Intermittent hypoxia-induced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea.
BACKGROUND
An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice.


OBJECTIVE
To assess whether OSA-related adverse cancer outcomes occur via IH-induced changes in host immune responses, namely tumor-associated macrophages (TAMs).


RESULTS
Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs from tumors harvested from RA-exposed mice increased TC1 migration and extravasation, TAMs from IH-exposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10) and TC1 cells exposed to IH either in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present.


CONCLUSIONS
Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA.
1 Department of Pediatrics, Comer Children's Hospital, Pritzker School of Medicine, and.
Isaac
I
Almendros
Yang
Y
Wang
Lev
L
Becker
Frances E
FE
Lennon
Jiamao
J
Zheng
Brittney R
BR
Coats
Kelly S
KS
Schoenfelt
Alba
A
Carreras
Fahed
F
Hakim
Shelley X
SX
Zhang
Ramon
R
Farré
David
D
Gozal
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D000860:Hypoxia / Q000209:etiology / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D010641:Phenotype; D020181:Sleep Apnea, Obstructive / Q000276:immunology / Q000503:physiopathology*; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology