Semaphorins in cancer: Biological mechanisms and therapeutic approaches

The hallmarks of cancer include multiple alterations in the physiological processes occurring in normal tissues, such as cell proliferation, apoptosis, and restricted cell migration. These aberrant behaviors are due to genetic and epigenetic changes that affect signaling pathways controlling cancer cells, as well as the surrounding “normal” cells in the tumor microenvironment. Semaphorins and their receptors (mainly plexins and neuropilins) are aberrantly expressed in human tumors, and multiple family members are emerging as pivotal signals deregulated in cancer. Notably, different semaphorins can promote or inhibit tumor progression, depending on the implicated receptor complexes and responsive cell type. The important role of semaphorin signals in the regulation of tumor angiogenesis, invasion and metastasis has initiated multiple experimental approaches aimed at targeting these pathways to inhibit cancer.

► Semaphorin signaling is deregulated in multiple cancers
► Semaphorins can either promote tumorigenesis or inhibit it depending on receptor complex and intracellular signal transducers
► Semaphorins regulate multiple cell properties such as: proliferation, migration, adhesion, angiogenesis, invasion and metastasis
► Preclinical tests in mouse model have been done by delivery of tumor-suppressive semaphorins or inhibition of pro-tumorigenic semaphorins.