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A Role for Semaphorin 3A, a Novel Vascular Permeability Factor in Tumor Cell Extravasation and Metastasis

Lisette Acevedo

Appointment Period: 2008-2009 / Grant Year: [24]

Lisette AcevedoOur previous work has shown that Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning, induces vascular permeability and selectively inhibits VEGF-induced angiogenesis. Because various tumors express Sema3A, we sought to determine its role in tumor growth and metastasis. Since Sema3A is a secreted protein, to establish its function within the tumor microenvironment, we have utilized Sema3A siRNA to knock-down protein expression in various tumor cell lines that have high levels of Sema3A: CT26 (colon), Pan02 (pancreas), and B16-BL6 (skin). Experiments with CT26 carcinoma cells show that, while decreased expression did not affect tumor size in a subcutaneous tumor model, it did diminish tumor cell extravasation after tail-vein injection. These findings define a potential pathological role for Sema3A as a potentiator of tumor cell extravasation and metastasis. Future studies with pancreatic and skin orthotopic tumor models will further elucidate the role of Sema3A in tumor growth and metastasis.

As a permeability factor, Sema3A induces tyrosine phosphorylation of VE-cadherin and disrupts adherens junctions. We also recently established that Sema3A interacts with VE-cadherin. Future studies will investigate whether this interaction alters VE-cadherin signaling to downstream effectors and is a potential mechanism by which Sema3A induces vascular permeability.

Acevedo LM, Cheresh DA. Suppressing NFAT increases VEGF signaling in hemangiomas. Cancer Cell. (2008) 14:429-30. PMID: 19061833.

Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. (2008) 456:809-13. PMID: 18997771; PMCID: PMC2605188.

Acevedo LM, Weis SM, Cheresh DA. Robo4 counteracts VEGF signaling. Nat Med. (2008) 14:372-3. PMID: 18391935.

Schleicher M, Shepherd BR, Suarez Y, Fernandez-Hernando C, Yu J, Pan Y, Acevedo LM, Shadel GS, Sessa WC. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J Cell Biol. (2008) 180:101-12. PMID: 18195103; PMCID: PMC2213620.

Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA. Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood. (2008) 111:2674-80. PMID: 18180379; PMCID: PMC2254547.

Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Soll R, Wrasidlo W, Acevedo LM, Cheresh DA. Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther. (2009) 328:758-65. PMID: 19056934.

Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, King PD, Weis SM, Cheresh DA. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med. (2010) 16:909-14. PMID: 20676106.

Murphy EA, Shields DJ, Stoletov K, Dneprovskaia E, McElroy M, Greenberg JI, Lindquist J, Acevedo LM, Anand S, Majeti BK, Tsigelny I, Saldanha A, Walsh B, Hoffman RM, Bouvet M, Klemke RL, Vogt PK, Arnold L, Wrasidlo W, Cheresh DA. Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRbeta/B-RAF. Proc Natl Acad Sci USA. (2010) 107:4299-304. PMID: 20154271; PMCID: PMC2840076.

Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, Acevedo LM, Manglicmot JR, Song X, Wrasidlo W, Blair SL, Ginsberg MH, Cheresh DA, Hirsch E, Field SJ, Varner JA. Receptor tyrosine kinases and TLR/IL1Rs unexpectedlyactivate myeloid cell PI3k, a single convergent point promoting tumorinflammation and progression. Cancer Cell. 2011 Jun 14;19(6):715-27. doi:10.1016/j.ccr.2011.04.016. PubMed PMID: 21665146; PubMed Central PMCID:PMC3144144.

 Chen XL, Nam JO, Jean C, Lawson C, Walsh CT, Goka E, Lim ST, Tomar A, TancioniI, Uryu S, Guan JL, Acevedo LM, Weis SM, Cheresh DA, Schlaepfer DD. VEGF-induced vascular permeability is mediated by FAK. Dev Cell. 2012 Jan 17;22(1):146-57.PubMed PMID: 22264731; PubMed Central PMCID: PMC3266538.