Semaphorins as Regulators of Phenotypic Plasticity and Functional Reprogramming of Cancer Cells

Semaphorins, initially found as neuronal guidance cues in embryo development, are now appreciated as major regulators of tissue morphogenesis and homeostasis, as well as of cancer progression. In fact, semaphorin signals have a profound impact on cell morphology, which has been commonly associated with the ability to regulate monomeric GTPases, cell-substrate adhesion, and cytoskeletal dynamics. Recently, however, several reports have indicated a novel and additional function of diverse semaphorins in the regulation of gene expression and cell phenotype plasticity. In this review article, we discuss these novel findings, focusing on the role of semaphorin signals in the regulation of bi-directional epithelial-mesenchymal transitions, stem cell properties, and drug resistance, which greatly contribute to the pathogenesis of cancer. Semaphorins form a large family of extracellular signals, acting via plexin and neuropilin receptors; these signals are well known to control small GTPase activity, integrin function, and cytoskeletal dynamics at the post-translational level. Accumulating reports indicate additional functions of diverse semaphorins in the regulation of gene expression and cell phenotype plasticity, especially in the cancer context. In particular, semaphorins, and their receptors control bi-directional epithelial-mesenchymal transitions (EMTs), through the regulation of diverse implicated signaling pathways. Certain semaphorins and neuropilins are also involved in the regulation of stem cell properties and drug resistance, which greatly contribute to cancer malignancy.