Relation of immune semaphorin/plexin signaling to carcinogenesis

Abstract

Semaphorins and plexins represent a highly conserved group of proteins that have recently been found to exert widespread regulatory functions outside the nervous system, including angiogenesis and immune regulation. Furthermore, these molecules are definitely implicated in the etiology of carcinogenesis and immune disorders. Their expression patterns and levels are deregulated in cancer cells and in cells of the tumor milieu. During the multistep development of cancer, its characteristic features include sustained tumor cell proliferation, resistance to cell death, limitless replicative capacity, activation of angiogenesis along with invasion and metastatic spread, cancer-related smoldering inflammation, and evasion of antitumor immune responses. The diversity of the semaphorin/plexin complexes and, thus, the multiple stimulated molecular interactions allow varied and diverse cell signaling events. The elicited transduction pathways might be involved in modifying the intricate mechanisms of tumorigenesis. Indeed, these pleiotropic signals may influence not only the intrinsic properties of cancer cells but they could also represent a possible link in mediating the cross-talk between tumor cells and the surrounding multiple stromal cells. In tumorigenesis, however, a dual role of different semaphorins is proposed, as some of them may elicit tumor regression, whereas others definitely promote cancer cell survival and progression. The current antitumoral or prosurvival responsiveness to semaphorins is mainly cell context dependent; nevertheless, their precise relation to cancer networks has not yet been fully elucidated. Here, we survey the many faces of a subset of the large semaphorin family, termed immune semaphorins, in carcinogenesis.

SEMA6B Overexpression Predicts Poor Prognosis and Correlates With the Tumor Immunosuppressive Microenvironment in Colorectal Cancer

“…Semaphorin family members were initially characterized as axon-guidance factors with functions in axonal navigation, but have subsequently also been linked to the pathology of various diseases, such as cancer, immune disease and neurodegenerative disease ( Műzes and Sipos 2014 ; Neufeld and Mumblat 2016 ; Franzolin and Tamagnone 2019 ). Accumulated studies have shown that some semaphorins—including semaphorin 3E (SEMA3E), SEMA4D, SEMA5A, SEMA6D, and SEMA7A—play vital roles in tumorigenesis and tumor development by promoting angiogenesis and tumor-cell migration, as well as the epithelial-mesenchymal transition (EMT); in contrast, SEMA3A, SEMA3B, and SEMA3F exhibit tumor-inhibitory effects ( Neufeld et al, 2012 ; Neufeld and Mumblat 2016 ; Gurrapu and Tamagnone 2019 ).…”

Canine Somatic Mutations from Whole-Exome Sequencing of B-Cell Lymphomas in Six Canine Breeds—A Preliminary Study

“…Semaphorin 6b (SEMA6B) is a member of the semaphoring axon-guidance family and was initially characterized as an axon guidance factor with axon navigation functions but has also been demonstrated to induce or inhibit tumor progression. The overexpression of this gene is related to colorectal cancer in humans [ 45 , 46 , 47 ]. ADORA2B encodes a protein belonging to the G protein-coupled receptor superfamily that plays a role in tissue distribution along with A1, A2A, and A3.…”

Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis

“…The VCRC GWAS in AAV identified a potential association of GPA with the gene SEMA6A (P = 2.09 × 10 −8 ) encoding the protein semaphorin 6A [7]. The function of the proteins belonging to this family is unclear, but it has been proposed that they may be involved in immune regulation [57]. The association between the rs26595 SNP of the SEM6A gene and GPA was recently investigated also in a different cohort of Northern European patients, including 879 GPA, 150 MPA and 191 EGPA [58].…”