title: Hypothermia activates adipose tissue to promote malignant lung cancer progression.
abstract: Microenvironment has been increasingly recognized as a critical regulator of cancer progression. In this study, we identified early changes in the microenvironment that contribute to malignant progression. Exposure of human bronchial epithelial cells (BEAS-2B) to methylnitrosourea (MNU) caused a reduction in cell toxicity and an increase in clonogenic capacity when the temperature was lowered from 37°C to 28°C. Hypothermia-incubated adipocyte media promoted proliferation in A549 cells. Although a hypothermic environment could increase urethane-induced tumor counts and Lewis lung cancer (LLC) metastasis in lungs of three breeds of mice, an increase in tumor size could be discerned only in obese mice housed in hypothermia. Similarly, coinjections using differentiated adipocytes and A549 cells promoted tumor development in athymic nude mice when adipocytes were cultured at 28°C. Conversely, fat removal suppressed tumor growth in obese C57BL/6 mice inoculated with LLC cells. Further studies show hypothermia promotes a MNU-induced epithelial-mesenchymal transition (EMT) and protects the tumor cell against immune control by TGF-β1 upregulation. We also found that activated adipocytes trigger tumor cell proliferation by increasing either TNF-α or VEGF levels. These results suggest that hypothermia activates adipocytes to stimulate tumor boost and play critical determinant roles in malignant progression.
authors.affiliation: Institute of Pharmacy, Pharmaceutical College of Henan University, Jinming District, Kaifeng, Henan, China.
authors.forename: Gangjun
authors.initials: G
authors.lastname: Du
authors.forename: Bei
authors.initials: B
authors.lastname: Zhao
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.forename: Weijie
authors.initials: W
authors.lastname: Liu
authors.forename: Jiahuan
authors.initials: J
authors.lastname: Li
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Liu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Xidong
authors.initials: X
authors.lastname: Hou
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058639:Cold-Shock Response; D004249:DNA Damage; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D047368:Tumor Burden; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D008770:Methylnitrosourea