PMID- 22006996
OWN - NLM
STAT- MEDLINE
DCOM- 20120306
LR  - 20161125
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 71
IP  - 24
DP  - 2011 Dec 15
TI  - Hypoxia induces escape from innate immunity in cancer cells via increased 
      expression of ADAM10: role of nitric oxide.
PG  - 7433-41
LID - 10.1158/0008-5472.CAN-11-2104 [doi]
AB  - 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 alpha-subunit of HIF-1 
      (HIF-1alpha), 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-1alpha 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.
FAU - Barsoum, Ivraym B
AU  - Barsoum IB
AD  - Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, 
      Canada.
FAU - Hamilton, Thomas K
AU  - Hamilton TK
FAU - Li, Xin
AU  - Li X
FAU - Cotechini, Tiziana
AU  - Cotechini T
FAU - Miles, Ellen A
AU  - Miles EA
FAU - Siemens, D Robert
AU  - Siemens DR
FAU - Graham, Charles H
AU  - Graham CH
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111017
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (MHC class I-related chain A)
RN  - 0 (Membrane Proteins)
RN  - 0 (Vasodilator Agents)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.81 (ADAM10 Protein)
RN  - EC 3.4.24.81 (ADAM10 protein, human)
RN  - G59M7S0WS3 (Nitroglycerin)
SB  - IM
EIN - Cancer Res. 2012 Feb 1;72(3):827
MH  - ADAM Proteins/genetics/*metabolism
MH  - ADAM10 Protein
MH  - Amyloid Precursor Protein Secretases/genetics/*metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Flow Cytometry
MH  - Histocompatibility Antigens Class I/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - *Immunity, Innate
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasms/genetics/*metabolism/pathology
MH  - Neoplasms, Experimental/genetics/metabolism/pathology
MH  - Nitric Oxide/*metabolism
MH  - Nitroglycerin/pharmacology
MH  - RNA Interference
MH  - Transplantation, Heterologous
MH  - Tumor Burden/drug effects
MH  - Tumor Microenvironment/drug effects/genetics/immunology
MH  - Vasodilator Agents/pharmacology
EDAT- 2011/10/19 06:00
MHDA- 2012/03/07 06:00
CRDT- 2011/10/19 06:00
PHST- 2011/10/19 06:00 [entrez]
PHST- 2011/10/19 06:00 [pubmed]
PHST- 2012/03/07 06:00 [medline]
AID - 0008-5472.CAN-11-2104 [pii]
AID - 10.1158/0008-5472.CAN-11-2104 [doi]
PST - ppublish
SO  - Cancer Res. 2011 Dec 15;71(24):7433-41. doi: 10.1158/0008-5472.CAN-11-2104. Epub 
      2011 Oct 17.