The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

Abstract

In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

Keywords: Cancer stem cells; Epithelial-mesenchymal transition; Hypoxia; Sorafenib resistance; Tumor metabolism; Tumor microenvironment.

Fig. 1

Pathways involved in cell proliferation, EMT, CSCs and tumor metabolism in sorafenib resistance.

Fig. 2

Cancer stem cells, Epithelial-mesenchymal transition and Sorafenib resistance. (a) The existence of CSCs with the help of HBx or oncoprotein HLF contributes to primary sorafenib resistance. Some HCC cells could induce EMT or dedifferentiation under long term exposure to sorafenib, acquiring stemness and plasticity and leading to second sorafenib resistance. Not all CSCs are naturally resistant to sorafenib and they also undergo clonal evolution and transform to be sorafenib resistant, especially. (b) CSCs dedifferentiation and EMT scale account for cellular heterogeneity within a tumor. Distinct tumor subpopulations exhibit diverse degrees of sensitivity to sorafenib. (c) HCC cell with mesenchymal states or stemness have higher invasive ability and become CTCs that have higher tumor-initiating ability to seed second tumors. (d) Mesenchymal HCC cells and liver stem cells share common gene signatures. (e) Schematic diagram of the relationship among tumor heterogeneity, tumor metabolism and tumor microenvironment. Abbreviation: CSC, cancer stem cell; EMT, epithelial-mesenchymal transition; CTCs, circulating tumor cells.

Fig. 3

The role of hypoxia and stromal cells infiltration in sorafenib resistance. (a) The role of HIF family in hypoxia-mediated sorafenib resistance. (b) The interaction between CAFs and HCC cells under sorafenib-induced hypoxia. (c) Sorafenib-induced hypoxia and HCC cells debris shape an immunosuppressive HCC microenvironment by recruiting BMDCs, Tregs and TAMs, promoting M2 polarization and educating PBNs into TANs. (d) EMT process and tumor plasticity are negatively associated with the TAMs infiltration, while the stemness among different EMT intermediate states keep the same. Abbreviation: CAFs, cancer-associated fibroblasts; PBNs, peripheral blood neutrophils; BMDCs, bone marrow-derived cells; TAMs, tumor-associated macrophages; TANs, tumor-associated neutrophils; Tregs, T regulatory cells.

Fig. 4

Metabolic homeostasis in sorafenib resistance. (a) OXPHOS is sustained in liver CSCs, and glutamine, fatty acids and acetate could be alternative energy sources to fuel HCC cells under sorafenib-induced hypoxia and relative glucose deprivation. (b) Redox production including GSH, NAPDH and thioredoxin involves multiple metabolic pathways and plays central role in against sorafenib-induced oxidative stress, especially in EMT process. NRF2 plays the key role in (c) Enhanced proteins, lipids and nucleotides biosynthesis are crucial to maintain cell structure, support DNA repair and supply pro-survival growth signals. Abbreviations: OXPHOS, Oxidative phosphorylation; TCA, tricarboxylic acid cycle; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate; R5P, Ribose 5-phosphate; ROS, reactive oxygen species.

Fig. 5

Epigenetic regulation links microenvironmental or metabolic changes to cell state transition. Abbreviation: m6A, N6-methyladenosine; ncRNAs, non-coding RNAs.