Blocking Neuropilin-2 Function Inhibits Tumor Cell Metastasis

Abstract

Metastasis, which commonly uses lymphatics, accounts for much of the mortality associated with cancer. The vascular endothelial growth factor (VEGF)-C coreceptor, neuropilin-2 (Nrp2), modulates but is not necessary for developmental lymphangiogenesis, and its significance for metastasis is unknown. An antibody to Nrp2 that blocks VEGFC binding disrupts VEGFC-induced lymphatic endothelial cell migration, but not proliferation, in part independently of VEGF receptor activation. It does not affect established lymphatics in normal adult mice but reduces tumoral lymphangiogenesis and, importantly, functional lymphatics associated with tumors. It also reduces metastasis to sentinel lymph nodes and distant organs, apparently by delaying the departure of tumor cells from the primary tumor. Our results demonstrate that Nrp2, which was originally identified as an axon-guidance receptor, is an attractive target for modulating metastasis.

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Mice deficient in Nrp2 show a variety of lymphatic defects, including reduction of small lymphatic vessels and capillaries [24]. Further, Nrp2 appears to be selectively expressed in tumor-associated lymphatic vessels, and inhibition of Nrp2 function blocked VEGF-C/VEGFR3-mediated lymphangiogenesis and reduced metastasis in vivo [90,91]. By extension, this suggests that anti-angiogenic semaphorins like Sema3F can function as anti-lymphangiogenic signaling molecules in vivo through their interaction with Nrp2.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…56 Among other structures, NRP-2 is expressed on veins and upregulated in tumorassociated lymphatic vessels, where it binds VEGF-C and VEGF-A, in addition to partially processed VEGF-D. 57 --59 Anti-lymphangiogenic therapy targeting NRP-2 reduced metastasis in a mammary tumor model. 57 A complex of NRP-2 and VEGFR-3 may include integrin b1 and possibly simultaneously interact with semaphorin 3 components for correct lymphangiogenic signaling. 33,60 A continuously growing number of additional factors are studied as potential modulators of lymphangiogenesis, including integrin a9 expressed specifically by lymphatic valve endothelial cells, hepatocyte growth factor, 61 the Tie-2 --angiopoietin signaling system, 27 fibroblast growth factor 2 62 and platelet-derived growth factor BB.…”

“…Recently, NRP-2 blocking antibodies have proven efficacy in blocking lymph node metastasis in a pre-clinical model, but one concern in their use is the wide NRP-2 expression outside the lymphatic system. 57 Lymphatic vessels are largely quiescent in adults, and thus lymphangiogenesis could provide a safe target. However, lymphangiogenesis appears to play a role in promoting wound healing.…”

Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

“…Blockade of VEGF receptors, in particular of the VEGF-C/VEGFR-3 pathway, resulted in a reduction of lymphatic metastases and of corneal transplant rejections in several experimental models (5). More recently, blockade of the neuropilin-2 receptor on activated lymphatic endothelium was reported to also reduce lymphatic cancer metastasis (8). Overall, however, the inhibitory effects observed in these studies were only partial or temporary, and there is an urgent need for the identification of novel targets for the therapeutic inhibition of lymphangiogenesis.…”