by Du et al., likely mirroring the complexity of the real tumor microenvironment and the intricacy of roles of different BMDC populations in mediating tumor neoangiogenesis.

Figure 1. Multifaceted Role of MMP-9 in Supporting Mobilization and Recruitment of Bone Marrow-Derived Cells in Tumor Vasculogenesis and Neoangiogenesis

Activated MMP-9, through increasing the bioavailability of Kit-ligand, VEGF-A, and SDF-1, supports the mobilization of the proangiogenic bone marrow-derived cells (BMDCs), including tumor-associated monocytes/macrophages (TAMs), Gr1⁺CD11b⁺ myeloid precursors, CXCR4⁺VEGFR1⁺ hemangiocytes, and EPCs to the circulation. Irradiation-induced vascular injury or hypoxia-driven upregulation of HIF-1α enhances the release of SDF-1 and VEGF-A, thereby recruiting MMP-9-bearing BMDCs to the neoangiogenic niches, augmenting tumor vasculogenesis, angiogenesis, invasive potential, and metastasis. MMP-9 delivered by BMDCs amplifies tumor neoangiogenesis by increasing the bioavailability of VEGF-A and stem cell active chemocytokines, including SDF-1 and Kit-ligand.