Chronic Inflammation and Cytokines in the Tumor Microenvironment
Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.
The role of inflammation in the development of cancer was described as early as 1863, by Rudolf Virchow. His observations that inflammatory cells infiltrate tumors led him to hypothesize that cancer arises from inflammatory sites (“lymphoreticular infiltration”) [1, 2]. In the last decades, Virchow’s postulation has been supported by abundant evidence that various cancers are triggered by infection and chronic inflammatory disease .
Inflammation is a beneficial response activated to restore tissue injury and pathogenic agents. However, if inflammation is unregulated, it can become chronic, inducing malignant cell transformation in the surrounding tissue. The inflammatory response shares various molecular targets and signaling pathways with the carcinogenic process, such as apoptosis, increased proliferation rate, and angiogenesis. Furthermore, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to decrease incidence and mortality of several cancers .
In relation to chronic inflammatory-associated neoplasias, this review article explores the involvement of cytokines in chronic inflammation and carcinogenesis, focusing on inflammatory bowel disease-associated cancer and cholangiocarcinoma (CCA) induced by chronic inflammation of biliary ducts, that is, primary sclerosing cholangitis (PSC) and liver fluke associated-CCA. Both cancers are examples of a localized, long-term inflammatory process increasing the risk of cancer.
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Journal of Cytokine Biology