• A novel role for Semaphorin 4D in tumor metastasis

      Binmadi, Nada Omar; Basile, John R. (2011)
      The semaphorin proteins were originally identified as axonal guidance factors expressed during neuronal development. In addition to this function, several semaphorins are now known to play diverse roles outside of the nervous system. Semaphorin 4D (Sema4D/CD100), a transmembrane molecule that shares structural homology with the scatter factors, exerts important biological effects on a variety of cells, including neural, epithelial and immune cells. Interaction between Sema4D and its receptor, Plexin-B1, has proven to be important in many facets of tumor progression such as tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. Invasion and metastasis are key components of cancer progression. A distinct and largely forgotten path for tumor spread is perineural invasion (PNI), defined as the presence of cancer cells in the perineural space. PNI is frequently used by many human carcinomas, in particular by pancreatic, prostate, and oral squamous cell carcinoma (OSCC), and is associated with tumor recurrence and pain in patients with advanced disease. The work presented in this thesis shows that Sema4D and Plexin-B1 are involved in PNI in tumors and identifies Sema4D as a new player in the complex interaction between tumor cells, nerve cells and the tumor microenvironment. We have previously found that Sema4D is able to promote angiogenesis in several in vitro assays and tumor growth and vascularity of head and neck squamous cell carcinoma xenografts in vivo, but the intracellular signaling pathways engaged and the mechanisms of regulation of this pro-angiogenic function remained unclear. Results presented in the second part of this thesis demonstrate that ligation of Plexin-B1 by Sema4D activates a RhoA-dependent pro-angiogenic phenotype in endothelial cells that signals through phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K) and generates lipid second messengers. We also discuss the essential role of hypoxia inducible factor (HIF) in endothelial cell migration and tumor vascularity. In conclusion, deciphering the regulatory and signaling mechanisms of Sema4D could lead to the identification of new therapeutic targets for anti-angiogenic and anti-metastatic cancer therapy.