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Cited by 189Cancer, Hypoxia, and MetabolismCancer Immunotherapy and BiomarkersImmune Cell Function and Interaction

The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.

Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide

Barsoum, Ivraym B., Hamilton, Thomas K., Li, Xin, Cotechini, Tiziana, Miles, Ellen A., Siemens, D. Robert, Graham, Charles H.·2011·Cancer Research
DOI 10.1158/0008-5472.can-11-2104

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Abstract

One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis mediated by immune effectors and that this resistance to lysis occurs via a hypoxia-inducible factor-1 (HIF-1)–dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC class I chain–related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α and with the hypoxia-induced upregulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics. Cancer Res; 71(24); 7433–41. ©2011 AACR.

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Crossref · 10.1158/0008-5472.can-11-2104

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Metadata

Authors
Barsoum, I. B., Hamilton, T. K., Li, X., Cotechini, T., Miles, E. A., Siemens, D. R., & Graham, C. H.
Affiliations
Queen's University (CA)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-12-15
Volume
71
Issue
24
Pages
7433-7441
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-11-2104
OpenAlex
W1969090863
Cited by
188
References
29
Citations by year
2026: 9 · 2025: 13 · 2024: 6 · 2023: 19 · 2022: 22 · 2021: 16 · 2020: 16 · 2019: 14 · 2018: 13 · 2017: 7 · 2016: 11 · 2015: 14 · 2014: 9 · 2013: 10 · 2012: 9
FWCI
3.05
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
tumor hypoxia, immune evasion, ADAM10, nitric oxide, HIF-1α, nitroglycerin, tumor microenvironment, immunotherapy
MeSH terms
ADAM10 Protein, Animals, Flow Cytometry, Nitroglycerin, Humans, Immunity, Innate, Membrane Proteins, Mice, Nude, Neoplasms, Neoplasms, Experimental, Nitric Oxide, Transplantation, Heterologous, Vasodilator Agents, Blotting, Western, Histocompatibility Antigens Class I, Cell Hypoxia, RNA Interference, Cell Line, Tumor, Tumor Burden, Mice, ADAM Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Amyloid Precursor Protein Secretases, Tumor Microenvironment

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