Plexins as Regulators of Cancer Cell Proliferation, Migration, and Invasivity

SIMPLE SUMMARY: Cancer is the second leading cause of death in the US. In 2023, approximately 609,820 deaths from cancer are expected. Plexins are a family of receptors that directly affect tumor cell invasiveness and proliferation and, as a result, promote or inhibit tumor progression and, as such, may also serve as potential biomarkers for various types of cancer. The main ligands of the plexin family of receptors are semaphorins. Here, we review only the direct effects of plexins-mediated signal transduction on the behavior of various types of tumor cells, excluding their effects on the various other types of cells that are recruited to the tumor microenvironment. Plexins also transduce the signals of additional ligands and associate with various cell membrane-bound and intracellular modulators that, in turn, modify their effects. ABSTRACT: Plexins are a family of nine single-pass transmembrane receptors with a conserved GTPase activating protein (GAP) domain. The plexin family is divided into four subfamilies: Type-A, type-B, type-C, and type-D plexins. Plexins function as receptors for axon guidance factors of the semaphorin family. The semaphorin gene family contains 22 genes that are divided into eight subclasses of which subclasses three to seven represent vertebrate semaphorins. The plexins and their semaphorin ligands have important roles as regulators of angiogenesis, cancer proliferation, and metastasis. Class 3 semaphorins, with the exception of sema3E, are the only semaphorins that do not bind directly to plexins. In order to transduce their signals, they bind instead to complexes consisting of receptors of the neuropilin family and various plexins. Some plexins also form complexes with tyrosine-kinase receptors such as the epidermal growth factor receptor ErbB2, the mesenchymal epithelial transition factor receptor (MET), and the Vascular endothelial growth factor receptor 2 (VEGFR2) and, as a result, can modulate cell proliferation and tumor progression. This review focuses on the roles of the different plexins in the control of cancer cell proliferation and invasiveness. Plexins also affect tumor progression and tumor metastasis by indirect mechanisms, such as modulation of angiogenesis and immune responses. However, these topics are not covered in the present review.