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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    • "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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    ABSTRACT: Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Here we hypothesize that obesity results in secreted products from adipose tissue that induce malignancy-related metabolic alterations in colon cancer cells. Human HCT116 colon cancer cells, were exposed to conditioned media from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, mostly mitochondrial respiration) and extracellular acidification rate (ECAR, mostly lactate production via glycolysis) were examined vis-à-vis cell viability and expression of related genes and proteins. Our results show that conditioned media from obese (vs. non-obese) subjects decreased basal (40%, p<0.05) and maximal (50%, p<0.05) OCR and gene expression of mitochondrial proteins and Bax without affecting cell viability or expression of glycolytic enzymes. Similar changes could be recapitulated by incubating cells with leptin, whereas, leptin-receptor specific antagonist inhibited the reduced OCR induced by conditioned media from obese subjects. We conclude that secreted products from the adipose tissue of obese subjects inhibit mitochondrial respiration and function in HCT116 colon cancer cells, an effect that is at least partly mediated by leptin. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues.
    PLoS ONE 09/2013; 8(9):e74843. DOI:10.1371/journal.pone.0074843 · 3.23 Impact Factor
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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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    ABSTRACT: Despite new therapies, breast cancer continues to be the second leading cause of cancer mortality in women a consequence of recurrence and metastasis. In recent years, a population of cancer cells has been identified, called cancer stem cells (CSCs) with self-renewal capacity, proposed to underlie tumor recurrence and metastasis. We previously showed that the adipose tissue cytokine LEPTIN, increased in obesity, promotes the survival of CSCs in vivo. Here, we tested the hypothesis that the Leptin Receptor (LEPR), expressed in mammary cancer cells, is necessary for maintaining CSC-like and metastatic properties. We silenced LEPR via shRNA lentivirus transduction and determined that expression of stem cell self-renewal transcription factors NANOG, SOX2, and OCT4 are inhibited. LEPR-NANOG signaling pathway is conserved between species because we can rescue NANOG expression in human LEPR-silenced cells with the mouse LepR. Using a NANOG promoter GFP reporter, we showed that LEPR is enriched in NANOG promoter active (GFP+) cells. Using lineage tracing, we showed that the GFP+ cells exhibit symmetric and asymmetric division and cell death. LEPR silenced MDA-MB-231 cells exhibit a mesenchymal to epithelial transition morphologically, increased E-CADHERIN and decreased VIMENTIN expression compared to control cells. Finally, LEPR silenced cells exhibit reduced cell proliferation, self-renewal in tumorsphere assays, and tumor outgrowth in xenotransplant studies. Given the emergence of NANOG as a pro-carcinogenic protein in multiple cancers, these studies suggest that inhibition of LEPR may be a promising therapeutic approach to inhibit NANOG and thereby neutralize CSC functions.
    Endocrine Related Cancer 09/2013; 20(6). DOI:10.1530/ERC-13-0329 · 4.81 Impact Factor
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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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    ABSTRACT: Obesity is a world health problem that increases the risk for developing type 2 diabetes, cardiovascular disease, fatty liver, and some types of cancer. In postmenopausal women, it represents an important risk factor for the development of breast cancer (BC). Leptin is an adipokine that is secreted by fatty tissue, and high leptin levels are observed both in mouse models of obesity and in obese subjects. High levels of leptin promote the proliferation and progression of various types of cancer, including BC. This review provides a general overview of the biology of leptin, important laboratory studies, and animal and clinical models that have provided evidence for an active role of leptin in the proliferation, progression, and survival of mammary tumors. Finally, this review addresses the most recent studies on the use of leptin receptor antagonists as a novel therapeutic treatment for BC.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 07/2013; 33(12). DOI:10.1089/jir.2012.0168 · 2.00 Impact Factor
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