Journal Article

Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer

NAKAMURA Fumio, WATANABE Seitaro, INAMORI Masahiko, MAEDA Shin, NAGASHIMA Yoji, TAGURI Masataka, MORITA Satoshi, KOBAYASHI Noritoshi, ISHIGURO Hitoshi, NAKAIGAWA Noboru, SHIMAMURA Takeshi, GOSHIMA Yoshio, NAKAGAWA Hitoshi, KATO Shingo, ENDO Itaru, KUBOTA Yoshinobu, NAKAJIMA Atsushi, KUBOTA Kensuke, SHINOHARA Yoshiyasu, YONEDA Masato

2011

Overview

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, for which the development of new biomarkers and therapeutic targets has become critical. The main cause of poor prognosis in PDAC patients is the high invasive and metastatic potential of the cancer. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer. Semaphorin 4D (Sema4D) is a ligand known to be expressed on different cell types, and has been reported to be involved in the regulation of immune functions, epithelial morphogenesis, and tumor growth and metastasis. In this study, we revealed for the first time that the cancer tissue cells expressing Sema4D in PDAC are tumor‐infiltrating lymphocytes. The overexpression of Sema4D and of its receptor, plexinB1, was found to be significantly correlated with clinical factors, such as lymph node metastasis, distant metastasis, and poor prognosis in patients with PDAC. Through in vitro analysis, we demonstrated that Sema4D can potentiate the invasiveness of pancreatic cancer cells and we identified the downstream molecules. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. In addition, in terms of potential therapeutic application, we clearly demonstrated that 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. Our findings provide new insight into possible prognostic biomarkers and therapeutic targets in PDAC patients. (Cancer Sci 2011; 102: 2029–2037)

• Publisher: Blackwell Publishing Ltd,Blackwell
• Subject: Aged / Antigens, CD - biosynthesis / Antigens, CD - genetics / Antigens, CD - physiology / Biological and medical sciences / Carcinoma, Pancreatic Ductal - metabolism / Carcinoma, Pancreatic Ductal - pathology / Cell Movement - physiology / Cells, Cultured - cytology / Cells, Cultured - metabolism / Culture Media, Serum-Free / Epithelial Cells - cytology / Epithelial Cells - metabolism / Female / Gastroenterology. Liver. Pancreas. Abdomen / Gene Expression Regulation, Neoplastic - drug effects / Humans / Kaplan-Meier Estimate / Liver. Biliary tract. Portal circulation. Exocrine pancreas / Male / MAP Kinase Signaling System / Medical sciences / Middle Aged / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Nerve Tissue Proteins - biosynthesis / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - physiology / Pancreatic Ducts - cytology / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Receptors, Cell Surface - biosynthesis / Receptors, Cell Surface - genetics / Receptors, Cell Surface - physiology / RNA, Messenger - biosynthesis / RNA, Neoplasm - biosynthesis / RNA, Small Interfering - pharmacology / Semaphorins - biosynthesis / Semaphorins - genetics / Semaphorins - physiology / Signal Transduction / Tumor Cells, Cultured - cytology / Tumor Cells, Cultured - metabolism / Tumors