Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice.
Mahmoud AliSandeep KowkuntlaDerick J DelloroCsaba GalambosDeep HathiSiegfried JanzMonica ShokeenChakrapani TripathiHongwei XuJisung YukFenghuang ZhanMichael H TomassonMelissa L BatesPublished in: American journal of physiology. Regulatory, integrative and comparative physiology (2019)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- bone marrow
- sleep apnea
- endothelial cells
- high fat diet induced
- multiple myeloma
- mesenchymal stem cells
- metabolic syndrome
- risk factors
- papillary thyroid
- signaling pathway
- obstructive sleep apnea
- adipose tissue
- body composition
- physical activity
- bone mineral density
- postmenopausal women
- squamous cell
- positive airway pressure