Semaphorin-3F Is an Inhibitor of Tumor Angiogenesis

Abstract

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF 165 . Human umbilical vein endothelial cells (HUVEC) express tyrosine-kinase receptors for VEGF and basic fibroblast growth factor (bFGF), as well as np1, np2, and several type-A plexins. We have found that semaphorin-3F (s3f), a semaphorin which signals through the np2 receptor, was able to inhibit VEGF 165 , as well as bFGF-induced proliferation of HUVECs. Furthermore, s3f inhibited VEGF as well as bFGF-induced phosphorylation of extracellular signalregulated kinase-1/2. Our experiments indicate that bFGF does not bind to neuropilins, nor does s3f inhibit the binding of bFGF to FGF receptors. It is therefore possible that s3f inhibits the activity of bFGF by a mechanism that requires active s3f signal transduction rather than by inhibition of bFGF binding to FGF receptors. s3f also inhibited VEGF 165 , as well as bFGF-induced in vivo angiogenesis as determined by the alginate micro-encapsulation and Matrigel plug assays. Overexpression of s3f in tumorigenic human HEK293 cells inhibited their tumor-forming ability but not their proliferation in cell culture. The tumors that did develop from s3f-expressing HEK293 cells developed at a much slower rate and had a significantly lower concentration of tumor-associated blood vessels, indicating that s3f is an inhibitor of tumor angiogenesis.

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.…”

Regulation of immune cell responses by semaphorins and their receptors

“…77,78 Similarly, Sema3F inhibits cell spreading and migration in breast carcinoma, melanoma and ECs, resulting in reduced metastatic dissemination. [78][79][80] Furthermore, since NP-1 is a receptor for both class III semaphorins and VEGF, class III semaphorins may function as antiangiogenic factors by competitively interfering with VEGF receptors. 68 …”

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

“…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.…”