Role of Neuropillins in Pancreatic Cancer

描述（申请人提供）：胰腺导管腺癌（PDAC）是一种预后极差的致命疾病。尽管决定其生物侵袭性的特定分子机制尚未阐明，但PDAC的特征是致癌基因和肿瘤抑制基因突变，以及有丝分裂和血管生成生长因子（如血管内皮生长因子- a (VEGF-A)）的过度表达。尽管这种强效血管生成剂在PDAC中明显丰富，但这种恶性肿瘤与粗大血管肿瘤无关。此外，VEGF-A已被证明在培养的胰腺癌细胞中发挥有丝分裂作用，这些细胞表达不同水平的高亲和力受体-1 （VEGFR-1）和VEGFR-2。这些观察结果提出了VEGF-A也可能在体内对胰腺癌细胞产生直接作用的可能性。最近，我们发现促进VEGF-A与其高亲和受体相互作用的跨膜共受体neuropilin-1 （Np-1）和-2 （Np-2）在PDAC的癌细胞中过度表达。由于神经匹林与促进细胞存活有关，在本研究中，我们将验证PDAC中癌细胞中Np- 1和Np-2的表达允许激活vegf - a依赖的自分泌途径，从而促进癌症的生长、存活和转移。为了验证这一假设，我们将首先确定经过工程改造过表达Np-1和Np-2的胰腺癌细胞是否在VEGF-A的作用下表现出增加的有丝分裂信号、增强的侵袭潜力或提高的存活率。相反，我们将评估抑制Np- 1和Np-2表达对VEGF-A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，并确定神经匹林的体内生长促进作用是否可以被VEGF-A隔离阻断。第三，我们将确定Np-1和Np-2表达与肿瘤分期和分级、肿瘤血管生成和术后生存时间是否存在显著相关性。总之，这些研究可能最终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.