Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids

Abstract

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. HCC accounts for up to 90% of all primary liver cancers and represents a major health problem 1,2 . Chronic infection by hepatitis B and C and chronic alcohol consumption are major causes, as well as metastasis from tumors elsewhere in the body. Because only 10-20% of liver cancers can be surgically removed, the prognosis for the disease is very poor 3 . The cumulative 3-year recurrence rate remains high, approximately 80% after resection with a curative aim, and usually results in a high rate of mortality 4 . Moreover, most HCC exhibit resistance to conventional chemotherapeutic agents. Therefore, the development of an effective HCC treatment strategy remains an unmet medical need 5 . Accordingly, researchers have aimed to derive target genes and drug candidates for HCC; however, the development of targeted drugs has not yet significantly improved outcomes 5,6 . Lately, the paradigm in cancer biology has shifted from the study of the genetics of tumor cells alone to the complicated crosstalk between cancer and the tumor microenvironment (TME) [7][8][9] . The TME is the cellular environment in which the tumor exists, including the surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix (ECM). Recent studies have shown that the stromal cells in HCC have a dynamic and flexible function in

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

“…It has also been reported that HSCs in multicellular tumor spheroids (MCTS) exhibited pronounced resistance to sorafenib and cisplatin compared to other types of stromal cells. Moreover, the therapeutic efficacy of sorafenib is increased in MCTS by using losartan which suppresses collagen I synthesis by HSCs [89].…”

Inhibiting endoplasmic reticulum stress decreases tumor burden in a mouse model for hepatocellular carcinoma

“…Stellate cells play a pivotal role in inducing a pro-metastatic phenotype and directing cell migration 45 . In the transwell co-culturing assay, we found that co-culturing HepG2 and Huh7-tumor cells with LX2-cells, significantly increased mRNA-expression of the pro-metastatic marker MMP9 in HepG2-cells (Figure 6A) and MMP1 in HepG2 and Huh7-cells (Figure 6B).…”

“…Activated stellate cells are known to enhance migration and proliferation of tumor cells in vitro 45 and in vivo 5 , possibly by producing extracellular matrix proteins and by producing growth factors. Extracellular matrix proteins such as collagen can act as a scaffold for tumor cell migration 18 , alter the expression of MMP’s 45 and induce epithelial-mesenchymal transition 27 . Activated stellate cells are also an important source of hepatocyte growth factor, which promotes proliferation, cell invasion and epithelial-mesenchymal transition via the c-MET signaling pathway 34 .…”

“…Hepatocellular carcinoma (HCC) is a primary liver tumor that arises in a background of chronic liver disease. Activated stellate cells play an essential role in the pathogenesis of HCC by creating a fibrotic micro-environment that sustains tumor growth and by producing growth factors and cytokines that enhance tumor cell proliferation and migration 11, 14, 45 . One of the key players in the progression of cirrhosis to HCC is the hepatic stellate cell, which is activated during liver damage and differentiates towards a contractile myofibroblast-like cell.…”

Engineering in vitro models of hepatofibrogenesis

“…High collagen content is a key barrier for interstitial drug penetration among ECM-related proteins and thereby reduces the efficacy of chemotherapeutics. Thus major efforts have been made using, for example, co-cultures of HSCs and hepatocytes/HCC cell lines in multicellular tumour spheroid models to investigate the complex signalling cascade between different cell types during liver diseases [118][119][120][121][122]. Furthermore, by using hepatic organoids it was shown that the fast and spontaneous activation of HSCs, as observed in 2D cultures on plastic, was prevented as a quiescent-like phenotype was maintained for 21 days in culture.…”