Cited by 188Cancer, Hypoxia, and MetabolismCancer Immunotherapy and BiomarkersImmune Cell Function and Interaction

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

Published version of a preprint

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.

Integrity signals

Registry

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

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte-mediated lysis.

    “Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte–mediated lysis”

    From Hypoxic control of metastasis (2016) · cites this paper as [53]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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)
Venue
Cancer Research
Published
2011-12-15
Volume
71
Issue
24
Pages
7433-7441
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review