Study of Inflammation Could Impact Understanding, Treatment of Cancer
A team of international scientists, including Duquesne University Professor of Biological Sciences Dr. Philip Auron, has studied metabolic and immune systems, how they contribute to fighting diseases and how cancer can use inflammation responses to overtake the body.
In a paper published in Nature this spring, the team determined that macrophages, the body’s disease-fighter cells, switch operational systems—much like a hybrid car does.
Normally, macrophages operate on a steady metabolism, the high efficiency side of the hybrid system. They split sugars through glycolysis and the Krebs cycle, efficiently producing usable energy at a slow but constant rate.
The team unexpectedly discovered that when the immune system is under fire, macrophages switch operating systems to be like a turbocharged gas engine. This system is designed to be quick but inefficient, producing energy faster, but with greater waste—and requiring less oxygen.
In switching to the “race” cycle, which is 20 times less efficient but 200 times quicker, the body’s defenses start behaving like cancer cells in a low-oxygen environment, a process Auron explains in a video.
At the first hint of a bacterial/viral invader, this “race” cycle creates an acidic environment, releasing succinate instead of a steadily produced sugar-sweet substance. An acid, succinate supports the inflammatory response, including fever, swelling and edema.
While these responses save the body in the short-term, anyone who has suffered chronic inflammation knows the down side. Additionally, as macrophages wage the inflammatory reaction and fight off cancer, they also may be tricked into helping cancer cells move around the body, leading to metastasis.
The researchers examined ways to dampen this inflammatory response, interrupting the signals that put the macrophages’ systems into overdrive. They focused on an important mediator of inflammation, interleukin 1 (IL-1).
Auron’s research group was instrumental in characterizing a protein called hypoxia-inducing factor (HIF), associated with activating the macrophage and IL-1. HIF, a switchable sensor of low-oxygen, is permanently activated in many cancer cells. Both cancer cells and stimulated macrophages operate in low-oxygen environments. Auron believes this suggests a molecular connection that, if disturbed, could disrupt metastasis.
“IL-1 generates many inflammatory responses, which are therapeutic at low doses but cause disease when over-expressed,” explained Auron, who holds a patent on an IL-1 inhibitor used to treat inflammatory diseases.
Auron’s latest findings, pending publication, determined that there is a distinct way molecular mechanisms “read” the IL-1 gene. This appears to be gene-specific, modifying common enzymes required to express most proteins, the building blocks for cell replication.
Armed with this new information about triggers and pathways, researchers can next examine selective ways to short-circuit inflammatory responses that may lead to metastasis.
Founded in 1878, Duquesne is consistently ranked among the nation's top Catholic research universities for its award-winning faculty and tradition of academic excellence. The University is nationally ranked by U.S. News and World Report and the Princeton Review for its rich academic programs in nine schools of study for nearly 10,000 graduate and undergraduate students, and by the Washington Monthly for service and contributing to students' social mobility. Duquesne is a member of the U.S. President's Higher Education Community Service Honor Roll with Distinction for its contributions to Pittsburgh and communities around the globe. The U.S. Environmental Protection Agency and the Princeton Review's Guide to Green Colleges acknowledge Duquesne's commitment to sustainability.