A group of immune proteins called an inflammasome may help prevent blood stem cells from becoming malignant by removing certain receptors from their surfaces and blocking the activity of cancer genes, according to a preclinical study by Weill Cornell Medicine researchers.
The study, published January 2 in nature immunologymay lead to therapies targeting the early stages of cancer. The findings reinforce the idea that the inflammasome has a dual role: it promotes inflammation associated with poor outcomes in the later stages of cancer, but in the early stages it can help prevent cells from becoming cancerous in the first place.
“What was surprising was that the innate immune system, which includes the inflammasome, has a role beyond infection,” said Dr. Julie Magarian Blander, Gladys and Roland Harriman Professor of Immunology in Medicine and member of the Jill Roberts Research Institute. . in Inflammatory Bowel Disease at Weill Cornell Medicine. “We found that it works by maintaining homeostasis in the tissue, monitoring whether stem cells proliferate too much. By doing so, it prevents cells from becoming cancerous, and this activity is independent of inflammation.”
Co-authors of the study are Dr. Andrew Kent, assistant professor of medicine and hematology at the University of Colorado School of Medicine, and Dr. Kristel Joy Yee Mon, a postdoctoral associate in Dr. Blander’s laboratory.
History of origin
When patients usually go to the doctor with symptoms of cancer, the tumors have already formed. As a result, very little is known about the beginnings of cancer.
To better understand how the disease develops, Dr. Blander and her colleagues decided to study a mouse model of B-cell lymphoma called myµ-myc, who has a mutation in the Myc oncogene. These mice have a long delay before tumors develop, giving researchers the opportunity to observe what happens in the early stages of cancer. Because B-cell lymphoma develops in a type of white blood cell, the team examined its precursors, called hematopoietic stem cells, in the mice.
Genetically alter inflammasome activity in the myµ-myc The mice greatly accelerated stem cell proliferation and tumor development. The researchers were surprised to find that stem cells in control mice lacking the inflammasome also proliferated at a rapid rate compared to wild-type mice, suggesting that the complex also plays an important role in healthy cells. The team discovered that without the inflammasome, the stem cells have high levels of the protein Ras, which is another oncogene product. This protein can work together with mutant Myc to cause cancer, so the inflammasome’s normal job of keeping Ras in check delays tumorigenesis.
Ground zero for protective activity was not the hematopoietic stem cells themselves, but the bone marrow stroma, a collection of many types of cells that surround and nourish the stem cells.
Higher levels of soluble tumor necrosis factor (TNF) receptors were found in the stroma of control mice compared to inflammasome-deficient mice. “It turned out that TNF receptors were being removed from stem cells in control mice, and were being retained in stem cells from inflammasome-deficient mice. Higher levels of TNF receptors lead to greater stem cell proliferation. Maintaining a healthy level of TNF receptors becomes important for these stem cells to maintain homeostatic control of proliferation,” said Dr. Blander. “We think the inflammasome in the stroma is orchestrating something that cleaves the TNF receptors, removing them from the stem cells.”
Next steps
Next, the team will test the protective effects of the inflammasome in other tissues. Additionally, they will determine which of the stromal cell types is responsible for the activity and which molecules the inflammasome uses to suppress cell growth.
Ultimately, researchers hope the study lays the groundwork for a therapy that prevents cancer. “A therapy could target the inflammasome, but it would have to target only the inflammatory side of its activity that is associated with tumor progression,” said Dr. Blander, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell. Medicine. “We want to protect the beneficial function of the inflammasome in delaying tumorigenesis.”