Abstract
Most Hepatocellular carcinoma (HCC) are resistant to conventional chemotherapeutic agents and remain an unmet medical need. Recently, multiple studies on the crosstalk between HCC and their tumor microenvironment have been conducted to overcome chemoresistance in HCC. In this study, we formed multicellular tumor spheroids (MCTS) to elucidate the mechanisms of environment-mediated chemoresistance in HCC. We observed that hepatic stellate cells (HSCs) in MCTS significantly increased the compactness of spheroids and exhibited strong resistance to sorafenib and cisplatin relative to other types of stromal cells. Increased collagen 1A1 (COL1A1) expression was apparent in activated HSCs but not in fibroblasts or vascular endothelial cells in MCTS. Additionally, COL1A1 deficiency, which was increased by co-culture with HSCs, decreased the cell-cell interactions and thereby increased the therapeutic efficacy of anticancer therapies in MCTS. Furthermore, losartan, which can inhibit collagen I synthesis, attenuated the compactness of spheroids and increased the therapeutic efficacy of anticancer therapies in MCTS. Meanwhile, activated HSCs facilitated HCC migration by upregulating matrix metallopeptidase 9 (MMP9) in MCTS. Collectively, crosstalk between HCC cells and HSCs promoted HCC chemoresistance and migration by increasing the expression of COL1A1 and MMP9 in MCTS. Hence, targeting HSCs might represent a promising therapeutic strategy for liver cancer therapy.
Highlights
Worldwide, hepatocellular carcinoma (HCC) is one of the human cancers with a high mortality rate despite its early diagnosis in patients and improvements in therapeutic technology
We examined the effect of crosstalk between tumors and their microenvironment on chemoresistance and migration using HCC-MCTS models and found that the interaction between HCC cells and Hepatic stellate cells (HSCs) could facilitate the compactness of HCC spheroids via the accumulation of collagen 1A1 (COL1A1), thereby leading to chemoresistance in HCC
Co-culture with HCC cells and hepatic stellate cells in MCTS exhibited the most significantly induced enhancement of spheroid compactness compared to HCC-MCTS with WI38 cells or Human umbilical vein endothelial cells (HUVEC)
Summary
Hepatocellular carcinoma (HCC) is one of the human cancers with a high mortality rate despite its early diagnosis in patients and improvements in therapeutic technology. HCC accounts for up to 90% of all primary liver cancers and represents a major health problem[1,2]. Hepatic stellate cells (HSCs) play critical roles in diverse aspects of liver physiology, including liver organogenesis, regeneration, and HCC. When the liver is wounded by viral infection or hepatic toxins, HSCs undergo a phenotypic transformation from quiescent cells to activated myofibroblast-like cells, and secret diverse cytokines, growth factors, and EMC proteins to protect the liver. ECM-related proteins in the TME play important roles in liver function in health and disease. A high collagen content is a key barrier for interstitial drug penetration among ECM-related proteins[21,22,23] and thereby reduces the efficacy of chemotherapeutics. Because HCC is developed from chronically damaged tissue that contains a large amount of inflammation and fibrosis, further knowledge of the crosstalk between HCC and their TME is essential for achieving a better understanding of tumor development, progression, and chemoresistance in HCC
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