Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Abstract

Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates. Class-3 semaphorins constitute a subfamily of seven vertebrate semaphorins which differ from the other vertebrate semaphorins in that they are the only secreted semaphorins and are distinguished from other semaphorins by the presence of a basic domain at their C termini. Class-3 semaphorins were initially characterized as axon guidance factors, but have subsequently been found to regulate immune responses, angiogenesis, lymphangiogenesis, and a variety of additional physiological and developmental functions. Most class-3 semaphorins transduce their signals by binding to receptors belonging to the neuropilin family which subsequently associate with receptors of the plexin family to form functional class-3 semaphorin receptors. Recent evidence suggests that class-3 semaphorins also fulfill important regulatory roles in multiple forms of cancer. Several class-3 semaphorins function as endogenous inhibitors of tumor angiogenesis. Others were found to inhibit tumor metastasis by inhibition of tumor lymphangiogenesis, by direct effects on the behavior of tumor cells, or by modulation of immune responses. Notably, some semaphorins such as sema3C and sema3E have also been found to potentiate tumor progression using various mechanisms. This review focuses on the roles of the different class-3 semaphorins in tumor progression.

A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer

“…SEMA3D is found to inhibit tumour growth in colorectal and breast cancers, but it correlates with metastatic disease and worse survival in patients with pancreatic cancer [15,18,19]. SEMA3E shows tumour promoter role in multiple cancer types such as gastric, breast, and pancreatic cancers [11,12,[20][21][22]. In another study, both SEMA3D and SEMA3E was found to inhibit glioblastoma cell growth [23].…”

“…Class-3 semaphorins (SEMA3) are the only group of secreted proteins among the vertebrate semaphorins, and they are further sub-grouped into seven members (SEMA3A to SEMA3G). Similar to other semaphorin members, this family of genes has been reported to exhibit pivotal roles in a broad spectrum of biological processes, and recently their function in the regulation of immune system, angiogenesis, local cancer spread and metastases are becoming increasingly prominent [6][7][8][9][10][11][12]. Recent studies have shown that SEMA3s are secreted from tumour cells as well as from macrophages and fibroblasts, thereby influencing cancer cells and their microenvironments through direct or indirect mechanism to regulate cell-cell communications in the tumour micro-environment or vasculature.…”

“…Recent studies have shown that SEMA3s are secreted from tumour cells as well as from macrophages and fibroblasts, thereby influencing cancer cells and their microenvironments through direct or indirect mechanism to regulate cell-cell communications in the tumour micro-environment or vasculature. SEMA3 family members have been reported to have both pro-and antitumour functions, which are cell type and context dependent [9,12]. For instance, SEMA3A induces invasion and correlates with poor survival in both pancreatic and colon cancers, but inhibits tumour invasion and metastasis in patients with prostate, breast, and lung cancer [9,13].…”

Pretreating Mesenchymal Stem Cells with Cancer Conditioned‐Media or Proinflammatory Cytokines Changes the Tumor and Immune Targeting by Nanoghosts Derived from these Cells

“…Four of these proteins, namely leukemia inhibitory factor, CXCL1, trefoil factor 2, and the macrophage migration inhibitory factor are known to be involved in or encourage MSC‐mediated immunosuppression, which may subsequently enhance immune‐targeting by CM‐NGs as well. Additionally, the presence of semaphorin‐3C in the CM, a protein which is known to be involved in tumorigenesis through stromal support and which has specific receptors and influence on MSCs, could also partially explain the higher affinity of CM‐NGs towards cancer cells, at least in vitro …”

Targeting Neurovascular Interaction in Retinal Disorders

“…Semaphorins were first identified as a family of genes encoding guidance molecules for the embryologic development of the nervous system [125,126]. The action mechanisms underlying semaphorins through their receptors from different cell types in different disease conditions had been summarized previously [127][128][129]. Cerani et al reported that neuron-derived Semaphorin3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1 [130].…”