Question ID: WS-30
Submitted by: Maria Teresa Landi
February 4, 2011
What molecular mechanism(s) are responsible for the association between inflammation and cancer risk or progression? Maria Teresa Landi, DCEG, GEB Background. A growing body of evidences supports the contribution of chronic inflammation to the development of malignancies. The association between the use of non-steroidal anti-inflammatory agents (NSAIDs) and protection against cancer further emphasizes the role of inflammation in carcinogenesis. Recently, inflammation has also been linked to the acquired capacity to metastasize during tumor progression. Basic research has shown that organ-specific carcinogenesis is linked to the development of a chronic local inflammatory micro-environment and obesity may play a role in this process. Although inflammatory signaling molecules in the tumor micro-environment have been identified, the molecular basis of the association between inflammation and cancer and why the inflammatory response to the same triggering agents varies across individuals remain largely unknown. Feasibility. Genome-wide association studies (GWAS) have identified genomic loci associated with different cancer types. Circulating inflammatory markers have been tested in inflammatory diseases. To investigate genetic susceptibility to inflammation, GWAS-derived genetic variants in the inflammatory pathway(s) can be tested in healthy controls in relation to circulating inflammatory markers. The genetic variants associated with markers of inflammation can be analyzed in relation to cancer risk in the presence of factors that may trigger inflammation, such as previous diseases (e.g., pancreatitis), obesity, infections (e.g., Helicobacter pylori), tobacco smoking, intermittent sun exposure, alteration of sex steroid hormones, or occupational exposures (e.g., asbestos). In outcome studies, the association between cancer treatment and disease-free survival or development of toxicities in relation to inflammation-related genetic variants can also be studied. If tissue specimens are available, presence of inflammatory elements in the tumor micro-environment in subjects exposed to triggering agents can be conducted in relation to cancer outcome. Experimental studies before and after administration of NSAIDs can be used to verify the role of these factors and the reversibility of the inflammatory environment. Implications of success. A deeper understanding of the mechanism(s) associated with inflammation-related carcinogenesis and individual susceptibility to inflammation-related cancer could suggest new prevention strategies particularly for at-risk subjects. Understanding the mechanistic link between treatment-associated inflammation and cancer outcome can improve cancer treatment strategies. Epidemiological, genetic, clinical and biological investigations can be integrated to reach these goals.
Average Score: 4.0
 (2 evaluations)Provocativeness - 3.5
Novelty - 3.0
Public Health Significance - 4.0
Feasibility - 4.5
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Comments
Submitted By Masoud Manjili
If this important question is answered we would be able to develop a highly tailored therapeutic approach for cancers. Actually, inflammatory type of the anti-tumor immune response such as IFN-g can also induce initial tumor inhibition but eventual tumor escape and progression. For example, pre-clinical studies have shown that IFN-g producing T cells can induce apoptosis in the tumors but at the same time result in tumor antigen loss and escape from further immune surveillance due to the induction of epigenetic changes in the tumors, including hypermethylation of the promoter region of certain genes. Clinical studies also showed that HER-2/neu-specific IFN-g producing T cell responses resulted in the regression of DCIS lesions and at the same time HER-2/neu loss in DCIS. Further studies will determine whether these HER-2/neu loss variants may progress to HER-2/neu negative invasive breast cancer.
