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

Abstract

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 P ancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA and the fifth in Japan, with an estimated 34 100 and 22 000 patients dying of this disease each year in the two countries, respectively.(1,2) Because of the aggressive growth characteristic and potential for early metastatic dissemination of PDAC, the overall 5-year survival rate of patients with this cancer is <5%. The poor prognosis of PDAC patients can be mainly attributed to the low curative resection rates; only 15-20% of patients have resectable PDAC because of the high frequency of distant metastases or severe local invasion present at diagnosis.(3) Thus, the intense invasive and metastatic potential of the tumor cells pose the greatest threats in patients with PDAC. In order to improve the dismal survival rate, it is necessary to clarify the signaling pathways that regulate the invasive potential of the pancreatic cancer cells. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer.Semaphorins are a large family of either membrane-bound or secreted proteins that were originally described in the nervous system, where they are involved in the establishment of accurate neural networks. (4,5) Most members of the semaphorin family have also been shown...

Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor

“…Cancer cell proliferation and tumour-related angiogenesis may vary to a greater extent under the influence of these molecules. Increased Sema4D and plexin-B1 expression in pancreatic ductal adenocarcinoma patients is correlated with lymph node involvement and metastasis (21). Similarly, in soft tissue sarcoma patients the elevated expression of Sema4D is associated with an increased mitotic division of cancer cells.…”

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

“…Plexins also participate in regulating angiogenesis. Plexins A1-A4 have been described as transducers of antiangiogenic signals conveyed by class-3 semaphorins such as sema3F, while the SEMA4D-PlexinB1 has been known as a potent inducer of angiogenesis and is associated with poor prognosis in various solid tumors (15,16). Angiogenesis and lymphangiogenesis intersect in the regulation of tumor microenvironment, and several recent studies also suggested that semaphorins may affect lymphangiogenesis (17,18).…”

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

“…Immunohistochemical (IHC) analysis of several tumor types revealed that both SEMA4D and its receptors are overexpressed on various human and murine tumors, including human head and neck, prostate, colon, breast, and lung cancers (20). Moreover, elevated expression correlates with invasive disease and poor prognosis in human cancer (21)(22)(23)(24)(25).…”