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Sylvester Researchers Discover New Pathway Linking Inflammation and Cancer

A team of researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, collaborating with outside investigators, has discovered a new pathway of inflammation-driven cancer development.

Their findings, “Initiation of Inflammatory Tumorigenesis by CTLA4 Insufficiency Due to Type 2 Cytokines,” were published online on January 26 by the Journal of Experimental Medicine, with print publication scheduled for March 5.

“Many types of human cancers develop in an asymptomatic process over decades until advanced stages. In most cases, the origin of cancer remains an enigma,” said Zhibin Chen, M.D., Ph.D., associate professor of microbiology and immunology, who was corresponding author of the article.

The immune system has key regulatory genes, called checkpoints, to assure that immune responses occur in a measured fashion with minimal collateral damage, he explained. Blocking these checkpoints can unleash the destructive power of the immune system against its targets, such as cancer cells.

“This is well illustrated in the remarkable breakthrough in cancer immune therapies through blocking immune checkpoints, of which CTLA4 is the prototypical example,” said Chen. “Paradoxically, recent genetic studies found that patients who harbor loss-of-function mutations on one copy of the CTLA4 gene, a condition called CTLA4 insufficiency, had high risks of developing cancer in the stomach.”

Spearheaded by two former Ph.D. students, Jason Miska and Jen Bon Lui, Chen’s laboratory tackled this conundrum in immunology and cancer biology in collaboration with Sylvester members and Miller School faculty Maria T. Abreu, M.D., professor of medicine, Diana M. Lopez, Ph.D., professor of microbiology and immunology, and Gaofeng Wang, Ph.D., associate professor of human genetics. Additional collaborators included Xiaodong Cai, professor of electrical and computer engineering at the University of Miami College of Engineering, who is also a Sylvester member, and JeanMarie Houghton, M.D., Ph.D., professor of medicine at the University of Massachusetts Medical School.

Using a transgenic animal model of CTLA4 insufficiency, they found that CTLA4 insufficiency indeed caused stomach cancer. They discovered that the cancer development was initiated by a particular type of inflammation called type 2 inflammation that is typically responsible for tissue repairing, but not by the type 1 inflammation that usually inflicts tissue damage. In other words, abnormal tissue repairing in the chronic inflammatory setting can cause cancer development. Furthermore, they discovered that type 2 inflammation drove cancer development at least in part by impinging on epigenetic reprogramming of cells in the stomach lining.

“Our study discovered a new pathway of cancer development,” said Chen. “In this pathway, chronic inflammatory signals from the immune system are sufficient to initiate cancer development, even in the absence of mutations in oncogenes or tumor suppressor genes.

“This finding, taken together with the data from many other groups, illustrates the power of the immune system as a double agent in both pro-tumor and anti-tumor activities. Harnessing the power of the immune system usually yields a mixed bag of inflammatory molecules. Our study offers clues on how to circumvent tumor-promoting inflammatory signals while preserving tumor-destructing mechanisms.

Furthermore, the newly identified role of type 2 inflammation in the early stage of cancer development offers plausible targets for cancer prevention. The paradox showcased in our study reminds us how much we do not know on the origin of cancer and its relationship with the immune system.”

The next step for the researchers, said Chen, will be to determine which sets of genes in the genome and epigenome are affected by chronic type 2 inflammation in a way that leads to the onset of cancer development. They expect the molecular profiles to be useful as biomarkers to detect the earliest transformative events along the cascade of cancer development. In the long term, they expect to target the molecular pathways imparted by those genes, to break the link between inflammation and cancer development.

Tags: cancer development, Inflammation and cancer, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami