The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease

Recent studies have demonstrated that angiogenesis and suppressed cell-medi ated immunity (CMI) play a central role in the pathogenesis of malignant di sease facilitating tumour growth, invasion and metastasis. In the majority of rumours, the malignant process is preceded by a pathological condition o r exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI, These include: cigarette smoking, chron ic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer, chronic viral infections such as human papilloma virus and ano-genital can cers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-B arr virus (EV) and lymphomas: chronic inflammatory conditions such as Crohn 's disease and ulcerative colitis and colorectal cancer: asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant mela noma, Chronic exposure to growth factors (insulin-like grow th factor-1 in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni synd rome) and long-term exposure to immunosuppressive agents (cyclosporin A) ma y also give rise to similar environments and are associated with the develo pment of a range of solid rumours. The increased blood supply would facilit ate the development and proliferation of an abnormal clone or clones of cel ls arising as the result of: (a) an inherited genetic abnormality; and/or ( b) acquired somatic mutations. the latter due to local production and/or en hanced delivery of carcinogens and mutagenic growth factors, With progressi ve detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process an d CMI suppression. thereby facilitating further tumour growth and metastasi s. There is accumulating evidence that long-term treatment with cyclo-oxyge nase inhibitors (aspirin and indomethacin), cytokines such as interferon-al pha. anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid rumours such as breast and colorectal cance r. These agents are anti-angiogenic and, in the case of aspirin, indomethac in and interferon-alpha have proven immunomodulatory effects. Collectively; these observations indicate that angiogenesis and suppressed CMI play a ce ntral role in the development and progression of malignant disease. (C) 200 0 Elsevier Science Ltd, All rights reserved.