title: Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation.
abstract: Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-I, growth hormone, vascular endothelial growth factor, and proinflammatory Th2 cytokines, such as interleukin (IL)-1beta, IL-4, and IL-6, were elevated in A-ZIP/F-1 mice. Additionally, we examined multiple phosphorylated proteins (i.e., protein kinase B/Akt and ErbB2/HER-2 kinase) associated with cancer development. Results show that many of these phosphorylated proteins were activated specifically in the A-ZIP/F-1 skin but not in the wild-type skin. These findings suggest that adipokines are not required for the promotion of tumor development and thus contradict the epidemiologic data linking obesity to carcinogenesis. We postulate that insulin resistance and inflammation are responsible for the positive correlation with cancer observed in A-ZIP/F-1 mice.
authors.affiliation: Laboratories of Biosystems and Cancer, Metabolism, Human Carcinogenesis and Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Nomeli P
authors.initials: NP
authors.lastname: Nunez
authors.forename: Won-Jun
authors.initials: WJ
authors.lastname: Oh
authors.forename: Julian
authors.initials: J
authors.lastname: Rozenberg
authors.forename: Chris
authors.initials: C
authors.lastname: Perella
authors.forename: Miriam
authors.initials: M
authors.lastname: Anver
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: Susan N
authors.initials: SN
authors.lastname: Perkins
authors.forename: David
authors.initials: D
authors.lastname: Berrigan
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.forename: Charles
authors.initials: C
authors.lastname: Vinson
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D020738:Leptin / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics; D052243:Resistin / Q000097:blood; D012878:Skin Neoplasms / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D052242:Adiponectin; D016207:Cytokines; D020738:Leptin; D052243:Resistin; C406806:Tg(AZIP-F)1Vsn protein, mouse; D014157:Transcription Factors