Function of VEGF Receptor-1 on Colorectal Cancer Cells

描述(申请人提供)：血管内皮生长因子(VEGF)是一种与肿瘤进展和转移相关的强有力的血管生成因子。血管内皮生长因子配体家族(-A、-B、-C、-E和PIGF)与三种酪氨酸激酶受体(VEGFR-1、-2和-3)结合，这三种受体在内皮细胞上都有很好的特性。最初，这些受体是在内皮细胞上发现的，并被认为是内皮细胞特异性的。近年来，这些受体在造血干细胞、单核细胞和成骨细胞上被发现，最近在肿瘤细胞上也被发现。然而，这些受体在肿瘤细胞上的功能仍有待阐明。 在初步研究中，我们发现VEGFR-1在人结直肠癌(CRC)细胞系和手术标本中频繁表达。此外，我们还发现，血管内皮生长因子配体可以激活下游信号通路，促进结直肠癌细胞的迁移和集落形成。这些初步发现表明，VEGFR-1可能在肿瘤进展中起作用，因此除了抗VEGFR-1治疗对肿瘤血管生成的影响外，VEGFR-1可能是治疗的直接靶点。 这项资助的总体目标是确定VEGFR-1在人类结直肠癌细胞中的功能作用。具体来说，我们会： 1)确定VEGFR-1在人结直肠癌细胞中激活的信号通路，并确定它们在肿瘤进展和转移过程中的作用 2)检测小鼠(宿主内皮细胞)和人(肿瘤细胞)VEGFR-1对裸鼠人结直肠癌模型的抑制作用 3)体外和体内检测VEGFR活性抑制对人结直肠癌细胞化疗敏感性的影响。 如果VEGFR-1介导了导致肿瘤进展和转移的过程，那么针对VEGFR-1的治疗药物可能对那些结直肠癌表达VEGFR-1的患者有利(除了这些药物的抗血管生成作用外)。此外，结直肠癌细胞上VEGFR-1的表达可能是抗血管内皮生长因子/受体抗肿瘤方案的“预测因子”。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with tumor progression and metastasis. The VEGF family of ligands (-A, -B, -C, -E, and PIGF) binds to three tyrosine kinase receptors (VEGFR-1, -2 and -3) that have been well characterized on endothelial cells. Initially, these receptors were identified on endothelial cells and were believed to be endothelial cell specific. In recent years, these receptors were noted on hematopoietic stem cells, monocytes, and osteoblasts and more recently on tumor cells. However, the function of these receptors on tumor cells remains to be elucidated. In preliminary studies, we found frequent expression of VEGFR-1 in human colorectal cancer (CRC) cell lines and surgical specimens. In addition, we found that VEGF ligands could activate downstream signaling pathways and increase migration and colony formation in CRC cells. These preliminary findings suggest that VEGFR-1 may play a role in tumor progression and thus may be a direct target for therapy, in addition to the effects of anti-VEGFR-1 therapy on tumor angiogenesis. The overall aim of this grant is to determine the functional role of VEGFR-1 on human CRC cells. Specifically we will: 1) Determine signaling pathways activated by VEGFR-1 in human CRC cells and determine their role in processes involved in tumor progression and metastasis 2) Determine the effect of inhibition of murine (host endothelial cell) and human (tumor cell) VEGFR-1 in a murine model of human CRC in nude mice 3) Determine the effect of inhibition of VEGFR activity on chemosensitivity of human CRC cells in vitro and in vivo. If VEGFR-1 mediates processes that lead to tumor progression and metastasis, therapeutic agents aimed at targeting VEGFR-1 may be of benefit to patients whose CRC tumors express VEGFR-1 (in addition to the antiangiogenic effect of these agents). In addition, it is possible that VEGFR-1 expression on CRC cells may serve as a "predictive factor" for anti-VEGF/receptor containing anti-neoplastic regimens.