A weighty problem: metabolic perturbations and the obesity-cancer link

Abstract

Obesity is an established risk factor for several cancers, including breast, colon, endometrial, ovarian, gastric, pancreatic and liver, and is increasingly a public health concern. Obese cancer patients often have poorer prognoses, reduced response to standard treatments, and are more likely to develop metastatic disease than normo-weight individuals. Many of the pathologic features of obesity promote tumor growth, such as metabolic perturbations, hormonal and growth factor imbalances, and chronic inflammation. Although obesity exacerbates tumor development, the interconnected relationship between the two conditions presents opportunities for new treatment approaches, some of which may be more successful in obese cohorts. Here, we discuss the many ways in which excess adiposity can impact cancer development and progression and address potential preventive and therapeutic strategies to reduce the burden of obesity-related cancers.

Figure 1

Obesity directly impacts a multitude of systems that are involved in tumor development and progression. Obesity causes many metabolic disturbances including excess blood glucose, insulin, and lipid levels, which can provide fuel and molecular precursors for synthetic pathways in proliferating tumor cells, and obesity is strongly correlated to insulin resistance. Excess adipose tissue can result in fatty acid deposits in both the liver and pancreas, causing NAFLD and NAFPD, both of which are significant risk factors for hepatocellular carcinoma and pancreatic cancer, respectively. Excess adipose tissue alters production of many hormones including increased levels of leptin, insulin, and estrogen, all of which can promote cancer development and decreased adiponectin, which is tumor suppressive. Obesity results in increased IGF-1, a major tumor promoter, activating a broad spectrum of intracellular signals associated with cancer cell growth, proliferation, survival, and migration. VEGF and PAI-1, key angiogenic factors, are also increased in the obese state. As in metabolic syndrome, obesity is characterized by a chronic, low level of inflammation, both locally (as macrophages recruited to necrotic adipocytes) and systemically (as dying adipocytes releasing free fatty acids and immune modulators such as TNF-α, IL-6, and MCP-1 into the circulation). Fatty acid deposits and an inflammatory microenvironment can cause several inflammatory lesions such as pancreatitis, gastritis, hepatitis, and IBD that lead to cancer development. A chronic state of inflammation will also promote tumor progression in cancers driven by other mechanisms. Obesity is linked with alterations in the intestinal microbiome, decreasing bacterial diversity, impairing gut barrier function, and increasing local inflammation.