Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells.

Journal: 
Proc Natl Acad Sci U S A
Publication Year: 
2012
Authors: 
Douglas Edmund Feldman , Chialin Chen , Vasu Punj , Hidekazu Tsukamoto , Keigo Machida
Public Summary: 
These findings raise the possibility that leptin signaling to OB-Rb functions as an independent signaling axis to maintain the pluripotent state in mouse blastocysts. Such a function may extend to human embryonic development.
Scientific Abstract: 
Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr(db/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC-signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.

© 2013 California Institute for Regenerative Medicine