Alcohol enhances colon cancer liver metastasis via cancer-associated fibroblasts

酒精通过癌症相关成纤维细胞增强结肠癌肝转移

• 批准号: 9331372
• 负责人: EKIHIRO SEKI
• 金额: $ 25.16万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331372
• 关键词: Acetaldehyde; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Biological Process; Blood; Bone Marrow; CD44 gene; Cancer Etiology; Cells; Cessation of life; Collagen; Colon Carcinoma; Colorectal Cancer; Country; Data; Deposition; Development; Extracellular Matrix; Fibroblasts; Goals; Growth; HAS2 gene; Hepatic; Hepatic Stellate Cell; Hepatocyte; Hyaluronic Acid; Incidence; Intervention; Knockout Mice; Knowledge; Kupffer Cells; Ligands; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Liver neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Neoplasm to the Liver; Molecular; Mus; Myofibroblast; Neoplasm Metastasis; Organ; Patients; Play; Prevalence; Production; Recruitment Activity; Role; Signal Transduction; Site; Source; TLR4 gene; Testing; Tumor-Derived; alcohol exposure; base; cancer cell; cancer stem cell; colon cancer patients; colon carcinogenesis; inhibitor/antagonist; malignant breast neoplasm; notch protein; novel therapeutic intervention; outcome forecast; overexpression; prevent; receptor; stemness; tumor; tumor growth; tumor microenvironment

Project Summary Colorectal cancer (CRC) is the second-most common cause of cancer death and exposure to alcohol and its metabolite acetaldehyde is associated with colorectal carcinogenesis. The liver is the most frequent site of metastasis of CRC. Previous studies demonstrated that alcohol consumption increases metastatic liver tumor growth in CRC patients and in animal model of CRC liver metastasis. The objective of this study is to determine the molecular mechanisms of enhanced metastatic liver tumor growth in alcoholic liver disease (ALD) and to develop new strategies for treating metastatic liver tumors coexisting with ALD. Cancer-associated fibroblast (CAF) is a component of tumor microenvironment and can produce extracellular matrix (ECM), which could play an important role in cancer growth, invasion, and metastasis. Our preliminary data showed that CAFs are derived from hepatic stellate cells (HSCs) and that ALD increases CAF recruitment and activation, and collagen production in tumors. We hypothesize that ALD induces CAF activation and ECM production in tumors, which enhances metastatic liver tumor growth. Hyaluronic acids (HA) are major components of ECM and mainly produced from HSCs. Our preliminary data showed that HA were accumulated only in tumors and coexisting ALD further increased hyaluronan synthase 2 (HAS2) expression and HA accumulation in tumors. HA are ligands for CD44 and Toll-like receptor 4, both of which are associated with malignant potential of cancer cells by acquiring "stemness". We hypothesize that coexisting ALD increases production of HA from CAFs that are derived from HSCs, which enhances metastatic tumor growth through promoting malignant potential of cancer cells. To test our hypothesis, Aim 1 will examine if HSC-derived CAF promotes metastatic tumor growth coexisting with ALD via HA. We will use HSC-specific HAS2 knockout mice. We will also test interventional potential of targeting HAS2 using 4-methyl-umbeliferone, an inhibitor for HA synthesis. We will then examine the molecular mechanism of how HAS2 expression is regulated in CAFs. Aim 2 will examine if CAF-derived HA enhances growth of metastatic liver tumors with ALD via Notch signaling. We will examine if HA-CD44 activation contributes to Notch1 activation and if Notch1 is required for enhanced tumor growth in ALD. We expect that CAF-derived HA drive Notch1 activation and it enhances metastatic tumor growth in ALD.

项目摘要 结直肠癌（CRC）是癌症死亡和暴露于酒精的第二常见原因 它的代谢物乙醛与结直肠癌的发生有关。肝脏是最常见的部位 CRC的转移。先前的研究表明，饮酒会增加转移性肝脏 CRC患者和CRC肝转移动物模型的肿瘤生长。这项研究的目的是 确定酒精性肝脏中转移性肝肿瘤生长增强的分子机制 疾病（ALD），并制定与ALD共存转移性肝肿瘤的新策略。 癌症相关的成纤维细胞（CAF）是肿瘤微环境的组成部分，可以产生 细胞外基质（ECM），可能在癌症生长，侵袭和转移中起重要作用。我们的 初步数据表明，CAF是从肝星细胞（HSC）得出的，ALD增加了CAF 肿瘤中的募集和激活以及胶原蛋白产生。我们假设ALD诱导CAF 肿瘤中的激活和ECM产生，可增强转移性肝肿瘤的生长。 透明质酸（HA）是ECM的主要成分，主要由HSC产生。我们的初步 数据表明，HA仅在肿瘤中积累，并共存ALD进一步增加了透明质酸 合成酶2（HAS2）表达和HA在肿瘤中的积累。 HA是CD44和Toll样受体的配体 4，两者都通过获得“茎”而与癌细胞的恶性潜力有关。我们 假设共存的ALD增加了来自HSC的CAF的HA产量， 这通过促进癌细胞的恶性潜力来增强转移性肿瘤的生长。 为了检验我们的假设，AIM 1将检查HSC衍生的CAF是否促进转移性肿瘤的生长 与ALD通过HA共存。我们将使用HSC特定的HAS2敲除小鼠。我们还将测试介入 使用4-甲基 - 近甲酮（用于HA合成的抑制剂）靶向HAS2的潜力。然后我们将检查 在CAF中调节HAS2表达的分子机制。 AIM 2会检查CAF衍生的HA是否 通过Notch信号传导增强使用ALD的转移性肝肿瘤的生长。我们将检查HA-CD44是否 激活有助于Notch1激活，如果需要Notch1来增强ALD的肿瘤生长。我们 预计CAF衍生的HA驱动Notch1激活并增强了ALD的转移性肿瘤生长。