Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer

Abstract

Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.

Keywords: cancer; neuropilin; plexin; predictive biomarkers; prognostic biomarkers; semaphorin; therapy.

Figure 1

Semaphorin signaling in cancer cells. Schematic representation of best known signaling mechanisms mediated in cancer cells by prototypic family members Sema3A (panel A) and Sema4D (panel B) (for a review see 7). The intracellular domain of the plexins deploys GAP activity for Rap1 and R-Ras monomeric GTPases. RTK indicates receptor tyrosine kinases associated with neuropilins and plexins. A few validated molecular tools interfering with these cascades are also indicated (in painted boxes).

Figure 2

Semaphorin signaling in the tumor microenvironment. Semaphorins are major regulators of angiogenesis, acting as inhibitors or as promoters of endothelial cell functions. Other semaphorins regulate the activity of tumor-associated macrophages (TAMs), in turn impacting on immune response and angiogenesis. A subset of so-called immunoregulatory semaphorins have also been implicated in tumor immune-evasion. In addition to their role in neural development, semaphorins may also control the functional coupling between cancer cells and neuronal projections found in the tumor microenvironment.