Editors' ChoiceCancer

Stimulate the Mind, Fight Cancer

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Science Signaling  20 Jul 2010:
Vol. 3, Issue 131, pp. ec217
DOI: 10.1126/scisignal.3131ec217

Cao et al. investigated the effect of enriched housing environments on tumor growth (see also Kappeler and Meaney). Mice living in enriched environments (EE mice) developed fewer, smaller, and slower-growing tumors when subcutaneously injected with B16 melanoma cells than control mice in standard group housing. In addition, EE mice showed altered serum concentrations of various circulating factors, such as increased adiponectin and decreased leptin concentrations. Sera from EE mice inhibited the in vitro proliferation of B16 melanoma cells, an effect also seen with sera from control mice pretreated with a neutralizing antibody directed against leptin. Gene expression analysis of nuclei in the hypothalamus revealed that the abundance of the mRNA encoding brain-derived neurotrophic factor (BDNF) was higher in the arcuate nuclei of EE mice compared with that in control mice. Overexpression of BDNF in the hypothalamus resulted in decreased serum leptin concentrations and smaller tumors, whereas hypothalamus-specific knockdown of BDNF by microRNA blocked the effect of EE on leptin concentrations and tumor growth. Adiponectin (which is encoded by Adipoq) and leptin (which is encoded by Lep) are secreted by white adipose tissue (WAT), and Lep abundance is decreased by β-adrenergic receptor stimulation. Analysis of gene expression in WAT indicated that mice living in EE had lower amounts of Lep and higher amounts of Adipoq, as well as increased abundance of Adrb1, Adrb2, and Adrb3 (which encode β-adrenergic receptor isoforms). Administration of the β-blocker propranolol blocked the effects of EE, as assessed by leptin and adiponectin concentrations and tumor growth. Increasing leptin concentrations would be expected to block the effects of EE and, indeed, mice implanted with leptin-releasing liposomes had larger tumors. In ob/ob mice, which are deficient in leptin, EE did not decrease tumor size, and leptin replacement to physiological concentrations through osmotic minipumps increased tumor size. Mice not placed into EE until after colon tumors had been established still showed lower leptin serum concentrations and decreased tumor mass compared with mice in regular housing environments. Furthermore, in ApcMin/+ mice, which have a mutation in the gene encoding adenomatous polyposis coli (APC) and are a model of colon cancer, EE decreased leptin serum concentrations and reduced the number and size of intestinal polyps. Thus, EE activates BDNF in the hypothalamus to suppress leptin release through β-adrenergic signaling and, in various cancer models, can reduce tumor burden and incidence.

L. Cao, X. Liu, E.-J. D. Lin, C. Wang, E. Y. Choi, V. Riban, B. Lin, M. J. During, Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142, 5264 (2010). [PubMed]

L. Kappeler, M. J. Meaney, Enriching stress research. Cell 142, 1517 (2010). [PubMed]

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