Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype

Abstract

Melanoma is the most lethal skin cancer. Most deaths from melanoma result from metastases. Semaphorins have been shown to inhibit neuronal and endothelial cell migration, but the effects of semaphorins on tumor metastasis have not been documented. We found that semaphorin 3F (SEMA3F) was markedly downregulated in highly metastatic human cell lines in vitro and in vivo, which suggested that it may be a metastasis inhibitor. Metastatic human melanoma cells were transfected with SEMA3F and implanted into mice; the resultant tumors did not metastasize. Rather, the primary tumors resembled benign nevi characterized by large areas of apoptosis, diminished vascularity, inhibition of hyperplasia in overlying epidermal cells, and encapsulated tumor borders delineated by thick layers of fibroblasts and collagen matrix. This phenotype is in stark contrast to highly invasive, vascular mock-transfected tumors. In vitro, tumor cells expressing SEMA3F had a diminished capacity to adhere and migrate on fibronectin. Consistent with semaphorin-mediated chemorepulsion of neurons, tumor cells expressing SEMA3F were chemorepulsive for vascular and lymphatic endothelial cells expressing neuropilin-2 (NRP2), a novel mechanism for a tumor angiogenesis inhibitor. The repulsive activity was abrogated by NRP2 RNA interference. Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential.

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

“…Sema3F, another inhibitor of angiogenesis, functions as a more global inhibitor in that it blocks angiogenesis in response to both VEGF and bFGF. 28,29 However, as we demonstrate, it does not induce VP (Figure 3). This may be caused by differential binding of these 2 proteins to their Nrp receptors, since Sema3A and Sema3F ligate Nrp-1 and Nrp-2, respectively.…”

“…However, it inhibits both VEGF-as well as bFGF-induced angiogenesis, indicating that it plays a broader role than Sema3A in regulating blood vessel formation. 28,29 To determine if other class 3 semaphorins can induce VP, we compared the effects of Sema3A, Sema3F, and Sema3B on permeability. Unlike Sema3A, subcutaneous injection of Sema3F or Sema3B did not lead to VP (Figure 3), suggesting that Sema3B and Sema3F are functionally distinct from Sema3A with respect to their influence on the biologic properties of blood vessels.…”

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Sema3F decreases tumor growth in a number of in vivo tumor models, and although Sema3F is capable of interacting with Nrp1, its higher-affinity interaction with Nrp2 appears to be required for its tumor-suppressive activity in many models [58][59][60]. Sema3F exerts a repulsive effect on breast cancer cells [61] and reduces the growth and metastatic activity of colorectal carcinoma cells by modifying integrin αvβ3 [62], suggesting that Sema3F affects tumor cells directly by controlling cell adhesion and migration.…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…36,46 More recently it was shown that SEMA3F overexpression in highly metastatic melanoma cells (that only express neuropilin-2 and not neuropilin-1, VEGF-R1 or VEGFR-2) inhibits adhesion and migration but not proliferation. 44 These SEMA3F-transfected melanoma cells injected into nude mice do not become metastatic. All these results suggest that SEMA3F could inhibit endothelial cell invasion and/or tumor cell migration.…”

“…Like Sema3A, Sema3F can inhibit angiogenesis and endothelial cell migration but through neuropilin-2 binding. 44,45 SEMA3F overexpression in mouse fibrosarcoma or ovarian cancer cells block their proliferation. 36,46 More recently it was shown that SEMA3F overexpression in highly metastatic melanoma cells (that only express neuropilin-2 and not neuropilin-1, VEGF-R1 or VEGFR-2) inhibits adhesion and migration but not proliferation.…”