Inflammationassociated Carcinogenesis

Damage due to ROS-induced lipid peroxidation and DNA destruction is accompanied by an inflammatory response. Inflammation, under both infectious and noninfectious conditions, has been considered a major precursor for the development of cancer.69 Helicobacter pylori infection is reported to increase the risk of gastric cancer.70 Mice fed inflammatory agents such as dextran sodium sulfate develop inflammation and, eventually, colon cancer.7172 Inflammation alone can lead to cancer, even in the absence of a specific carcinogen. The surgical procedure of opening the duodenum to the gastroesophageal junction causes esophageal inflammation that can lead to cancer of the esophagus.7374

The inducible cyclooxygenase (COX-2) increase that is reported with inflammation correlates well with increase in colorectal adenocarcinoma75 in addition to breast, cervical, prostate, and lung tumors.76 In general, increased levels of COX-2 increase expression of mitogenic metabolites such as prostaglandins. The COX-2 and prostaglandin overexpression stimulate cell proliferation, the inhibition of apoptosis, the induction of angiogenesis, and a direct mutagenic effect.7778 Chronic injury and irritation with or without infection is also associated with the release of cytokines, such as TNFa, interleukins IL-10-6, and interferon y, and with the eventual recruitment of leukocytes and mast cells to the damage site. Activated neutrophils undergo a "respiratory burst", i.e., increase in oxyzen nutilization to generate large amounts of free radicals by several oxidant-generating enzymes such as NADPH oxidase, inducible nitric oxide synthase, myeloperoxidase, and eosinophil peroxidase. These enzymes produce high concentrations h *

of diverse free radicals such as - NO, H202, and HOC1, which also react with each other to generate the more potent free radicals such as •OH and ONOO-. These species can damage DNA, proteins, RNA, and lipids. Accumulation of mutations in DNA, posttranslational modification of proteins, and inadequate DNA repair can lead to increased local cell proliferation and shortened cell cycles in regions of chronic inflammation and can drive carcinogenesis.

Several infections play a role in the pathogenesis of cancer. Apart from Helicobacter pylori infection, which is a major environmental factor in the development of gastric adenocarcinoma, hepatitis B infection is reported to be associated with hepatocellular carcinoma. Cervical squamous cell cancer is associated with human papilloma virus.79

Besides ROS/RNS, alteration of host DNA can also be induced by integration of viral DNA into the genome. Such interactions often cause inactivation of the tumor suppressor genes such as p53. Moreover, viral infection causes immunosuppression, which can enhance malignancy. Several studies have targeted key molecules involved in inflammation such as interleukins, NO, and COX-2. Interleukin-10 is an antiinflammatory cytokine that regulates inflammatory responses and free-radical release. IL-10-/- mice have a high incidence of colorectal adenocarcinomas, which can be reduced by exogenous IL-10 administration.80 Administration of COX-2 inhibitor celecoxib caused tumor regression in patients with adenocarcinoma8182and inhibited experimentally induced colon, breast, bladder, and skin carcinogenesis.83,84

Gene knock-out of COX-2 (an isoform of COX) or inhibition of COX has been shown to protect against intestinal polyposis in mice.85 NO is also known to be involved in inflammation-mediated carcinogenesis. iNOS-- mice treated with trinitrobenzene show significant resistance to colonic damage.72 Also, when inoculated with B16-F1 melanoma cells, these mice develop fewer tumors.86

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