Abstract
Obesity and the resultant metabolic complications have been associated with an increased risk of cancer. In addition to the systemic metabolic disturbances in obesity that are associated with cancer initiation and progression, the presence of adipose tissue in the tumor microenvironment (TME) contributes significantly to malignancy through direct cell-cell interaction or paracrine signaling. This chronic inflammatory state can be maintained by p53-associated mechanisms. Increased p53 levels that are observed in obesity exacerbate the release of inflammatory cytokines that fuel cancer initiation and progression. Dysregulated adipose tissue signaling from the TME can reprogram tumor cell metabolism. The links between p53, cellular metabolism and adipose tissue dysfunction and how they relate to cancer, will be presented in this review.
Highlights
Cancers associated with obesity are estimated to account for up to 40% of all cancers diagnosed in the US (Centers for Disease Control and Prevention, CDC)
The bone marrow contains few adipocytes at birth, the number increases with age, and by adulthood, bone marrow adipose tissue constitutes over 10% of the total fat mass in lean, healthy humans
Using a murine model of diet-induced obesity (DIO) weight gain was reduced in p53-null mice, and the mechanism was through an increase in uncoupling protein 1 (UCP1) expression, both in brown and white adipose tissue [77]
Summary
Cancers associated with obesity are estimated to account for up to 40% of all cancers diagnosed in the US (Centers for Disease Control and Prevention, CDC). Its significant role in tumor suppression is dependent on its activity as a transcription factor regulating expression of genes in cell cycle regulation, apoptosis, DNA repair, differentiation, and senescence pathways (Figure 1). Transcription-dependent functions of p53 play a key role in cell-fate decisions by regulating expression of genes that control cell cycle arrest, DNA repair, apoptosis, senescence, and autophagy to limit the propagation of cells with damaged genomes [33,34,35,36]. In contrast to increased proliferation observed in cancer cells upon the loss of p53, the response of Drosophila Myc+ cells to p53 loss is impaired metabolism and reduced viability, suggesting a cell-context dependent regulation of cellular processes. Obesity is recognized as a state of dysregulated cell metabolism, and p53 is influential in adipose tissue differentiation, accumulation, and cytokine secretion
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