Obesity increases cancer risk by anywhere from 10% to 300% depending on the type of cancer.1
Obesity is also often associated with a poor prognosis, including higher risk of recurrence. For example, obesity (BMI >30) increases mortality in prostate cancer by about 25%2
and in breast cancer by about 35%.3
Similarly, in colon cancer, the very obese (with a BMI >35) face a 38% greater chance that their cancer will return after treatment.4
Given the current obesity epidemic and an aging population susceptible to cancer, significant efforts are being undertaken to understand the foundations of the obesity-cancer link. Today, we have an emerging picture of how obesity creates a tumorigenic environment through inflammation, altered adipokines, metabolic changes, and reshaping the microbiome.
Obesity increases the abundance of proinflammatory macrophages in adipose tissue, which release cytokines including TNF, IL-6, and IL-1β. These signaling molecules promote a number of cell events that promote tumorigenesis, including survival, proliferation, DNA damage, angiogenesis, and invasiveness. This multitude of procancer effects has led to recognition of inflammation as a fuel that feeds the flame of cancer progression.
Large amounts of adipose tissue lead to high levels of the hormone leptin, which directly enhances angiogenesis and activates a gene expression program that supports cell proliferation, survival, and invasiveness. Obesity also decreases levels of adiponectin, a hormone with significant antiangiogenic and tumor growth-limiting properties.
The metabolic changes that follow increased adiposity include hyperinsulinemia and hyperglycemia, both of which favor cancer development. Insulin intrinsically promotes cell growth and inhibits apoptosis. Hyperglycemia enhances glycolysis, increasing energy supplies in tumor cells, and activates a pathway that enables survival despite hypoxia.
Finally, in many obese patients, the consumption of a high fat, low fiber diet alters the gut microbiota, which may worsen metabolic imbalances and enhance inflammation. Studies in mice suggest that these changes affect host gene expression to increase fat storage and intestinal permeability, which exacerbates inflammation by enhancing absorption of endotoxins.
Our laboratory has had a long-term interest in the protein p62. Since our initial discovery of the ubiquitously expressed protein, we have shown that p62 is an adapter that creates protein-protein complexes to produce key cellular signals. Our research so far, summarized here, suggests that p62 may represent a link connecting obesity, inflammation, and progression of certain cancers. By studying p62, we aim to delineate how various signaling pathways are altered in these conditions, which could lead to interventions that break the link and limit cancer risk.
p62 in Obesity
p62 plays a key role in controlling metabolism, limiting adiposity and maintaining normal responses to glucose. Loss of p62 leads to enhanced activity of the kinase ERK1, promoting insulin resistance and decreasing metabolic rate.5
The latter effect results from an increase in the ratio of white to brown adipose tissue, favoring fat storage over energy consumption.6