Importance of semaphorins in cancer immunity

The semaphorin family is characterized by the presence of a sema domain and plexin-semaphorin integrin domains. Although, when they were first discovered, semaphorins were reported for their axon-guidance ability (1), recent studies indicate that semaphorins regulate several hallmarks of cancer (2-4). For example, semaphorin 3A (SEMA3A) reduced tumor growth and angiogenesis through upregulating the forkhead box O3a (FOXO3a) dependent, melanoma cell adhesion molecule (MelCAM) in breast cancer in xenograft NOD-SCID mouse model (5). SEMA3B was found to inhibit tumor growth, while increasing metastatic dissemination by activating the p38- MAPK-p21 pathway in immunocompromised CD1–/– nude athymic female mice (6). SEMA6A employed the FAS-associated death domain protein (FADD) and heme oxygenase 1 (HMOX1) to suppress survival and migration, respectively, in lung cancer cells (7,8). Moreover, the high expression of SEMA6D in the Tie-2 expressing monocyte subset within the tumor suggests that SEMA6D might induce angiogenesis by PlexinB1 or vascular endothelial growth factor receptor (VEGFR) signalling (9).