Multifaceted Functional Role of Semaphorins in Glioblastoma

Abstract

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent trials based on the molecular targeting of some of the GBM hallmark pathways (e.g., angiogenesis) have not produced any significant improvement in overall survival. The urgent need to develop more efficacious targeted therapies has led to a better molecular characterization of GBM, revealing an emerging role of semaphorins in GBM progression. Semphorins are a wide group of membrane-bound and secreted proteins, originally identified as axon guidance cues, signaling through their receptors, neuropilins, and plexins. A number of semaphorin signals involved in the control of axonal growth and navigation during development have been found to furthermore participate in crosstalk with different dysfunctional GBM pathways, controlling tumor cell proliferation, migration, and invasion, as well as tumor angiogenesis or immune response. In this review, we summarize the regulatory activities mediated by semaphorins and their receptors on the oncogenic pathways implicated in GBM growth and invasive/metastatic progression.

Keywords: angiogenesis; cell invasiveness; cell migration; cell proliferation; glioblastoma; immune response; neuropilins; plexins; semaphorins.

Figure 1

Schematic overview of the histopathological hallmarks of glioblastoma (GBM). CSC: cancer stem cell; TAM: tumor-associated macrophage.

Figure 2

Semaphorin signals regulating GBM cells and the tumor microenvironment. The figure summarizes pro- or anti-tumorigenic activities mediated by diverse semaphorins controlling GBM progression by the regulation of diverse cell populations in the tumor microenvironment. Divergent semaphorin functions may be explained by specific plexin–neuropilin (NRP) receptor complexes or intracellular effector pathways (also indicated, as reported in literature).