Although much of the emphasis in tumor immunology has been on the role of the immune system in eradicating tumors, it is clear that the immune system may also contribute to the development of some solid tumors. In fact, chronic inflammation has long been recognized as a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrett's esophagus, Crohn's disease, pancreatitis, and prostatitis, for example. Some cancers associated with infections are also considered to be an indirect result of the carcinogenic effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric cancer in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections. Although the mechanisms by which chronic inflammation can promote tumor development are not well understood, there are several possibilities, supported by data in rodent models. Cells of the innate immune system are considered the most direct tumor-promoting culprits among immune cells. Tumor-associated macrophages of the M2 phenotype as well as other cells are sources of VEGF, which promotes angiogenesis, and matrix metalloproteinases, which modify the extracellular tissue. Therefore, chronic activation of some innate immune cells is characterized by angiogenesis and tissue remodeling, which favor tumor formation and spread. Innate immune cells may also contribute to malignant transformation of cells by generating free radicals that cause DNA damage and lead to mutations in tumor suppressor genes and oncogenes. Some data suggest that cells of the innate immune system, including mast cells, neutrophils, and macrophages, secrete soluble factors that promote cell cycle progression and survival of tumor cells. The transcription factor NF-kB, which is a key mediator of innate immune responses, may play an important role in inflammation-associated cancer progression. The adaptive immune system can promote chronic activation of innate immune cells in several ways, including T cell-mediated activation of macrophages in the setting of persistent intracellular microbial infections as well as during early malignant disease even when infectious agents are not present. There is also experimental evidence that B lymphocytes may contribute to tumor progression by their secretion of factors that directly regulate proliferation programs in tumor cells as well as by their ability to chronically activate innate immune cells present in early tumors. Thus, the adaptive immune system may indirectly enhance the tumor-promoting activities of the innate immune system. The tumor-promoting effects of the immune system are paradoxical and a topic of active investigation at present. These effects of chronic inflammation are theoretically also excellent targets for pharmacologic intervention because there are a large variety of effective anti-inflammatory drugs already available. The challenge for oncologists is to achieve a beneficial balance in which protective anti-tumor adaptive immune responses are not compromised while potentially harmful chronic inflammatory reactions are controlled.
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