Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth and abrogates tumor initiating cell survival

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NC10, Cleveland, Ohio 44195, USA.
Endocrine Related Cancer (Impact Factor: 4.81). 06/2011; 18(4):491-503. DOI: 10.1530/ERC-11-0102
Source: PubMed


Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

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Available from: Sarah Dunlap, Dec 28, 2015
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    • "It is known to affect food intake via central actions [38], however, it also exerts peripheral actions via its receptors in peripheral tissues (such as: liver, muscle, AT, colon [7,39]) and can be present at high concentrations within peripheral tissues surrounded by the visceral fat depot. In fact, accumulating reports suggest leptin as being a key candidate linking obesity and cancer, including: (a) leptin promotes colon cancer progression and aggressiveness [7,40], cell proliferation and tumor growth [17,18]; (b) leptin promotes mammary tumors in obese mice [41]; (c) leptin receptor’s expression is increased in tumor tissues and is necessary to promote tumor progression [42]; and (d) leptin and leptin receptor levels are used to indicate breast cancer progression [43]. Indeed, our data present evidence for metabolic alterations induced by leptin in HCT116 colon cancer cells that are similar to the ones observed by the obese CM. "
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    • "cancer cells because LEP deficiency leads to reduced CSCs (Zheng et al. 2011). NANOG, SOX2, OCT4, and BMI1 were analyzed by RT-PCR. "
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    • "Zheng and others (2011) suggested that a functional obR is required in tumorous cells and that an environment with excess leptin promotes the development of the tumor. Using tumorous cells derived from a transgenic MMTV-Wnt-1 mouse that were transplanted into WT, db/db, and ob/ob mouse, leptin deficiency was found to suppress the growth of mammary, and phosphorylated Akt (p-Akt) was also dependent on leptin (Zheng and others 2011). These data suggest that both leptin and an intact leptin-signaling pathway are necessary for normal mammary gland development and for mammary gland tumorigenesis in vivo (Hu and others 2002), and elevated serum leptin levels may enhance cell signaling and promote proliferation (Cleary and others 2004). "
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