Paracrine Role of Endothelial Cells on the Colorectal Cancer Stem Cell Phenotype

描述(申请人提供)：结直肠癌(CRC)是美国癌症死亡的第二大原因，因为几乎所有患者都会产生化疗耐药性，导致每年约50,000人死亡。转移性结直肠癌的靶向治疗(如抗血管生成)对患者预后的影响有限，导致大多数无法切除的转移性疾病患者在2年内死亡。越来越多的证据表明，结直肠癌干细胞(CSC)的存在，它介导了肿瘤化疗后的复发。CSC的表型受肿瘤微环境的影响。因此，调节肿瘤微环境可能是逆转CSC表型的未来策略。这种方法需要更好地了解调节CSC表型的微环境因素和机制。我们的初步研究表明，内皮细胞(EC)分泌的可溶性因子可以增强结直肠癌细胞的CSC表型和化疗耐药性。我们推测，肿瘤内皮细胞不仅形成了微血管网络，为营养和氧气输送提供了管道，而且还为肿瘤微环境贡献了旁分泌因子，介导了CSC的表型和化疗耐药性。为了检验这一假设，我们设计了以下具体目标。具体目的1：确定新鲜分离的人内皮细胞在体外对结直肠癌细胞CSC表型、化疗耐药和激活途径的促进作用。特异性目的2：确定内皮细胞分泌的介导诱导结直肠癌细胞表型和化疗耐药的因素。特异性目的3：验证ECs在体内促进结直肠癌CSC表型的旁分泌作用。这项提案的总体目标是为内皮细胞在肿瘤微环境中的作用提供新的见解。我们的研究将确定调控结直肠癌细胞CSC表型的EC旁分泌因子，这将为转移性结直肠癌新疗法的开发奠定基础。除了抗血管生成药物外，阻断或干预异常的EC旁分泌信号将被纳入抗癌方案，以改善转移性结直肠癌患者的预后。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, due to the fact that chemoresistance develops in nearly all patients leading to ~50,000 deaths each year. Targeted therapies (such as anti-angiogenesis) for metastatic CRC have a limited impact of patient outcomes, leaving the majority of patients with unresectable metastatic disease dying within 2 years. There is accumulating evidence for the existence of colorectal cancer stem cells (CSC), which mediate the cancer relapse after chemotherapy. CSC phenotype can be influenced by the tumor microenvironment. Thus, modulation of the tumor microenvironment could be a future strategy to reverse the CSC phenotype. This approach requires a better understanding of the microenvironmental factors and mechanisms that regulate the CSC phenotype. Our preliminary studies demonstrate that endothelial cells (EC) secrete soluble factors that enhance the CSC phenotype and chemoresistance of CRC cells. We hypothesize that tumor ECs not only form the microvasculature network providing a conduit for nutrient and oxygen delivery, but also contribute paracrine factors to the tumor microenvironment that mediate the CSC phenotype and chemoresistance. The following specific aims are designed to test this hypothesis. Specific Aim 1: To determine the effect of freshly isolated human ECs on promotion of the CSC phenotype, chemoresistance, and activated pathways in CRC cells in vitro. Specific Aim 2: To identify factors secreted by ECs that mediate the induction of the colorectal CSC phenotype and chemoresistance. Specific Aim 3: To validate the paracrine effect of ECs on promoting the colorectal CSC phenotype in vivo. The overall goal of this proposal is to provide new insights into the role of ECs in the tumor microenvironment. Our proposed study will identify the EC paracrine factors that regulate the CSC phenotype in CRC cells, and this will form the foundation for the development of new therapeutics for metastatic CRC. Blockade or intervention of aberrant EC paracrine signaling will be incorporated into anti-cancer regimens, in addition to anti-angiogenic agents, to improve the outcome of patients with metastatic CRC.