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Published on: September 12, 2019
Molecular regulation and therapeutic targeting of programmed cell death in hepatocellular carcinoma
Yu Zhao1, Liuxin Yang1, Peng Wang2
1Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China.
Background:
Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.
Objective:
This review comprehensively elucidates the molecular mechanisms governing these PCD pathways, their dysregulation in HCC, and the resulting therapeutic opportunities.
Methods:
We systematically analyzed current literature to detail the core regulators of each PCD pathway, summarize how HCC cells evade them, and evaluate preclinical and clinical strategies for therapeutic targeting.
Key Findings:
HCC cells hijack multiple mechanisms to suppress apoptosis and divert necroptosis. Pyroptosis exhibits a dual role, acting as a tumor suppressor but also contributing to an immunosuppressive microenvironment in established tumors. Autophagy serves a context-dependent function, preventing tumor initiation but sustaining advanced tumors. Promisingly, preclinical studies demonstrate that resensitizing HCC cells to PCD, particularly through combination therapies, can overcome resistance. Early-phase clinical trials targeting these pathways, especially with autophagy inhibitors, have shown manageable safety profiles and hints of efficacy, though larger trials are needed.
Conclusion:
The precise modulation of PCD pathways represents a promising frontier in HCC therapy. Future efforts must focus on patient stratification, biomarker development, and rational combination strategies that exploit the crosstalk between different PCD modalities to improve clinical outcomes.
Insights
Hepatocellular carcinoma (HCC) cells evade programmed cell death (PCD) pathways like apoptosis and necroptosis. Targeting these pathways, especially with combination therapies, offers new hope for treating HCC.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health challenge with limited therapeutic options.
- Tumor cells' ability to evade programmed cell death (PCD) is a major contributor to HCC's resistance to treatment.
- Dysregulation of apoptosis, necroptosis, pyroptosis, and autophagy is central to HCC development, progression, and treatment failure.
Purpose of the Study:
- To review the molecular mechanisms of key programmed cell death (PCD) pathways.
- To elucidate how these PCD pathways are dysregulated in hepatocellular carcinoma (HCC).
- To explore emerging therapeutic strategies targeting PCD in HCC.
Main Methods:
- Systematic literature analysis of programmed cell death (PCD) pathway regulators.
- Summarization of evasion mechanisms employed by hepatocellular carcinoma (HCC) cells.
- Evaluation of preclinical and clinical strategies for targeting PCD pathways.
Main Results:
- HCC cells employ diverse strategies to suppress apoptosis and redirect necroptosis.
- Pyroptosis has a dual role in HCC, acting as a tumor suppressor initially but promoting immunosuppression in later stages.
- Autophagy's function is context-dependent, inhibiting tumor initiation but supporting advanced tumor survival; combination therapies show promise in resensitizing HCC cells to PCD, with early clinical trials indicating manageable safety and potential efficacy for autophagy inhibitors.
Conclusions:
- Targeting programmed cell death (PCD) pathways offers a promising therapeutic avenue for hepatocellular carcinoma (HCC).
- Future research should prioritize patient stratification and biomarker development.
- Rational combination strategies exploiting the interplay between different PCD modalities are crucial for improving HCC treatment outcomes.
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