Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

Abstract

Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one‐third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta‐analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity‐induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer‐associated genetic instability. In addition, the by‐products of the oxidative degradation of lipids (e.g., malondialdehyde, 4‐hydroxynonenal, and acrolein), and gut microbiota‐mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity‐related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity‐related cancers.

The Exposome in Human Evolution: From Dust to Diesel

“…Although these obese subjects lacked clinical indications of infections, low-grade bacterial and viral infections could still contribute elevated cytokine production in adipose-embedded macrophages. With or without infections, we suggest that obesity be recognized as a major proinflammatory factor in the modern exposome that contributes to major diseases of aging, including cancer (Kompella and Vasquez 2019), cardiovascular disease (Packer 2018), and dementia (Finch and Kulminski 2019), among other pathogenic processes of aging (Pérez et al 2016).…”

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

“…Another possible pathway correlating obesity with cancer development is genetic instability through oxidative stress-induced DNA damage and impaired DNA repair pathways. 115 Multiple preclinical studies show that obesity causes DNA damage in multiple organs, including brain, liver, colon, and testes. 116 Obesity may directly impact oncogenic mutation rates to rewire metabolic pathways and enhance the proliferative capacity of malignant cells to promote their survival.…”

“…116 Obesity may directly impact oncogenic mutation rates to rewire metabolic pathways and enhance the proliferative capacity of malignant cells to promote their survival. 115,117,118 However, a lack of longitudinal, mechanistic studies makes it difficult to draw direct links. Additionally, obesity can promote glycolytic cancer cell metabolism through changes in sex hormone levels, inflammatory signals, metabolic signals (eg, insulin and IGF-1), and/or adipokine hormone levels.…”

“…In humans, obesity is associated with an increased risk for developing 13 different types of cancer, including renal and postmenopausal breast, but it is not known whether these trends are due to obesity‐associated decreases in immune surveillance by T cells and other cytotoxic leukocytes, such as natural killer (NK) cells. Another possible pathway correlating obesity with cancer development is genetic instability through oxidative stress‐induced DNA damage and impaired DNA repair pathways . Multiple preclinical studies show that obesity causes DNA damage in multiple organs, including brain, liver, colon, and testes .…”

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

“…For instance, obesity increases inflammatory factors and adipokines (TNF, leptin, IL-1β and IL-6), subsequently promoting oxidative stress and suppressing the immune system. These alterations often end up in aberrant cell signaling, increased cell growth and angiogenesis [10,11]. Disturbances in DNA damage levels, antioxidant status and capacity for DNA repair result in the accumulation of mutations and genomic instability.…”