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Chronic inflammation, a persistent state of immune activation, has long been recognized as a major contributor to cancer development worldwide. An estimated 20% of all cancers are linked to chronic inflammation caused by infections, autoimmune diseases, or environmental irritants. Now, researchers have uncovered a key molecular pathway that links inflammation to cancer and discovered that a common class of cholesterol-lowering drugs called statins can disrupt this dangerous connection.
The study, published in Nature Communications and led by researchers from Massachusetts General Hospital and Harvard Medical School, focused on a protein called interleukin-33 (IL-33). IL-33 acts as an “alarmin” - it's released by damaged cells to alert the immune system of trouble. In normal circumstances, this triggers a helpful inflammatory response to combat infection or promote healing. However, in chronic inflammation, IL-33 levels remain persistently high, creating an environment that nurtures tumor development.
How scientists found link between statins, cancer development
The researchers found that IL-33 production is switched on by a signaling cascade involving proteins called toll-like receptors (TLRs), TBK1, and IRF3. TLRs sit on the surface of cells and detect molecular patterns associated with pathogens or cell damage. When activated, they relay the signal inside the cell, eventually causing IRF3 to enter the nucleus and turn on the IL-33 gene.
Crucially, the researchers discovered that pitavastatin, a member of the statin drug class, can throw a wrench into this inflammatory machinery. Statins are widely prescribed to lower cholesterol levels and prevent heart disease. They work by blocking an enzyme called HMG-CoA reductase, which plays a central role in cholesterol production.
But statins also deplete a molecule called geranylgeranyl diphosphate (GGPP). The researchers found that GGPP is required for TBK1, a key component of the inflammatory signaling cascade, to anchor to the cell membrane and become activated. By reducing GGPP levels, pitavastatin prevents TBK1 activation, thereby shutting down IL-33 production.
In mouse models of inflammatory skin conditions and pancreatitis (a risk factor for pancreatic cancer), pitavastatin treatment significantly reduced inflammation and IL-33 levels. In mice genetically engineered to develop pancreatic cancer, pitavastatin slowed tumor progression and extended survival.
The clinical relevance of these findings was underscored by the analysis of human pancreatic cancer samples, which showed high levels of IRF3 and IL-33 in cancerous and inflamed tissues. Importantly, patient data revealed that individuals taking pitavastatin had a markedly lower risk of developing pancreatitis and pancreatic cancer compared to those taking a different class of cholesterol-lowering drugs.
What's needed to repurpose these drugs?
This study sheds new light on how chronic inflammation fuels cancer development and uncovers a surprising anti-inflammatory benefit of a widely used class of medications. Statins, with their well-established safety profile and low cost, could potentially be repurposed as chemopreventive agents for individuals at high risk of developing inflammation-associated cancers.
“Chronic inflammation is a major cause of cancer worldwide,” says senior author Dr. Shawn Demehri, a principal investigator at the Center for Cancer Immunology and Cutaneous Biology Research Center of Massachusetts General Hospital, in a statement. “We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas.
“Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath,” adds Demehri, who is also an associate professor of Dermatology at Harvard Medical School.
Still, the researchers caution that more clinical studies are needed to confirm the cancer-preventive effects of statins in humans. They also stress that not all inflammatory conditions are created equal - while blocking IL-33 may be beneficial in some contexts, it could be detrimental in others where IL-33 plays a protective role. The team plans to continue their research in hopes of bringing another targeted therapy option for cancer patients.
“Next, we aim to further examine the impact of statins in preventing cancer development in chronic inflammation in liver and gastrointestinal tract and to identify other novel, therapeutic approaches to suppress cancer-prone chronic inflammation,” says Demehri.
