Hepatic Stellate Cells Secreted Hepatocyte Growth Factor Contributes to the Chemoresistance of Hepatocellular Carcinoma

Abstract

As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs) have a great impact on biological behaviors of hepatocellular carcinoma (HCC). In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium) exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT) and upregulation of cancer stem cell (CSC) -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF) into the CM. HGF receptor tyrosine kinase mesenchymal–epithelial transition factor (Met) was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

“…Accordingly, reciprocal signaling between hepatic stellate cells and precancerous hepatoma cells induced an EMT and CSC-like properties in HCC mediated by hepatocyte growth factor (HGF)/Met signaling [91]. Similarly, exposure to conditioned media from tumor infiltrating macrophages (TAMs) rich in TGF-β1 promoted hepatoma cells to undergo EMT and to gain CSC-like properties [76].…”

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors and the largest cancer-related deaths ranking only second to lung cancer, with a fairly high and increasing incidence, frequently relapse and dismal prognosis [1,2]. Despite the remarkable progress in the prevention, detection, and treatment of cancer over the last five decades, no adequate therapy remains sufficiently effective due to late stage diagnosis and inadequate clinical strategies for inhibiting metastasis and promoting apoptosis [3][4][5][6].…”

Resistance to targeted cancer drugs through hepatocyte growth factor signaling

“…Indeed, HGF has been implicated in chemoresistance. [51][52][53][54] Targeting MET with inhibitors has recently been shown to revert chemoresistance in Small Cell Lung Cancer, 55 showing the potential of MET inhibition beyond targeted therapies. Checking MET activity in chemoresistant tumors could therefore be an opening in attempting to resensitize such tumors to chemotherapy.…”