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Investigating the Role of Inflammasome in Cancer Prevention

A recent study led by researchers at Weill Cornell Medicine has revealed that a group of immune proteins known as the inflammasome plays a crucial role in preventing blood stem cells from becoming cancerous. This mechanism is achieved by eliminating specific receptors from the cells’ surfaces and inhibiting cancer-related gene activity.

Published on January 2 in Nature Immunology, this groundbreaking research could pave the way for new therapies aimed at the earliest stages of cancer development. The findings support the emerging understanding of the inflammasome’s dual function; while it is known to contribute to inflammation linked with poor cancer outcomes at advanced stages, it appears to prevent initial carcinogenesis in early stages.

“What struck us was the expanded role of the innate immune system, particularly the inflammasome, which extends beyond just responding to infections,” explained Dr. Julie Magarian Blander, the Gladys and Roland Harriman Professor of Immunology in Medicine and a researcher at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. “Our research suggests it is also essential for maintaining tissue stability by monitoring stem cell activity. This function helps avert the transformation into cancerous cells, and notably, this occurs independently of inflammatory processes.”

The study’s co-first authors, Dr. Andrew Kent from the University of Colorado School of Medicine and Dr. Kristel Joy Yee Mon, a postdoctoral researcher in Dr. Blander’s lab, contributed significantly to these findings.

Understanding Cancer’s Origins

Typically, by the time individuals seek medical attention for cancer symptoms, significant tumor development has already occurred, complicating efforts to understand the early stages of the disease.

To better grasp how cancer initiates, Dr. Blander and her team focused on a mouse model of B-cell lymphoma known as Eµ-myc, which harbors a mutation in the Myc oncogene. This model is advantageous as tumors take a notably long time to manifest, allowing researchers to investigate the preliminary stages of cancer development. The research specifically examined hematopoietic stem cells, the precursors to B-cell lymphomas, within these mice.

The team observed that genetically altering inflammasome function in the Eµ-myc mice significantly sped up stem cell growth and tumor formation. Furthermore, they discovered that stem cells in control mice with an intact inflammasome had lower proliferation rates compared to those lacking the inflammasome, indicating its critical function even in healthy cells. The absence of the inflammasome resulted in elevated levels of the Ras protein, another oncogene product that can cooperate with mutant Myc to facilitate cancer development. Thus, the inflammasome serves to regulate Ras levels, postponing the onset of tumors.

Interestingly, the protective role of the inflammasome is not localized to the hematopoietic stem cells themselves; it instead operates within the bone marrow stroma, a supportive environment composed of various cell types around the stem cells.

In their findings, researchers noted that soluble tumor necrosis factor (TNF) receptors were present in greater quantities in the stroma of control mice compared to those that were deficient in inflammasomes. “Our observations revealed that in control mice, TNF receptors were being shed from stem cells, while inflammasome-deficient mice retained these receptors. Elevated levels of TNF receptors are linked to increased stem cell proliferation, highlighting the importance of maintaining balanced TNF receptor levels for homeostatic control of stem cell growth,” Dr. Blander noted. “We hypothesize that the inflammasome plays a role in this context by cleaving TNF receptors off the stem cells.”

Future Directions

The research team plans to further explore the protective effects of the inflammasome in other tissues. They are also interested in identifying which types of stromal cells are involved in this process and the specific molecules that enable the inflammasome to suppress cell proliferation.

The long-term goal of this research is to establish a foundation for potential therapies that could reduce cancer risk. “A targeted therapeutic approach could focus on the inflammasome’s inflammatory activities associated with tumor progression, while preserving its beneficial role in preventing tumorigenesis,” Dr. Blander remarked. She is also affiliated with the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It is vital to maintain the inflammasome’s protective functions against cancer development.”

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