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 (MMTV)-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin-receptor deficient (db/db) mice grow to 8-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 to WT or db/db mice. Further, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the leptin receptor (LepRb), compared to 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.
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.
Transforming growth factor beta1 (TGF-b1) suppresses tumor development at early stages of cancer, but enhances tumor invasion and formation of metastasis. TGF-b1-mediated tumor invasion is associated with epithelial to mesenchymal transition (EMT) and matrix proteolysis. The mechanisms of these TGF-b1 responses in normal and tumor cells are not well understood. Recently, we have reported that TGF-b1 increases expression of high-molecular weight tropomyosins (HMW-tropomyosins) and formation of actin stress fibers in normal epithelial cells. The present study investigated the role of tropomyosin in TGF-b1-mediated cell motility and invasion. We found that TGF-b1 restricts motility of normal epithelial cells although it promotes EMT and formation of actin stress fibers and focal adhesions. Cell motility was enhanced by siRNA-mediated suppression of HMW-tropomyosins. TGF-b1 stimulated migration and matrix proteolysis in breast cancer MDA-MB-231 cells that express low levels of HMW-tropomyosins. Tet-Off-regulated expression of HMW-tropomyosin inhibited cell migration and matrix proteolysis without affecting expression of matrix metalloproteinases. Tropomyosin increased cell adhesion to matrix by enhancing actin fibers and focal adhesions. Finally, tropomyosin impaired the ability of tumor cells to form lung metastases in SCID mice. Thus, these results suggest that HMW-tropomyosins are important for TGFb-mediated control of cell motility and acquisition of the metastatic potential. ' 2007 Wiley-Liss, Inc.Key words: tropomyosin; TGF-beta; actin filaments; invasion; migration Transforming growth factor b (TGF-b) cytokines are critical for embryonic development, normal homeostasis and human diseases including chronic fibrosis and cancer. 1 Although TGF-b1 is a potent tumor suppressor, malignant cancers frequently express high levels of TGF-b1. [2][3][4] The experimental evidence implicate TGF-b1 signaling in promoting tumor progression and metastasis via induction of epithelial to mesenchymal transition (EMT), cell migration and matrix proteolysis. 1 EMT and cell migration play critical roles during morphogenesis and organogenesis, as well as in wound healing, chronic fibrosis and cancer progression (reviewed in Ref. 5). EMT is associated with disintegration of the polarized epithelial architecture leading to dissociation of cellular contacts and remodeling the cellular filamentous structures such as actin filaments. Depending on cellular context, TGF-b can induce EMT alone 6,7 or in cooperation with other factors including oncogenic Ras 8 and TNF-alpha. 9 The mechanism of EMT in response to TGF-b1 requires de-novo protein synthesis and transcription. 10,11 Signaling pathways mediated by Smads, PI3 kinase and mitogen-activated protein (MAP) kinases (p38 MAPK, ERK) have been implicated in EMT induced by . It is generally considered that EMT increases motility and invasiveness of cells. TGF-b1-mediated EMT in mammary epithelial cells expressing active Ras increases cell motility and invasion. 8 However, several studies ind...
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