Neuropilin-1-expressing monocytes: Implications for therapeutic angiogenesis and cancer therapy

Abstract

Besides acting as a common receptor for both vascular endothelial growth factors and semaphorins on the endothelial cell surface, neuropilin-1 is also expressed by a variety of circulating immune cells. We have characterized a population of circulating myeloid cells, characterized by the expression of neuropilin- 1, able to promote vessel maturation and contributing to cancer vessel normalization. These neuropilin-1-expressing monocytes (NEMs) represent a specific subset of CD11b+NRP1+Gr1-resident monocytes, producing several factors involved in vessel maturation, including PDGF-B, TGF-β, and thrombospondin- 1, acting as chemoattractant for vascular smooth muscle cells. NEMs can be isolated from either the bone marrow or Sema3A-expressing muscles. Their direct injection at sites of neoangiogenesis results in the maturation of growing capillaries into functional arterial vessels. When directly injected into growing tumors, NEMs exert potent antitumor activity despite having no effect on cancer cell proliferation. Instead, NEMs promote mural cell coverage of tumor vessels and reduce vascular leakiness, resulting in smaller, better perfused, and less hypoxic tumors. We conclude that NEMs represent a novel, unique population of myeloid cells that can be exploited for multiple therapeutic applications. On the one hand, they can improve functional maturation of neo-vessels for the induction of therapeutic angiogenesis, while, on the other hand, they promote tumor vessel normalization, thereby inhibiting tumor growth.