Semaphorin Signaling in Cancer-Associated Inflammation

Abstract

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients' prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

Keywords: cancer; immunity; inflammation; lymphocyte; macrophage; neuropilin; plexin; semaphorin; signaling.

Figure 1

Highlighted in the cartoon are major semaphorin signals potentially relevant for the regulation of diverse inflammatory and immune cells found in the tumor microenvironment. Semaphorins are in fact produced by both cancer cells and cells recruited from the circulation in the inflammatory process. Dotted connecting lines indicate semaphorin molecules secreted or proteolytically shed from the cell surface. Ligand-engaged transmembrane receptors illustrate known autocrine/paracrine signaling mechanisms. Membrane anchored semaphorins might provide juxtacrine proximity signals to neighboring cells (not depicted in the cartoon, for sake of simplicity). A very complex network of signals between different cells in the tumor microenvironment is therefore envisaged. The drawing also summarizes several evidences about semaphorin signaling in normal immune response, the relevance of which in cancer context needs to be assessed. Notably, while for Sema4D there is a consensus on its pro-tumorigenic role, and the multifaceted activity of Sema3A in the tumor microenvironment is under intense investigation, for other immuno-semaphorins, more experimental data are warranted to understand whether they act in cancer-related inflammation as promoters or suppressors.