Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.
“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an email to Medscape Medical News.
“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.
The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.
Tissue samples were obtained from 38 lean and 61 individuals who were obese, and further divided into those with or without colon cancer.
A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Catalan elaborated.
Investigators also found upregulated levels of IL-1β in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.
Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.
“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Catalan cautioned.
Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 — its main effector in the intestine — has been associated with increased mortality in colorectal cancer.
“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.
Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Catalan observed.
The researchers speculate that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1β is currently an important area of research.
Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1β antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1β receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1β signaling, Catalan pointed out.
Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Catalan speculated.
“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers commented.
European Congress on Obesity. Abstract 0400. Presented May 10, 2021.