title: The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease.
abstract: 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 tumours, 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 (EBV) 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 growth factor-I 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 tumours. 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 tumours 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.
authors.affiliation: University Department of Oncology, Leicester Royal Infirmary, UK. kobyrne@lri.org.uk
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
authors.forename: M J
authors.initials: MJ
authors.lastname: Browning
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D018450:Disease Progression; D020868:Gene Silencing; D016158:Genes, p53 / Q000276:immunology; D006801:Humans; D006920:Hygiene; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology; D017471:Receptors, Interferon / Q000276:immunology
chemical_list: D017471:Receptors, Interferon; D011451:Prostaglandin-Endoperoxide Synthases