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: 8141290
• 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/8141290
• 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; GRP gene; 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 或铃蟾肽 (BN)（GRP 的药理学同系物）可促进结直肠癌的生长和进展。以前的研究主要集中在癌细胞上，而我们提供了令人信服的数据，在检测的 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 会刺激其增殖，激活 NF(B)，并以 MEK/ERK 途径依赖性方式诱导环氧合酶 (COX2)。BN 诱导 CAF 释放 PGE2 增加，而 PGE2 刺激体外结肠上皮细胞的迁移。该提案的新假设是 BN 刺激结直肠癌发生，而不是直接通过 激活结肠上皮细胞，而是通过激活 CAF 间接激活。为了检验这一假设，我们将实现以下两个目标： 目标 1：确定 BN 激活结直肠 CAF 的机制。我们将检查 BN 介导的 CAF 增殖、MEK/ERK 通路的激活、COX-2 启动子活性的调节以及 CAF 中肝细胞生长因子的上调。 目标 2：确定 BN 激活的 CAF 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 及其 shRNA-GRPR 敲低对应物与人结直肠癌细胞共同植入小鼠异种移植和肝转移模型中时的差异。该提案的短期目标是确定机制 CAF 通过其调节肿瘤上皮细胞的生物学。这些目标的成功完成将推进确定G1肽激素通过介导基质/上皮相互作用来调节肿瘤进展的作用的长期目标。由于只有 8% 的结直肠癌实际上含有 APC、K-ras 和 p-53 的伴随突变，因此需要额外的表观遗传事件，例如 CAF 中的 GRPR 可能是结直肠癌进展和转移的致病性改变的另一个考虑因素。将 CAF 上的这些细胞表面受体与抗血管生成和细胞毒性药物相结合，可能会提供额外的、合理的治疗选择。最后，由于我们已经证明 GRPR 是结肠癌 CAF 中 COX2 的上游激活剂，因此对 GRPR 信号传导机制的研究可能 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着一些基因，这些基因可以增加肿瘤的生长、运动和酶的分泌，从而使癌细胞扩散。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针对这些支持细胞中GRPR的药物，从而提高患者的生存率。