“Inflammasomes” may play a role in obesity-related CRC

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Protein complexes called inflammasomes, which are part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity. colon cancer, if not other cancers, according to new research.

“Population-based studies have shown that individuals prone to developing chronic inflammatory diseases have an increased risk of cancer and inflammasomes play an important role in the development of cancer, showing actions to promote or suppress the tumor according to type one. specific inflammasome involved and downstream effector molecules “, explained Victoria Catalan, PhD, Institute of Health Research of Navarra, Pamplona, ​​in an e-mail to Medscape Medical News.

“Therefore, inflammasomes are not only implicated in obesity-associated colon cancer, but their role may be more relevant in patients with obesity“, added.

The new research was presented during the recent European Congress on Obesity, held virtually due to the pandemic.

Tissue samples

Tissue samples were obtained from 38 lean individuals and 61 who were obese and divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase the levels of gene expression of the proteins NLRP3, NLRP6, ASC and NOD2 in visceral adipose tissue (IVA), “suggesting that inflammation of the visceral adipose tissue associated with obesity creates a favorable microenvironment for the development of colon cancer “, elaborated the Catalan.

The researchers also found regulated levels of IL-1β in VAT in obese and colon cancer individuals, an observation that strengthens the hypothesis that the production of these inflammasome-dependent cytokines may influence colon tumorigenesis. add.

Catalan noted that his team has done so previously shown which blocks 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 non-alcoholics fatty liver disease.

“Whether obesity has an impact on colon cancer through the improvement of inflammation or through a direct mechanism is not very clear and the role of inflammasomes in the development of cancer is still controversial,” the Catalan warned.

However, the study showed that tissue samples from colon cancer patients were associated with reduced expression of NLRP6 i EL 18. Catalan explained that NLRP6 is an important factor in the response to intestinal lesions that regulates aspects of the healing of inflammation. The same protein is also linked to epithelial integrity and loss of NLRP6, and IL-18, its major effector in the gut, has been associated with increased mortality in colon cancer.

“Therefore, reduced expression of NLRP6 i EL 18 in the colon of patients with colon cancer suggests an alteration in the regulation of the inflammatory cascade and a decrease in the integrity of the intestinal barrier “, suggested Catalan. The same experiment revealed that the levels of gene expression of adiponectin , an anti-inflammatory protein produced by adipose similarly reduced VAT in obese people and in people with colon cancer.

In turn, low levels of adiponectin have been linked to an increased risk of colorectal cancer, Catalan noted. But it has also recently been shown that normal adiponectin levels inhibit the growth of colorectal cancer cells. “It is very important to keep in mind that inflammasomes have contrasting roles in tumorigenesis, demonstrating harmful and beneficial effects,” said the Catalan.

Researchers speculate that NLRP3 agonists may improve immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For example, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair after the development of colon cancer triggering the reepithelialization process. Currently, the development of NLRP3 antagonists that can block the IL-1β signaling pathway is an important area of ​​research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing antibody of IL-1β canakinumab (Ilaris, Novartis), and the soluble decoy IL-1β receptor rilonacept (Arcalyst, Regeneron) are being evaluated as a strategy to block IL-1β signaling, the Catalan noted.

Several inhibitors of the NLRP3 inflammasome are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could provide a [viable] treatment option in a wide range of chronic and autoinflammatory diseases for which there are currently no adequate therapies “, speculated Catalan.

“Strategies to restore the immunosurveillance functions of inflammasome components could represent an interesting goal to identify and treat obese patients at increased risk of developing colon cancer,” the researchers commented.

European Congress on Obesity. Summary 0400. Filed May 10, 2021.

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