Abstract 1629: Semaphorin 4D has a dual role in the tumor microenvironment of pancreatic ductal adenocarcinoma.
Authors: Kato Shingo , Kebota Kensuke , Kobayashi Noritoshi , Hosono Kunihiro , Watanabe Seitaro , Sekino Yusuke , Sato Takamitsu , Maeda Shin , Nakajima Atsushi 
Published: August 2014

Pancreatic ductal adenocarcinoma (PDAC) contains a dense, fibrotic tissue called stroma. The stroma, consisting of connective tissue, fibroblasts, leukocytes, and blood vessels, accompanies most solid tumors, but its extent and compactness are exceptional in PDAC. A detailed understanding of cells contained in the stroma is an essential step for control of PDAC. In this study, we focused on the molecule called Semaphorin4D (Sema4D), which is involved in tumor-stromal signal transduction pathways in several kinds of cancer, and analyzed its expression patterns and functions in PDAC. First, we examined the expression of Sema4D and its receptor, plexin B1, in surgically resected specimens of human PDAC, and also the effect of Sema4D stimulation using human pancreatic cancer cells in vitro. Immunohistochemical staining revealed that Sema4D was expressed on the tumor-infiltrating lymphocytes. On the other hand, plexin B1 was expressed on the cancer cells. The overexpression of Sema4D was found to be significantly correlated with invasive or metastatic clinical factors, and poor prognosis in patients with PDAC. Also, stimulation by Sema4D caused a significant increase in the invasiveness of pancreatic cancer cells measured by matrigel invasion chambers. The enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Next, we analyzed the tumor growth of mouse pancreatic cancer cells in vivo using wild type (WT) and Sema4D Knock Out (KO) mice. In a breast cancer model, it was reported that tumor growth and vascularization in the tumor were severely impaired in Sema4D KO mice. However, in contrast, in pancreatic cancer, tumor growth and vessel formation in tumors were not impaired in Sema4D KO mice. In fact, tumor growth was accelerated in Sema4D KO mice. We performed further analysis and found that there were fewer infiltrating CD8+ T cells in tumors of Sema4D KO mice compared to tumors of WT mice. It has been reported that Sema4D has an immunoregulatory function through another receptor, CD72, in the immune system, and that Sema4D KO mice have functional defects in their immune system. These results suggest that Sema4D has multiple functions in controlling tumor formation, invasiveness, vascularization, and anti-tumor immunity, and that its role in the regulation of anti-tumor immunity is more apparent in the pancreatic cancer model. Our findings suggest that Sema4D can play a dual role in PDAC. One role is to enhance tumor invasiveness through plexinB1 on tumor cells, while the other is to regulate the immune response to tumor through CD72 on lymphocytes. Our findings provide insight into new molecular targets for the development of treatments for PDAC.

Citation Format: Shingo Kato, Kensuke Kebota, Noritoshi Kobayashi, Kunihiro Hosono, Seitaro Watanabe, Yusuke Sekino, Takamitsu Sato, Shin Maeda, Atsushi Nakajima. Semaphorin 4D has a dual role in the tumor microenvironment of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1629. doi:10.1158/1538-7445.AM2013-1629