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.

Public Health Relevance

Colorectal cancer (CRC) is one of the most common cancers in the world and the liver is the most favorable organ for CRC metastasis. The extent of liver metastasis is an important determinant of the prognosis of CRC. Alcohol and its metabolite can mediate colorectal carcinogenesis. Alcohol consumption also increases the incidence of CRC liver metastasis. The goal of this study is to investigate the role of cancer-associated fibroblasts and an extracellular matrix hyaluronic acids in the enhancement of metastatic liver tumor growth in ALD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Murray, Gary
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Cedars-Sinai Medical Center
Los Angeles
United States
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