Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition

• Published in: Cell Vol. 142; no. 1; pp. 52 - 64
• Main Authors: Cao, Lei, Liu, Xianglan, Lin, En-Ju D., Wang, Chuansong, Choi, Eugene Y., Riban, Veronique, Lin, Benjamin, During, Matthew J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-07-2010
• Subjects: Adipocytes - metabolism; Animals; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - physiopathology; Genes, APC; Housing, Animal; HUMDISEASE; Hypothalamus - cytology; Hypothalamus - metabolism; Immunocompetence; Leptin - metabolism; Melanoma - genetics; Melanoma - metabolism; Melanoma - physiopathology; Mice; Mice, Inbred C57BL; MOLNEURO; Neoplastic Processes; Random Allocation; Receptors, Adrenergic, beta - metabolism; Signal Transduction; Social Environment; HUMDISEASE; MOLNEURO
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2010.05.029

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural β-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.
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► Mice housed in an enriched environment (EE) show decreased cancer growth and remission ► EE stimulates the expression of BDNF within the hypothalamus ► BDNF, via a sympatho-adipocyte axis, shuts down the fat hormone leptin ► The suppression of leptin mediates the anticancer effects