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Hypoxia-inducible factors and innate immunity in liver cancer
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(10):5052-5062. https://doi.org/10.1172/JCI137553.
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Hypoxia-inducible factors and innate immunity in liver cancer

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Abstract

The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.

Authors

Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong

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Figure 3

Roles of the hypoxia/HIF signaling pathway in HCC cells that affect innate immune cells in the tumor microenvironment.

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Roles of the hypoxia/HIF signaling pathway in HCC cells that affect inna...
HIFs activate the transcription and secretion of the chemokines CCL20, VEGF, and CCL26 in HCC cells. These chemoattractants recruit immunosuppressive TAMs and MDSCs to HCC. HIFs activate the transcription of the don’t-eat-me signal surface markers (CD47, CD24) in cancer cells including HCC cells. CD47 and CD24 are well-characterized liver cancer stem cell markers. CD47 and CD24 prevent cancer cells from being phagocytosed by the macrophages. HIFs activate the transcription of members of the purinergic signaling pathway (CD39, CD39L1, CD73) in HCC cells to create an adenosine- and AMP-rich microenvironment that favors the accumulation of MDSCs. HIFs activate the transcription of members of the LOX family in HCC cells. The LOX family cross-links collagen in the primary cancer and metastatic niches. At the primary liver cancer niche, the LOX family increases tissue stiffening and promotes local invasion of cancer cells. At the metastatic niche in the lung, cross-linking of collagen mediated by the LOX family helps to recruit MDSCs, creating a favorable niche for HCC cell colonization.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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