Castro-Rivera E, Ran S, Thorpe P, Minna JDSemaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci USA 101: 11432-11437

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2004; 101(31):11432-7. DOI: 10.1073/pnas.0403969101
Source: PubMed


Semaphorin 3B (SEMA3B) is a secreted member of the semaphorin family, important in axonal guidance. We and others have shown that SEMA3B can act as a tumor suppressor by inducing apoptosis either by reexpression in tumor cells or applied as a soluble ligand. The common method of inactivation of SEMA3B is by allele loss and tumor-acquired promoter methylation. We studied the mechanism of SEMA3B-induced tumor cell apoptosis and found that vascular endothelial growth factor (VEGF)165 significantly decreased the proapoptotic and antimitotic effect of transfected or secreted SEMA3B on lung and breast cancer cells. VEGF165 binds to neuropilin, receptors for SEMA3B, and we found that SEMA3B competed for binding of 125I-VEGF165 to lung and breast cancer cells. We also found that small interfering RNA knockdown of tumor-produced VEGF-A or the use of an anti-VEGF neutralizing antibody (Ab) significantly inhibited tumor cell growth in vitro. By contrast, VEGF121, a VEGF variant that lacks binding to neuropilin (NP)-1 or NP-2 receptors, was not expressed in tumor cells and had no effect on SEMA3B growth-suppressing activities. In conclusion, we hypothesize that VEGF165, produced by tumor cells, acts as an autocrine survival factor and that SEMA3B mediates its tumor-suppressing effects, at least in part, by blocking this VEGF autocrine activity.

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    • "In addition to up-regulation of the well-known angiogenic growth factor VEGFA in clusters A and B, several anti-angiogenic semaphorins were down-regulated. SEMA3B and SEMA3F have both anti-tumorigenic and anti-angiogenic properties [23], [30], [31], [36], [37], [50], [51]. SEMA3C, whose role in angiogenesis is less well-understood [32], [33], was also consistently down-regulated in tumors with high expression of VEGFA. "
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    • "Such pathways contribute to their self-renewal and de-differentiation (Scheel et al, 2011), and they are potential targets for therapeutic intervention (Korkaya et al, 2011; Marotta et al, 2011). In this context, VEGF receptors expressed on breast carcinoma cells can mediate autocrine VEGF signalling that contributes to tumour initiation and progression (Bachelder et al, 2001, 2002, 2003; Bae et al, 2008; Bagri et al, 2009; Barr et al, 2005; Bates et al, 2003; Cao et al, 2008; Castro-Rivera et al, 2004; Gray et al, 2008; Hu et al, 2007; Lichtenberger et al, 2010; Matsushita et al, 2007; Mercurio et al, 2004). These findings challenge the notion that the function of VEGF in cancer is limited to its role in angiogenesis and that therapeutic approaches based on the inhibition of VEGF and its receptors target only this function (Ferrara, 2005). "
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