A group of immune proteins called the inflammasome can protect against premalignant-to-malignant transformation of blood stem cells in cancer.
The inflammasome has a role in maintaining tissue homeostasis, blocking the activity of a protein usually associated with malignancy and protecting against the premalignant proliferation of haematopoietic stem cells (HSCs), or blood stem cells, according to a study published in Nature Immunology. The findings suggest the inflammasome as a potential target of future therapies in the earlier stages of cancer.
'What was striking was that the innate immune system, which includes the inflammasome, has a role beyond infection,' said Professor Julie Blander, from Weill Cornell Medicine, New York, and co-author of the study. 'We found that it functions in maintaining homeostasis in the tissue, keeping an eye on whether stem cells are proliferating too much. By doing so, it prevents cells from becoming cancerous and this activity is independent of inflammation.'
Researchers used a mouse model of B-cell lymphoma, a type of cancer that affects white blood cells. This model, called Eµ-myc has a genetic change in the Myc oncogene (a gene linked to cancer growth), making it easier to study how this cancer develops and behaves.
The model has a characteristic prolonged premalignant stage, before spontaneous tumours develop, allowing the researchers to focus on immune regulation in the earlier stages of cancer. Less is known about this stage in humans, as patients usually only present clinically when their cancer has reached later, malignant stages. The researchers focused on HSCs, the precursors of white blood cells, found within the stroma of the bone marrow.
Genetically modified Eµ-myc mice, inflammasome-deficient, had increased proliferation of HSCs within the bone marrow and a shorter premalignant stage, leading to a faster onset of malignancy compared to control mice. Researchers found HSCs within these mice had higher levels of a protein called Ras, an oncogenic product, which commonly cooperates with Myc to drive cancer. Heightened Ras caused increased levels of cytokine, chemokine and growth factor receptors on HSCs which led to hastened malignancy.
Increased proliferation of premalignant HSCs was also seen in control mice that were inflammasome-deficient. The team concluded that the inflammasome within the stroma maintains tissue homeostasis by inhibiting Ras and its effect on proliferation of HSCs, protecting against premalignant-to-malignant transformation.
The team now plans to research the function of the inflammasome within different tissue types and propose that, in the future, the inflammasome could be a cellular target for therapy in premalignant stages of cancer.
'A therapy could target the inflammasome, but it should be directed only to the inflammation side of its activity that is associated with tumour progression,' added Professor Blander. 'You want to protect the inflammasome's beneficial function of delaying tumorigenesis.'
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