Targeting Neuropilin 2 with Semaphorin 3F during Pancreatic Carcinoma Progression

描述（由申请人提供）：贝伦贝格实验室的研究重点是研究癌症转移的生物学，即恶性肿瘤细胞通过血管和淋巴管从体内的一个部位扩散到另一个部位。胰腺癌是一种毁灭性的疾病，由于缺乏有效的治疗方法，5年生存率仅为4%。我们提出了一种新的治疗方法，胰腺癌的治疗，涉及使用神经元的指导分子称为脑信号蛋白，以抑制肿瘤的生长和发展。我们已经确定了一种常见的细胞表面受体，表达于胰腺癌细胞、胰腺癌相关内皮细胞（血管）和淋巴管内皮细胞（淋巴管）上，称为神经纤毛蛋白2（NRP 2）。在肿瘤微环境中的几种细胞类型上找到共同的靶标是不寻常的。因此，NRP 2是胰腺癌治疗的一个很好的靶点。我们假设NRP 2在癌细胞中充当VEGF储库，并且在内皮细胞中充当与VEGFR的增强共受体。我们将通过检查NRP 2在癌细胞中作为VEGF的储存库或作为VEGF信号传导的自分泌介导剂（通过在胰腺癌细胞中过表达NRP 2）的作用来检验这一假设。此外，我们将测试NRP 2在小鼠原位胰腺癌模型和使用NRP 2缺陷小鼠的转基因（K-ras+）胰腺癌模型中的肿瘤相关血管生成和淋巴管生成中的必要性。我们预测，内皮细胞中缺乏NRP 2的小鼠将具有减小的肿瘤大小、减少的增殖毛细血管（血管生成）、减少的淋巴管面积和降低的转移潜力。最后，我们假设，脑信号蛋白3F（SEMA 3F），NRP 2的抑制性配体，将抑制（淋巴）血管生成和转移在体内。我们建议在胰腺癌（人类和小鼠原位模型）中进行临床前试验，以测试作为每日注射或缓释泵递送的SEMA 3F纯化蛋白。此外，我们将测试SEMA 3F逆转录病毒感染以消除胰腺癌在肝脏中的转移。总的来说，我们的计划是研究胰腺癌的新方法和新靶点。

DESCRIPTION (provided by applicant): Research in the Bielenberg laboratory focuses on studying the biology of cancer metastasis, the spread of malignant tumor cells from one site in the body to another, through blood vessels and lymphatic vessels. Pancreatic adeno-carcinoma is a devastating disease with only a 4% 5-year survival rate due to the lack of effective therapies. We propose a novel therapeutic approach to pancreatic carcinoma treatment that involves using neuronal guidance molecules called Semaphorins to inhibit neoplastic growth and progression. We have identified a common cell surface receptor that is expressed on pancreatic cancer cells, pancreatic carcinoma-associated endothelial cells (blood vessels), and lymphatic endothelial cells (lymphatic vessels) called Neuropilin 2 (NRP2). It is unusual to find a common target on several cell types within the tumor microenvironment. Therefore, NRP2 is an excellent target for therapy in pancreatic adenocarcinoma. We hypothesize that NRP2 is acting as a VEGF-reservoir in the cancer cells and as an enhancing co-receptor with VEGFR in the endothelial cells. We will test this hypothesis by examining the role of NRP2 in cancer cells as a reservoir for VEGF or as an autocrine mediator of VEGF signaling by overexpressing NRP2 in pancreatic carcinoma cells. In addition, we will test the necessity of NRP2 in tumor-associated angiogenesis and lymphangiogenesis in murine orthotopic pancreatic carcinoma models and in transgenic (K-ras+) pancreatic carcinoma models using NRP2-deficient mice. We predict that mice lacking NRP2 in the endothelial cells will have decreased tumor size, decreased proliferating capillaries (angiogenesis), decreased lymphatic vessel area, and decreased metastatic potential. Lastly, we hypothesize that Semaphorin 3F (SEMA3F), an inhibitory ligand of NRP2, will inhibit (lymph)-angiogenesis and metastasis in vivo. We propose preclinical trials in pancreatic carcinoma (both human and murine orthotopic models) to test SEMA3F purified proteins delivered as daily injections or in slow-release pumps. In addition, we will test SEMA3F retroviral infection to obliterate pancreatic cancer metastasis in the liver. Overall, our plans are to investigate a novel approach and a new target in pancreatic cancer.