The Role of Inflammation In Causing GI Cancers

The Role of Inflammation In Causing GI Cancers

Inflammation has been linked with various diseases, including many types of malignancies. This association has become well enough known that a cover of Time magazine in recent years pronounced inflammation the “surprising killer,” noting the “surprising link” between inflammation and cancer.

The fact that cancer was deemed to be the leading cause of death worldwide in 2008 by the World Health Organization is less known and speaks to the importance of understanding mechanisms that lead to cancer. It’s also important to note that the five cancers causing the most deaths worldwide – lung, gastric, colon, liver, and breast – include three malignancies of the digestive system.

Chronic inflammatory conditions of the entire digestive tract have been associated with malignancy, ranging from tobacco use and gingivitis in oropharyngeal carcinomas to inflammatory bowel disease–associated colitis and colon cancer. Other well known associations include GERD and Barrett’s esophagus associated with esophageal adenocarcinoma, and H. pylori infection associated with gastric adenocarcinoma.

Chronic inflammation associated with celiac disease predisposes to enteropathy associated T cell lymphoma. Inflammatory conditions of other organs of the digestive system, including chronic forms of hepatitis, cholangitis, and pancreatitis are associated with malignancies of the liver, biliary tract, and pancreas.

Inflammation impacts key steps involved in cancer biology including mutagenesis, tumor progression, and metastasis.

Factors that contribute to the development of GI cancers that arise from inflammation include infectious agents such as H. pylori, gut microbiota, and dietary factors, as well as host factors such as genetics, obesity, and the nature of the immune response. Not all individuals with a given risk factor, whether it be GERD, IBD, or H. pylori infection, develop cancer.

A complex interaction of host, environment, and luminal factors is the likely determinant of the clinical outcome arising from the potentially carcinogenic agent or condition. A variety of cell types produce mediators such as reactive oxygen and nitrogen species that damage DNA, and cytokines and growth factors that affect proliferation, cell death, and repair processes. Subsets of immune cells including cytotoxic T cells, helper T cells, and NK cells are involved in immunosurveillance.

Together, the components of the immune/inflammatory response modulate proliferation, differentiation, angiogenesis, stem cell recruitment, and mutation – events that are integral in the process of carcinogenesis. H. pylori infection has been well studied in an attempt to understand factors that may result in gastric adenocarcinoma.

Research indicates that host genetics, dietary factors, bacterial genotype, and the inflammatory response all contribute. Signaling pathways activated by chronic IBD that may lead to colon cancer have also been elucidated and it is thought that some of these mechanisms may relate to more common forms of colon cancer.

Further research is needed, as a better understanding of the inflammatory events regulating carcinogenesis may identify new biomarkers or therapies that change the detection and management of inflammatory diseases that can lead to malignancy.

■ SHEILA E. CROWE, M.D., FRCPC, FACP, FACG, AGAF, is Professor of Medicine and Director of Research, Division of Gastroenterology, Department of Medicine, University of California, San Diego.