Abstract
Abstract Purpose: Semaphorins are a large family of proteins that provide axonal guidance in neuronal tissues and regulate cell motility in many types of cells. In recent studies, Semaphorin 4D (Sema4D) has been demonstrated to enhance the motility and invasiveness of cancer cells through its receptor, plexin B1, in vitro and also to increase the metastatic potential of breast cancer in vivo. However, the expression patterns and functions of Sema4D in pancreatic cancer remain unknown. Experimental Design: We examined the expressions of Sema4D and plexin B1 in surgically resected specimens of pancreatic ductal adenocarcinoma by immunohistochemistry, and also the effect of Sema4D stimulation on the invasiveness of pancreatic cancer cells. Results: Immunohistochemical staining revealed that Sema4D was expressed on the T cells and B cells in the cancer stroma. Plexin B1 was expressed in the cancer cells, whereas its expression was only faintly detected in the normal pancreatic ductal cells. Tumors with higher expression levels of Sema4D showed a significantly higher tendency towards lymph node metastasis (p = 0.0068), distant metastasis (p = 0.036), extrapancreatic nerve plexus invasion (p = 0.0073), and a poor prognosis (p = 0.024). Increased expression of both Sema4D and plexin B1 was associated with an additive worsening of the prognosis, independent of the tumor-node-metastasis classification and the World Health Organization tumor grade (p = 0.045). Stimulation with Sema4D caused a significant increase in the invasiveness of pancreatic cancer cells, and the knockdown of plexin B1 by siRNA could block the enhanced invasive activity by Sema4D. Conclusion: Sema4D could play a role in the interactions between the tumor cells and the tumor microenvironment in pancreatic cancer. In the context of numerous attempts currently ongoing to target the tumor stroma, our findings provide insight into new molecular targets for the development of treatments for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2011-3107
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