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Adipose tissue dysfunction and its effects on tumor metabolism - PubMed

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Adipose tissue dysfunction and its effects on tumor metabolism

Jonathan Diedrich et al. Horm Mol Biol Clin Investig. 2015 Jan.

Abstract

Growing by an alarming rate in the Western world, obesity has become a condition associated with a multitude of diseases such as diabetes, metabolic syndrome and various cancers. Generally viewed as an abnormal accumulation of hypertrophied adipocytes, obesity is also a poor prognostic factor for recurrence and chemoresistance in cancer patients. With more than two-thirds of the adult population in the United States considered clinically overweight or obese, it is critical that the relationship between obesity and cancer is further emphasized and elucidated. Adipocytes are highly metabolically active cells, which, through release of adipokines and cytokines and activation of endocrine and paracrine pathways, affect processes in neighboring and distant cells, altering their normal homeostasis. This work will examine specifically how adipocyte-derived factors regulate the cellular metabolism of malignant cells within the tumor niche. Briefly, tumor cells undergo metabolic pressure towards a more glycolytic and hypoxic state through a variety of metabolic regulators and signaling pathways, i.e., phosphoinositol-3 kinase (PI3K), hypoxia-inducible factor-1 alpha (HIF-1α), and c-MYC signaling. Enhanced glycolysis and high lactate production are hallmarks of tumor progression largely because of a process known as the Warburg effect. Herein, we review the latest literature pertaining to the body of work on the interactions between adipose and tumor cells, and underlining the changes in cancer cell metabolism that have been targeted by the currently available treatments.

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Conflict of interest statement

The authors disclose no potential conflicts of interest.

Figures

Figure 1
Figure 1

The proposed schematic of possible mechanisms of metabolic regulation of tumor cells by dysfunctional adipocytes in obesity The major consequence of obesity is adipose tissue inflammation and associated increases in circulating levels of lipolysis-generated lipids and pro-inflammatory cytokines and adipokines. Through paracrine, autocrine, and endocrine effects, adipocyte-derived factors activate metabolic pathways in tumor cells and facilitating growth and survival. Pathways of interest include the following: phosphoinositol 3-kinase (PI3-K) signaling cascade, hypoxia-inducible factor 1α (HIF-1α), increased glucose uptake and enhanced glycolysis, and the potentially oncogenic endoplasmic reticulum (ER stress) pathway. The stimulation of PI3-K pathway leads to downstream activation of Akt and mTOR, enhancing the transcription of genes involved in growth, proliferation and survival. PI3-K signaling can also activate c-MYC and lead to the induction of glycolytic genes. A potential crosstalk between the glycolysis pathway and the HIF-1α signaling axis potentiates HIF activity, and exacerbates the glycolytic and hypoxic phenotypes. HIF-1α signaling leads to the expression of miRNA-210, which disrupts mitochondrial integrity, affecting cellular metabolism. Additionally, FFA have the ability to disrupt mitochondrial and ER membrane integrity and cause mitochondrial dysfunction and ER stress. The interactions of the ER stress response protein, XBP-1, with HIF-1α drive the expression of HIF- and glycolysis-targeted genes. This adipocyte-driven dynamic network of events results in metabolic adaptation of tumor cells, implicating adiposity in tumor aggressiveness and chemoresistance to therapy. PI3K, phosphoinositide 3-kinase; AKT, protein kinase b; mTOR, mammalian target of rapamycin; c-MYC, myc proto-oncogene; HIF-1α, hypoxia-inducible factor 1; HK2, hexokinase 2; PKF, phosphofructokinase; GAPDH, glyceralaldehyde-3-phosphate dehydrogenase; PKM2, pyruvate kinase isoform; LDHα, lactate dehydrogenase; FFA, free fatty acids; miR-210, micro RNA 210.

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