Role of Neuropillins in Pancreatic Cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种致命的疾病，预后极差。尽管决定其生物学侵袭性的具体分子机制尚不清楚，但PDAC的特征是癌基因和肿瘤抑制基因的突变，以及有丝分裂和血管生成生长因子的过度表达，如血管内皮生长因子-A(VEGF-A)。尽管这种强有力的血管生成剂在PDAC中有显著的丰富，但这种恶性肿瘤与粗大的血管肿瘤无关。此外，血管内皮生长因子-A对体外培养的胰腺癌细胞具有促有丝分裂作用，这些细胞表达不同水平的高亲和力受体-1(VEGFR-1)和VEGFR-2。这些观察结果表明，在体内，血管内皮生长因子-A也可能对胰腺癌细胞产生直接作用。最近，我们发现促进血管内皮细胞生长因子-A与其高亲和力受体相互作用的跨膜共受体--神经粘连蛋白-1(NP-1)和神经粘连蛋白-2(NP-2)在PDAC的癌细胞中高表达。由于神经粘连蛋白与促进细胞存活有关，在目前的提案中，我们将测试假设，即在PDAC的癌细胞中NP-1和NP-2的表达允许激活依赖于VEGF-A的自分泌途径，从而促进肿瘤的生长、存活和转移。为了验证这一假设，我们将首先确定被设计为过表达NP-1和NP-2的胰腺癌细胞是否表现出对血管内皮生长因子-A的反应增加了有丝分裂信号，增强了侵袭潜力，或者提高了生存能力。相反，我们将评估抑制NP-1和NP-2表达对血管内皮生长因子-A的反应性的影响。其次，我们将使用转移性PDAC裸鼠模型来研究这些操作对肿瘤生长和转移的影响，并确定神经毛刺素的体内促生长作用是否可以被VEGF-A封存所阻断。第三，我们将确定NP-1和NP-2的表达是否与肿瘤的分期和分级、肿瘤血管生成和术后生存时间显著相关。总而言之，这些研究最终可能为这种致命疾病的治疗干预提供新的途径。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a devastatingly lethal disease with an extremely poor prognosis. Although the specific molecular mechanisms that dictate its biological aggressiveness are yet to be elucidated, PDAC is characterized by mutations in oncogenes and tumor suppressor genes, and by the overexpression of mitogenic and angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). In spite of the marked abundance of this potent angiogenic agent in PDAC, this malignancy is not associated with grossly vascular tumors. Furthermore, VEGF-A has been shown to exert mitogenic effects on pancreatic cancer cells in culture, and these cells express variable levels of high affinity receptor-1 (VEGFR-1) and VEGFR-2. These observations raise the possibility that VEGF-A may also exert direct effects on pancreatic cancer cells in vivo. Recently, we determined that neuropilin-1 (Np-1) and -2 (Np-2), transmembrane co-receptors that promote VEGF-A interactions with their high affinity receptors, are overexpressed in the cancer cells in PDAC. Because neuropilins have been implicated in promoting cell survival, in the present proposal we will test the hypothesis that expression of Np- 1 and Np-2 in the cancer cells in PDAC allows for the activation of a VEGF-A-dependent autocrine pathway that promotes cancer growth, survival and metastasis. To test this hypothesis, we will first determine whether pancreatic cancer cells engineered to overexpress Np-1 and Np-2 exhibit increased mitogenic signaling in response to VEGF-A, enhanced invasive potential, or enhanced survival. Conversely, we will assess the consequences of suppressing Np- 1 and Np-2 expression on responsiveness to VEGF-A. Second, we will use a metastatic nude mouse model of PDAC to study the consequences of these manipulations on tumor growth and metastasis, and to determine whether the in vivo growth promoting effects of neuropilins can be blocked by VEGF-A sequestration. Third, we will determine whether there are significant correlations between Np-1 and Np-2 expression and tumor stage and grade, tumor angiogenesis, and duration of post-operative survival. Together, these studies may ultimately yield novel avenues for therapeutic intervention in this deadly disease.