Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice. Am J Physiol Regul Integr Comp Physiol 2019 May 01;316(5):R678-R686
Date
03/21/2019Pubmed ID
30892915Pubmed Central ID
PMC6589607DOI
10.1152/ajpregu.00388.2018Scopus ID
2-s2.0-85066056744 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.
Author List
Ali M, Kowkuntla S, Delloro DJ, Galambos C, Hathi D, Janz S, Shokeen M, Tripathi C, Xu H, Yuk J, Zhan F, Tomasson MH, Bates MLAuthors
Mahmoud Ali Mohamed Ali MBBS Assistant Professor in the Pathology department at Medical College of WisconsinSiegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin
Mahmoud Mohamed Ali MBBS Assistant Professor in the Pathology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Cell Proliferation
Chronic Disease
Disease Progression
Female
Hypoxia
Mice, Inbred C57BL
Multiple Myeloma
Time Factors
Tumor Burden
Tumor Hypoxia
Tumor Microenvironment
