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

Proceedings of the National Academy of Sciences of the United States of America | February 05, 2012 |

Feldman, Douglas Edmund | Chen, Chialin | Punj, Vasu | Tsukamoto, Hidekazu | Machida, Keigo
Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

Abstract

Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tum ... wth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.

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.

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Pnas.1114438109fig01
Fig 1. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.
Pnas.1114438109fig01
Fig 1. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

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Pnas.1114438109fig02
Fig 2. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.
Pnas.1114438109fig02
Fig 2. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

Fig 2

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Pnas.1114438109fig03
Fig 3. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.
Pnas.1114438109fig03
Fig 3. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

Fig 3

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Pnas.1114438109fig04
Fig 4. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.
Pnas.1114438109fig04
Fig 4. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

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Pnas.1114438109fig05
Fig 5. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.
Pnas.1114438109fig05
Fig 5. Feldman, Chen, et al. "Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells." Proceedings of the National Academy of Sciences of the United States of America 109.3 (2012): 829-34. Web.

Fig 5

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