Bombesin-Activated Carcinoma Associated Fibroblasts in Colorectal Cancer

铃蟾肽激活结直肠癌中癌相关成纤维细胞

• 批准号: 7921556
• 负责人: CELIA CHAO
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921556
• 关键词: Address; Adverse effects; Amphibia; Award; Behavior; Biology; Bombesin; Bombesin Receptor; Carcinoma; Cell Surface Receptors; Cellular biology; Clinical; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Complement; Cytotoxic agent; DNA biosynthesis; Data; Dinoprostone; Drug Design; Endothelial Cells; Enzymes; Epigenetic Process; Epithelial Cells; Epithelial-Stromal Communication; Event; Fibroblasts; Figs - dietary; G-Protein-Coupled Receptors; Gastrin releasing peptide; Genes; Goals; Growth; Harvest; Hepatocyte Growth Factor; Homologous Gene; Human; Implant; In Vitro; Laboratories; Large Intestine Carcinoma; MEKs; Malignant Epithelial Cell; Mediating; Metastatic Neoplasm to the Liver; Methods; Modeling; Mus; Mutation; NF-kappa B; Neoplasm Metastasis; PTGS2 gene; Pathway interactions; Patients; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Receptor Activation; Regulation; Research; Role; Signal Transduction; Solid Neoplasm; Supporting Cell; Testing; Therapeutic; Tumor Biology; Up-Regulation; Xenograft procedure; cancer cell; cancer prevention; carcinogenesis; career; cell motility; follow-up; improved; in vivo; interest; migration; novel; overexpression; peptide hormone; promoter; receptor; research study; small hairpin RNA; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Colorectal cancers aberrantly express gastrin-releasing peptide (GRP) hormone and its cognate receptor (GRPR). Ample in vivo and in vitro experiments suggest that GRP, or bombesin (BN), the pharmacological homologue of GRP, promotes colorectal cancer growth and progression. Previous studies have focused on the cancer cells, whereas, we provide compelling data, that in 95% of freshly harvested human colorectal cancers examined, functional GRPR is expressed by "carcinoma-associated fibroblasts" (CAFs), not the malignant epithelial cells. BN treatment of these CAFs stimulates their proliferation, activates NF(B, and induces cyclooxygenase (COX2) in an MEK/ERK pathway-dependent manner. BN induces increased PGE2 release from CAFs and PGE2 stimulates the migration of colonic epithelial cells in vitro. The novel hypothesis of this proposal is that BN stimulates colorectal carcinogenesis, not by directly activating the colonic epithelial cell, but rather, indirectly, by activating the CAFs. To test this hypothesis, we will address the following two aims: Aim 1: To determine the mechanisms by which BN activates colorectal CAFs. We will examine BN-mediated CAF proliferation, activation of the MEK/ERK pathway, regulation of COX-2 promoter activity and upregulation of Hepatocyte Growth Factor in CAFs. Aim 2: To determine how BN-activated CAFs contribute to neoplastic progression and metastasis in colorectal cancer. We will compare the differences between normal fibroblasts, BN-activated CAFs, and their shRNA-GRPR knockdown counterparts when co-implanted with human colorectal cancer cells in murine xenograft and liver metastasis models. The short-term goal of this proposal is to identify mechanisms by which CAFs modulate the biology of tumor epithelial cells. Successful completion of these aims will advance the long-term goal of defining the role of Gl peptide hormones in regulating tumor progression by mediating stromal/epithelial interactions. Since only 8% of colorectal cancers examined actually harbor concomitant mutations of APC, K-ras, and p-53, additional epigenetic events, such as the overexpression of GRPR, in CAFs may be an additional consideration in the pathogenic alterations of colorectal cancer progression and metastasis. Targeting these cell surface receptors on CAFs, combined with anti-angiogenic and cytotoxic drugs, may provide an additional, rational therapeutic option. Finally, because we have shown that GRPR is an upstream activator of COX2 in CAFs in colon cancer, the study of signaling mechanisms by GRPR may elucidate methods of colon cancer prevention with fewer side effects. RELEVANCE: Colon cancers aberrantly express gastrin-releasing peptide hormone (GRP) and its receptor (GRPR). Activation of this receptor controls genes which can increase tumor growth, motility, and secretion of enzymes that allow cancer cells to spread. We show that 95% of colon tumors express GRPR in supporting cells called fibroblasts, which interact with the colon cancer cells. By studying the relevant mechanisms, we may better design drugs to target GRPR in these supporting cells, and thus improve patient survival.

描述（由申请人提供）： 结直肠癌异常表达胃泌素释放肽（GRP）激素及其同源受体（GRPR）。大量的体内和体外实验表明，GRP或蛙皮素（BN），GRP的药理学同系物，促进结直肠癌的生长和进展。以前的研究集中在癌细胞上，然而，我们提供了令人信服的数据，在95%的新鲜收获的人类结直肠癌中，功能性GRPR由“癌相关成纤维细胞”（CAF）表达，而不是恶性上皮细胞。BN处理这些CAF刺激其增殖，激活NF（B），并以MEK/ERK途径依赖性方式诱导环氧合酶（COX 2）。BN诱导CAFs释放PGE 2增加，PGE 2刺激结肠上皮细胞体外迁移。该提议的新假设是BN刺激结肠直肠癌发生，不是通过直接激活结肠上皮细胞，而是间接激活CAFs。为了验证这一假设，我们将解决以下两个目标：目标1：确定BN激活结直肠CAFs的机制。我们将研究BN介导的CAF增殖，MEK/ERK通路的激活，考克斯-2启动子活性的调节和CAF中肝细胞生长因子的上调。 目的2：确定BN激活的CAFs如何促进结直肠癌的肿瘤进展和转移。我们将比较正常成纤维细胞、BN激活的CAF和它们的shRNA-GRPR敲低对应物在与人结肠直肠癌细胞共植入小鼠异种移植物和肝转移模型中时的差异。该提案的短期目标是确定CAFs调节肿瘤上皮细胞生物学的机制。这些目标的成功完成将推进定义GI肽激素在通过介导基质/上皮相互作用调节肿瘤进展中的作用的长期目标。由于只有8%的结直肠癌检查实际上窝藏APC，K-ras和p-53的伴随突变，额外的表观遗传事件，如GRPR的过度表达，在CAFs可能是一个额外的考虑因素，在结直肠癌的进展和转移的致病性改变。靶向CAF上的这些细胞表面受体，结合抗血管生成和细胞毒性药物，可能提供额外的，合理的治疗选择。最后，因为我们已经证明GRPR是结肠癌CAFs中COX 2的上游激活剂，所以GRPR信号机制的研究可能阐明副作用较少的结肠癌预防方法。 相关性：结肠癌异常表达胃泌素释放肽激素（GRP）及其受体（GRPR）。这种受体的激活控制基因，可以增加肿瘤的生长，运动和允许癌细胞扩散的酶的分泌。我们发现，95%的结肠肿瘤在称为成纤维细胞的支持细胞中表达GRPR，这些细胞与结肠癌细胞相互作用。通过研究相关机制，我们可以更好地设计药物来靶向这些支持细胞中的GRPR，从而提高患者的生存率。