Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation

Abstract

There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. MethodsWe review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. ResultsLocally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. ConclusionThe tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.

FGFR1 underlies obesity-associated progression of estrogen receptor–positive breast cancer after estrogen deprivation

“…Another critical finding is the identification of pathways associated with ER-positive tumor promotion in the context of obesity, despite estrogen deprivation -namely, FGFR1 signaling. Inflamed adipose tissue is known to produce estrogen through elevated aromatase production by stromal cells (51,53,54). While this estrogen-dependent scenario is likely to contribute to the increased incidence of ER-positive disease in women with obesity, it is unclear whether elevated estrogen contributes to poor outcomes after treatment.…”

Insights into the Link Between Obesity and Cancer

“…Inflammation and expansion of the adipose tissue in the setting of obesity mimics chronic tissue injury, with an influx of immune cells, such as macrophages, T cells, and NK cells [56][57][58], production of pro-inflammatory mediators, tissue remodeling, and angiogenesis [56]. Some tumors such as breast, prostate, and gynecologic cancers develop within adipose tissue.…”

Crown-like Structures in Breast Adipose Tissue from Normal Weight Women: Important Impact

“…The Dannenberg laboratory has demonstrated the presence of CLS in WAT of the breast (CLS-B) in women with and without breast cancer, as well as in the noninvolved breast in women with breast cancer (16). CLS number and density increased with body mass index (BMI) and increased adipocyte size.…”

“…Proinflammatory ATMs generate reactive oxygen species and reactive nitrogen species (5), both of which are potential mutagens. CLSs are associated with NF-kB activation and secretion of multiple inflammatory factors, including TNFa, IL1b, IL6, and COX-2-derived prostaglandin E2 (5,6,16). A variety of additional important immune abnormalities occur in inflamed adipose tissue (5).…”