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

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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-α, 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-α 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.

Introduction

Angiogenesis plays a central role in ovulation, implantation of the fertilised ovum, fetal growth and gestation, and wound healing and repair following surgery and trauma [1]. These situations are paralleled by reduced cell-mediated immune responses (CMI) and upregulation of the humoral immune response (HI) 2, 3, 4 suggesting a close inter-relationship between the immune system and the angiogenic process in normal physiological processes.

The discovery of immune cytokines such as the interleukins (IL) and interferons (IFN) led to investigations of the types of cytokine produced by different immune cells in response to different antigenic stimuli. The results were complex and confusing until two main patterns of cytokine response in T-helper (CD4+) lymphocytes (Th cells) were identified [5]. Th1 lymphocytes synthesise IL-2, IFN-γ and tumour necrosis factor (TNF) in response to antigenic stimuli and are associated with CMI. These cytokines are part of the pro-inflammatory cytokine group which also includes IL-1α and IL-1β. IL-12, a more recently identified cytokine produced by macrophages and dendritic cells, plays a central role in CMI, inducing the conversion of Th0 cells to a Th1 phenotype. Th2 lymphocytes synthesise IL-4, IL-5, IL-6, IL-10 and IL-13. These are associated with the development of HI and, in general, are classified as anti-inflammatory cytokines 6, 7. The balance between CMI and HI is relevant to a range of human diseases. In particular, chronic infectious diseases such as tuberculosis [8], leprosy [9], leishmaniasis [10], hepatitis B and C 11, 12, 13, 14 and HIV/AIDS 15, 16 are characterised by loss of the CMI response associated with an overcompensated HI response. The impact of this polarisation of cytokine response in chronic disease, including malignancy, has led to new approaches in treatment such as boosting CMI responses with agents including IL-2, IFN-α and thalidomide 17, 18, 19.

Section snippets

Angiogenesis and malignant disease

Many malignant diseases, including those of the breast, lung, colon, cervix, bladder and skin, begin as in situ carcinomas. These tumours usually measure less than 1–2 mm in diameter and may be present for years until malignancy develops. Current opinion suggests that with time a subgroup of cells within the tumour takes on an angiogenic phenotype with the capacity to induce new blood vessel formation. As a result the disease develops the capacity to grow and metastasise. This is known as the

Immune responses and malignant disease

As is the case for angiogenesis there is considerable evidence to suggest that suppression of Th1, often associated with upregulation of Th2 responses, is a common feature of both malignant tumours and of disease processes known to predispose to the development of cancer.

Suppression of local and systemic CMI responses has been confirmed in studies evaluating inflammatory cellular infiltrates of tumours and peripheral blood mononuclear cell responses of patients with malignant disease including

Angiogenesis and the immune system

The nature of the immune response to any given insult may have a major impact on angiogenesis. Macrophages play an important role in the angiogenic process associated with inflammation, wound healing and tumour growth. The angiogenic potential of interferon-γ Th1-induced and IL-4/glucocorticoid Th2-induced macrophages has been evaluated in vitro. These subsets were analysed for a panel of 10 angiogenic growth factors 3 and 6 days after stimulation and compared with unstimulated control

Cyclo-oxygenases-1 and -2 (COX-1 and -2)

COX-1 and COX-2 catalyse the first two steps in prostanoid synthesis. COX-1 activity is constitutively expressed in nearly all cell types and plays a central role in many normal physiological processes, such as cytoprotection of gastric mucosal surfaces, through synthesis of prostacyclin and PGI2. COX-2 is rarely expressed in normal tissues but is induced in response to inflammatory stimuli. These stimuli include the pro-inflammatory cytokines, IL-1β, IL-2, IFN-γ and TNF-α which in turn are

Chemoprevention studies

Recent work has demonstrated that long-term ingestion of aspirin protects against the development of cancer, in particular colorectal disease where the incidence is reduced by as much as 45% and oesophageal cancer 228, 229, 230. Furthermore, natural and synthetic non-specific COX-1 and -2 and specific COX-2 antagonists have been shown to inhibit carcinogenesis in lung [231], breast [232], oral [233], gastric, duodenal and colon 234, 235 cancer while sulindac causes a reduction in the number of

Hygiene, immunisation and cancer

Western countries have seen a significant rise in the incidence of many malignant diseases over the past few decades. This has affected all age groups with particularly significant annual rises being observed in germ cell tumours, lymphoma and melanoma 137, 249, 250. The increase in malignant disease has occurred on a background of an increased incidence of other conditions characterised by a predominant Th2 immune response including the atopic conditions allergic rhinitis, eczema and asthma

Conclusions

Prolonged exposure to known carcinogenic infective, chemical or physical agents and growth factors, or inhibiton of the function of tumour suppressor genes, may predispose the individual to the development of a local and/or systemic environment in which angiogenesis is upregulated, Th1/CMI responses are suppressed and Th2/HI responses predominate. The likelihood of such an environment occurring is potentiated by a Western lifestyle in which: (a) the development of Th2/HI, rather than Th1/CMI

Acknowledgements

This work was supported by the Institute of Cancer Studies, Leicester, UK.

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