A set of immune proteins known as the inflammasome may play a crucial role in stopping blood stem cells from turning cancerous by eliminating specific receptors from their surfaces and inhibiting the actions of cancer-related genes, according to a recent preliminary study conducted by investigators at Weill Cornell Medicine.
A set of immune proteins known as the inflammasome may play a crucial role in stopping blood stem cells from turning cancerous by eliminating specific receptors from their surfaces and inhibiting the actions of cancer-related genes, according to a recent preliminary study conducted by investigators at Weill Cornell Medicine.
The findings of the study, released on January 2 in Nature Immunology, could pave the way for new treatments targeting the very early stages of cancer. This research reinforces the notion that the inflammasome serves dual purposes: although it may encourage inflammation that leads to negative outcomes in advanced cancer, it also has a protective effect in the early stages, preventing cells from becoming cancerous in the first place.
“It was surprising to discover that the innate immune system, including the inflammasome, plays a role beyond just fighting infections,” said Dr. Julie Magarian Blander, the Gladys and Roland Harriman Professor of Immunology in Medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. “We observed that it helps maintain tissue balance, monitoring whether stem cells are over-proliferating, thereby preventing cells from turning cancerous—independently of any inflammatory process.”
The study’s co-first authors are Dr. Andrew Kent, an assistant professor of medicine-hematology at the University of Colorado School of Medicine, and Dr. Kristel Joy Yee Mon, a postdoctoral associate in Dr. Blander’s lab.
Background
Often, by the time patients seek medical help for cancer symptoms, tumors have already developed. Consequently, there’s limited understanding of how cancer initially starts.
To gain insights into the onset of the disease, Dr. Blander and her team investigated a mouse model for B-cell lymphoma known as Eµ-myc, which contains a mutation in the Myc oncogene. These mice take a significant amount of time before tumors manifest, allowing researchers to observe the early phases of cancer development. Since B-cell lymphoma originates in a specific type of white blood cell, the researchers focused on their precursors, termed hematopoietic stem cells, within these mice.
By genetically disrupting the function of the inflammasome in the Eµ-myc mice, researchers noted a significant increase in stem cell proliferation and tumor formation. Surprisingly, stem cells in control mice that lacked the inflammasome also exhibited rapid proliferation in comparison to wild-type mice, indicating that the inflammasome is crucial even for normal cell functionality. The team discovered that the absence of the inflammasome resulted in elevated levels of the Ras protein in stem cells, known for its oncogenic properties. This protein can interact with mutant Myc to promote cancer development, thus the inflammasome’s role in regulating Ras levels is vital in delaying tumor formation.
The key area for this protective function was not the hematopoietic stem cells but rather the bone marrow stroma—a diverse group of cell types that surround and support the stem cells.
In control mice, there were elevated levels of soluble tumor necrosis factor (TNF) receptors in the stroma compared to those deficient in the inflammasome. “We discovered that TNF receptors were released from the stem cells in control mice, while they were retained in stem cells of inflammasome-deficient mice. Higher TNF receptor levels corresponded with increased stem cell proliferation. Therefore, maintaining appropriate levels of TNF receptors is essential for these stem cells to control their growth effectively,” Dr. Blander explained. “We believe the inflammasome in the stroma plays a regulatory role by trimming TNF receptors off the stem cells.”
Future Directions
The next step for the research team is to assess the inflammasome’s protective capabilities in other tissues. They will also identify which stromal cell types are responsible for this activity and determine the molecules involved in the inflammasome’s growth-suppressing effects.
Ultimately, the researchers aim for this study to establish a foundation for therapies that could prevent cancer. “A treatment might aim at the inflammasome, but it should focus solely on the inflammatory aspect linked to tumor development,” stated Dr. Blander, who is also affiliated with the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It is crucial to preserve the inflammasome’s protective role in delaying tumor formation.”
