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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    ABSTRACT: Triple negative breast cancers (TNBC) are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families - VEGFs and semaphorins - that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.
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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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    ABSTRACT: The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the α6β1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of α6β1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, α6β1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2-based therapy for the treatment of TNBC that targets and impedes the function of TICs. → See accompanying article
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    • "Indeed, these chaperones are required for the stability and activity of a range of client proteins playing a critical role in signal transduction, cellular trafficking, chromatin remodeling, cell growth, differentiation, and apoptosis [18]. Furthermore, the expression changes measured for Hsp90, 14-3-3 and T-complex proteins easily associate with an apoptosis reduction [19,20,21,22,23,24,25], and the anti-apoptotic role of perthamide C is also confirmed by the level alteration of other proteins, as annexin 5, dihydropyrimidinase-related protein 2 and gelsolin, independent from the folding process but in any case implicated in the apoptosis regulation [26,27,28]. "
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