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-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of rumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI, These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer, chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr 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 melanoma, Chronic exposure to growth factors (insulin-like grow th factor-1 in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid rumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations. the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors, With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression. thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha. anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid rumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively; these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease. (C) 2000 Elsevier Science Ltd, All rights reserved.