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）是癌症死亡和酒精暴露的第二大常见原因 其代谢产物乙醛与结直肠癌的发生有关。肝脏是最常见的部位 大肠癌的转移。先前的研究表明，饮酒会增加转移性肝脏 CRC患者和CRC肝转移动物模型中的肿瘤生长。本研究的目的是 确定酒精性肝中转移性肝肿瘤生长增强的分子机制 目的是研究肝转移性肝病（ALD）的临床特征，并开发治疗ALD合并转移性肝肿瘤的新策略。 癌相关成纤维细胞（CAF）是肿瘤微环境的组成部分，可产生多种细胞因子， 细胞外基质（ECM）在肿瘤的生长、侵袭和转移中起重要作用。我们 初步数据显示CAF来源于肝星状细胞（HSC），ALD增加CAF 募集和激活以及肿瘤中的胶原蛋白产生。我们假设ALD诱导CAF 活化和ECM的产生，这增强了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 数据显示HA仅在肿瘤中积累，并且共存的ALD进一步增加透明质酸 合成酶2（HAS 2）表达和肿瘤中HA积累。HA是CD 44和Toll样受体的配体 4，两者都与癌细胞通过获得“干性”而具有恶性潜能有关。我们 假设共存的ALD增加了来自HSC的CAF的HA的产生， 其通过促进癌细胞的恶性潜能而增强转移性肿瘤生长。 为了验证我们的假设，目标1将检查HSC衍生的CAF是否促进转移性肿瘤生长 通过HA与ALD共存。我们将使用HSC特异性HAS 2敲除小鼠。我们还将测试干预性 使用HA合成抑制剂4-甲基伞形酮靶向HAS 2的潜力。然后我们将检查 HAS 2在CAFs中表达调控的分子机制。目标2将检查CAF衍生的HA 通过Notch信号传导增强ALD转移性肝肿瘤的生长。我们将检查HA-CD 44 激活有助于Notch 1激活，并且如果Notch 1是ALD中增强肿瘤生长所必需的。我们 预期CAF衍生的HA驱动Notch 1活化，并增强ALD中的转移性肿瘤生长。