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

描述（由申请人提供）：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耐药性，每年导致约50，000例死亡。 转移性CRC的靶向治疗（如抗血管生成）对患者结局的影响有限，导致大多数患有不可切除转移性疾病的患者在2年内死亡。 越来越多的证据表明，大肠癌干细胞（CSC）的存在介导了化疗后的癌症复发。 肿瘤微环境可影响CSC的表型。 因此，肿瘤微环境的调节可能是未来逆转CSC表型的策略。 这种方法需要更好地了解微环境因素和机制，调节CSC表型。 我们的初步研究表明，内皮细胞（EC）分泌可溶性因子，增强CSC表型和CRC细胞的耐药性。 我们推测，肿瘤EC不仅形成微血管网络，提供营养和氧气输送的管道，但也有助于旁分泌因子的肿瘤微环境，介导CSC表型和化疗耐药性。 以下具体目标旨在检验这一假设。 具体目标1：确定新鲜分离的人EC对体外CRC细胞中CSC表型、化疗耐药性和活化途径的促进作用。 具体目标2：鉴定由EC分泌的介导结肠直肠CSC表型和化学抗性诱导的因子。 具体目标3：验证EC在体内促进结直肠CSC表型的旁分泌作用。 该提案的总体目标是为EC在肿瘤微环境中的作用提供新的见解。 我们提出的研究将确定EC旁分泌因子，调节CRC细胞中的CSC表型，这将为开发转移性CRC的新疗法奠定基础。 阻断或干预异常EC旁分泌信号传导将被纳入抗癌方案，除了抗血管生成剂，以改善转移性CRC患者的结局。 公共卫生相关性：越来越多的证据表明，在主要肿瘤块内存在一群结直肠癌细胞，这些细胞负责癌症的起始和对化疗的抵抗;这些细胞被称为癌症干细胞。 我们的实验室发现，血管内皮细胞可以分泌能够增加肿瘤内癌症干细胞数量的因子。 该项目的最终目标是发现由内皮细胞分泌的新的治疗靶点，以降低肿瘤中癌症干细胞的百分比，并改善转移性结直肠癌患者的治疗结果。

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. PUBLIC HEALTH RELEVANCE: There is accumulating evidence for the existence of a population of colorectal cancer cells within the main tumor mass, that are responsible for the initiation of cancer and resistance to chemotherapy; these cells are termed cancer stem cells. Our laboratory has found that the cells lining blood vessels, endothelial cells, can secrete factors that have the ability to enhance the number of cancer stem cells within the tumor. The ultimate goal of this project is to discover novel therapeutic targets secreted by endothelial cells in order to decrease the percent of cancer stem cells within a tumor and to improve the therapeutic outcome of patients with metastatic colorectal cancer.