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

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. 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, 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. cancer cells endowed with typical stem cell properties, such as unlimited self-renewal ability associated with the tendency to generate differentiated cell progeny. They are also indicated as cancer-initiating cells. Cell plasticity is the ability to modify cell phenotype, cell behavior, and/or cell differentiation fate. Differentiation is the process by which a less-specialized (undifferentiated) cell becomes more specialized, both in structural and functional terms. More differentiated cancer cells often (though not always) resemble normal cells of the tissue of origin. the reduction or failure in the effectiveness of a therapy (individual drug or combination) used to treat a disease or specific illness. a process by which epithelial cells undergo phenotypic conversion into mesenchymal type, for example, by losing cell-to-cell adhesions and layer polarity and attaining a migratory and tissue-invasive behavior. secondary tumor foci derived from the dissemination of cancer cells to different tissues throughout the body, even distant from the original site, via the lymphatic system or bloodstream. molecular signatures that specifically distinguish stem cells from differentiated cells. In some cases, the expression of these molecules has also been associated causally with the establishment and maintenance of the stem cells.