Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models

Bowers, Laura W.; Rossi, Emily L.; McDonell, Shannon B.; Doerstling, Steven S.; Khatib, Subreen A.; Lineberger, Claire G.; Albright, Jody; Tang, Xiaohu; deGraffenried, Linda A.; Hursting, Stephen D.

doi:10.1158/1541-7786.mcr-17-0508

Cited by 59 publications

(53 citation statements)

References 48 publications

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“…Sox2 has been shown to increase CSCs, enhance tumor cell invasion, and promote tamoxifen resistance in breast cancer lines [37,38]. Leptin, which is secreted by adipocytes and significantly enhanced in obesity, has been shown to promote CSCs [39], potentially through regulation of Notch signaling [40]. Adipocytes may also induce invasive and aggressive tumor cell behavior through secretion of cytokines [25], and we have previously observed that adipose-derived stromal cells isolated from the mammary glands of obese mice enhanced local invasion of Met-1 and EO771 cells through secretion of insulin-like growth factor-1 [41].…”

Section: Discussionmentioning

confidence: 99%

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

Hillers‐Ziemer

McMahon

Hietpas

et al. 2020

Cancers

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Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

Hillers‐Ziemer

McMahon

Hietpas

et al. 2020

Cancers

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“…In addition to its effect on breast cancer growth, leptin may also play an important role in bone metastasis. A growing body of evidence shows that leptin may promote epithelial to mesenchymal transition (EMT) by up-regulating the expression of EMT-and metastasis-related genes (Twist2, Foxc2, Vim, Akt3, and Sox2) in the mouse mammary tumour virus (MMTV)-Wnt-1 transgenic mouse model of triple-negative breast cancer [72], highlighting the potential roles of leptin in metastasis development. Bowers and colleagues hypothesized that regulation of the EMT gene, via stimulation of the JAK2/STAT3 and/or PI3K/AKT pathways, may mediate the leptin-induced CSC/EMT-related phenotype.…”

Section: Leptin and Bone Metastasismentioning

confidence: 99%

“…Tumourigenesis + [60,121,122] − [123][124][125] + [94,125] Tumour progression + [126][127][128] − [42,50,129] or + [51,130] + [96,125] Cancer cell invasion + [131,132] − [50,74] or + [130,133] + [134] Metastasis + [72,135] − [50] or + [51] + [134] Angiogenesis + [65,136,137] − [138] or + [139,140] ?…”

Section: Breast Cancer Progress Leptin Adiponectin Sam68mentioning

confidence: 99%

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Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Maroni

2020

IJMS

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The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

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“…There is some evidence that breast cancer patients with metabolic pathologies, such as diabetes and obesity, are less responsive to therapies and have a higher overall mortality rate, with hyperglycemia appearing to be responsible for this. It is also possible that the excess leptin production leads to an upregulation of the leptin receptor and subsequent stimulation of the JAK2/STAT3 or PI3K/AKT signaling pathways via the gene regulation of Foxc2, Twist2, Vim, Akt3, and Sox2 to a CSC/EMT phenotype determined in triple-negative breast cancer cells (178). Additionally, suppression of the pyruvate dehydrogenase (PDH) complex ( Figure 2U) via oncogenic microRNA-27b can deregulate breast cancer growth by shifting the metabolism from oxidative phosphorylation toward glycolysis, thus negatively affecting patient survival (151).…”

Section: The Metabolism Of Cancer Cell Metastasismentioning

confidence: 99%

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

2020

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Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO 2 , and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

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Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models

Abstract: 34Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). 35Preclinical models of TNBC were used to test the hypothesis that increased leptin 36 signaling drives obesity-associated TNBC development by promoting cancer stem cell

Cited by 59 publications

References 48 publications

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

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