<p>Suppl Materials, Figure Legends 1-7 and Tables showing clinico-pathological correlation of endogenous IRAK1, the effect of IRAK1 alternations on tumorigenicity as well as pathway analysis of HCC cells with or without IRAK1 suppressed</p>
Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
Abstract Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed countries. However, the mechanisms contributing to its formation remain largely unknown. Given the role of cancer stem cells (CSCs) in tumor initiation and therapeutic resistance, we hypothesize that adipocytes, one of the key cellular factors within the tumor microenvironment of NAFLD-induced HCC, may play a critical role in HCC development and drug resistance by regulating liver CSCs. Using a co-culture system in which differentiated adipocytes were grown with HCC cells, we found that adipocytes enhanced the self-renewal ability of HCC cells through indirect paracrine secretion. HCC cells pre-incubated with conditioned medium from adipocytes showed enhanced liver CSC properties including self-renewal, tumorgenicity, invasiveness and chemo-resistance to doxorubicin and sorafenib. Secretome profiles showed that FABP4 was preferentially secreted by adipocytes and its level was further augmented when co-cultured with HCC cells. Concurrently, recombinant FABP4 enhanced CSC properties of HCC cells. Drastic delay in the onset of tumor development in FABP4−/- mice upon DEN-injected and high fat diet-induced mouse models of NAFLD-HCC. Mass spectrometry analysis revealed ITGB1 as a direct binding partner of FABP4 for the first time. This data, together with the observation of significant downregulation of the Wnt/β-catenin pathway in tumors of FABP4−/− mice, revealed the role of adipocyte-derived FABP4 promotes liver CSC function by activating the PI3K/Akt/β-catenin signaling pathway via ITGB1. Overexpression of ITGB1 led to poorer survival of HCC patients with NAFLD as a risk factor. The development of a monoclonal neutralizing antibody against FABP4 successfully blocked FABP4-driven CSC functions, implicating the targetability of FABP4 for the treatment of NAFLD-induced HCC. Citation Format: Carmen Oi Ning Leung, Shilpa Gurung, Katherine Po Sin Chung, Sze Man Chan, Terence Kin Wah Lee. Adipocyte-derived FABP4 promotes non-alcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma by driving ITGB1-mediated β-catenin activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 574.
<p>By qPCR analysis, AKR1B10 was found to be overexpressed in a cohort of 79 HCC patients. AKR1B10 expression was significantly correlated with IRAK1 in our patient cohort as well as the publicly available dataset</p>
Abstract Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world with less than 10% 5-year survival rate. Liver cancer stem cells (CSCs) are sub-populations of the cancer cells that have been found to play a crucial role in tumor relapse and therapeutic resistance. Increasing reports showed the significant correlation between non-alcoholic fatty liver disease (NAFLD) and HCC development. Based on this evidence, we hypothesize adipocytes, one of the key cellular factors within the tumor microenvironment, play a crucial role in HCC development and progression via regulation of liver CSCs. To verify this, we have employed a co-culture system to dissect the potential cross-talk between fully differentiated adipocytes and HCC cells. Our pilot data showed that adipocytes enhanced the self-renewal ability of HCC cells through indirect paracrine secretion. Based on this finding, we examined the effect of the conditioned medium of adipocytes on regulation of liver CSC. Consistently, we found that HCC cells pre-incubated with conditioned medium of adipocytes showed enhanced in vivo tumorigenicity and chemo-resistance to doxorubicin and sorafenib. Furthermore, conditioned medium of adipocytes promoted the migration and invasion abilities of HCC cells. To delineate the molecular mechanism of how adipocytes, exert its CSC enhancing effect on HCC cells, we have collected the conditioned medium derived from adipocytes and analyzed their secretome profiles using Orbitrap Liquid Chromatography-Mass spectrometry. Upon analysis, we identified 209 proteins, among which we have focused on two proteins (CSF1 and FABP4) for further analysis as these are preferentially secreted from adipocytes. Respective inhibitors of the proteins are used to study the specificity of the protein in the medium and the downstream studied with the help of RNA sequencing which has been performed on conditioned medium treated HCC cells. Collectively, we demonstrated the pivotal role of adipocytes on regulation of liver CSCs through paracrine secretion. Thus, targeting adipocytes-derived signaling cascade may be a novel therapeutic strategy for treatment of fatty liver induced HCC. Citation Format: Shilpa Gurung, Terence Kin-Wah Lee. The pivotal roles of adipocytes on regulation of cancer stemness and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1988.
Fatty acid binding proteins (FABPs) are 15-kDa proteins responsible for the transport of fatty acids both intracellularly and extracellularly. Consisting of 12 different isoforms, some of the proteins have been found to be released in the serum and to be correlated with various diseases including cancer. Differential expression of these proteins has been reported to result in cancer pathogenesis by modulating various cancer signaling pathways; hence, in this review, we present the recent studies that have investigated the roles of different kinds of FABPs in different types of cancer and any possible underlying mechanisms to better understand the role of FABPs in cancer progression.
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