Neuropilin-2 in pancreatic cancer and Semaphorin-3F as a treatment
INTRODUCTION: Pancreatic cancer remains the fourth leading cause of cancer-related deaths with approximately 5% five-year survival and 3 months of median survival. The survival rate of pancreatic cancer has not improved substantially over the past 40 years. Therefore, a novel potential treatment for pancreatic cancer is urgently needed. Recently, a cell surface receptor, Neuropilin-2 (NRP-2), was found to competitively bind either stimulatory angiogenic ligands such as vascular endothelial growth factor-A (VEGFA) or inhibitory class 3 Semaphorin-3F (SEMA3F) ligands. Knowing that angiogenesis is necessary for pancreatic tumor growth, elucidating the role of NRP2 in angiogenesis may lead to curative treatment for pancreatic cancer. OBJECTIVES: Previously, NRP-2 has been shown to be expressed by human cells of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal forms of pancreatic cancer. Additionally, knockdown of NRP-2 in vivo inhibited PDAC tumorigenesis. In our current study, we aimed to investigate the role of endothelial cell derived-Nrp-2 in PDAC-associated tumor angiogenesis. Furthermore, we studied the efficacy of SEMA3F as a potential inhibitory factor for pancreatic tumor growth. METHODS: To investigate the role of Nrp-2 in tumor-derived angiogenesis, we injected Panc0H7 cells, a C57BL/6 syngeneic mouse PDAC cell line, orthotopically into the pancreas of Nrp-2+/+, Nrp-2+/-, and Nrp-2 -/- mice and compared tumor growth and angiogenesis. We next injected control adenovirus (Ad-control) or SEMA3F adenovirus (Ad-3F), which actively encodes SEMA3F in vivo, followed by orthotopic injection of Panc0H7 cells into C57BL/6 mice three days later. We studied the efficacy of SEMA3F as a potential treatment for pancreatic cancer by comparing the tumor growth and tumor-associated angiogenesis of the two groups of adenovirus-treated mice. RESULTS: Our results showed that Panc0H7 tumors were significantly smaller in Nrp-2-deficient mice as compared to that of Nrp-2-intact mice. Furthermore, tumor microvessel density was significantly lower in Nrp-2-knockout mice compared to wild-type mice, while there was no difference in tumor weight or angiogenesis between wild-type and Nrp2 heterozygous mice. Our results also demonstrated that pancreatic tumors harvested from SEMA3F-treated mice were significantly smaller than the tumors from the control-treated mice. Furthermore, micrometastases were detected in the livers of mice treated with Ad-control but not in the Ad-3F group. CONCLUSIONS: Taken together, our results suggested that NRP2 might facilitate in vivo angiogenesis and tumor growth. Furthermore, SEMA3F could be a potential treatment to inhibit the growth and metastases of pancreatic tumors.