Alcohol enhances colon cancer liver metastasis via cancer-associated fibroblasts

项目摘要 结直肠癌(CRC)是导致癌症死亡和饮酒的第二大常见原因 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 结直肠癌转移的可能性。先前的研究表明，饮酒会增加转移性肝脏 结直肠癌患者和结直肠癌肝转移动物模型中的肿瘤生长。这项研究的目的是 酒精性肝转移瘤生长增强的分子机制研究 并开发治疗与ALD并存的转移性肝肿瘤的新策略。 肿瘤相关成纤维细胞(CAF)是肿瘤微环境的组成部分，可产生 细胞外基质(ECM)可能在肿瘤的生长、侵袭和转移中发挥重要作用。我们的 初步数据显示，CAF来源于肝星状细胞(HSCs)，ALD可增加CAF 肿瘤中的募集和激活以及胶原蛋白的产生。我们假设阿尔茨海默病会诱发CAF 在肿瘤中激活和产生ECM，从而促进转移性肝肿瘤的生长。 透明质酸(HA)是ECM的主要成分，主要由HSCs产生。我们的预赛 数据显示，透明质酸仅在肿瘤中蓄积，并伴有ALD进一步增加透明质酸 合酶2(HAS2)在肿瘤中的表达和HA蓄积。透明质酸是CD44和Toll样受体的配体 4，两者都通过获得“干性”而与癌细胞的恶性潜能有关。我们 假设共存的ALD增加了来自HSC的CAF的HA的产生， 它通过促进癌细胞的恶性潜能来促进转移性肿瘤的生长。 为了验证我们的假设，目标1将检验HSC来源的CAF是否促进转移性肿瘤的生长。 通过HA与ALD共存。我们将使用HSC特异的HAS2基因敲除小鼠。我们还将测试干预性 使用HA合成抑制剂4-甲基伞花素靶向HAS2的可能性。然后我们将检查 HAS2在CAF中表达调控的分子机制。目标2将检查CAF衍生的HA 通过Notch信号增强ALD转移性肝肿瘤的生长。我们将检查HA-CD44是否 激活有助于Notch1的激活，以及Notch1是否是促进ALD肿瘤生长所必需的。我们 期望CAF来源的HA驱动Notch1的激活，并促进ALD转移瘤的生长。

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.