Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities

Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucia...

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Published in:Cancer and metastasis reviews 2023-09, Vol.42 (3), p.741-764
Main Authors: Sin, Shant Qinxiang, Mohan, Chakrabhavi Dhananjaya, Goh, Robby Miguel Wen-Jing, You, Mingliang, Nayak, Siddaiah Chandra, Chen, Lu, Sethi, Gautam, Rangappa, Kanchugarakoppal Subbegowda, Wang, Lingzhi
Format: Article
Language:English
Subjects:
Antisense oligonucleotides
Biomedical and Life Sciences
Biomedicine
Cancer Research
Health aspects
Hepatocellular carcinoma
Hepatoma
Hypoxia
Hypoxia-inducible factors
Liver cancer
Mortality
Nanotechnology
Oncology
Signal transduction
Structure-function relationships
Therapeutic targets
Tumor microenvironment
Tumors
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Summary:Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucial regulators in the TME, activate several cancer hallmarks leading to the hepatocarcinogenesis of HCC and resistance to current therapeutics. As such, HIFs and their signaling pathways have been explored as potential therapeutic targets for the future management of HCC. This review discusses the current understanding of the structure and function of HIFs and their complex relationship with the various cancer hallmarks. To address tumor hypoxia, this review provides an insight into the various potential novel therapeutic agents for managing HCC, such as hypoxia-activated prodrugs, HIF inhibitors, nanomaterials, antisense oligonucleotides, and natural compounds, that target HIFs/hypoxic signaling pathways in HCC. Because of HCC’s relatively high incidence and mortality rates in the past decades, greater efforts should be put in place to explore novel therapeutic approaches to improve the outcome for HCC patients.
ISSN:0167-7659
1573-7233
DOI:10.1007/s10555-022-10071-1