ReviewInflammation and cancer: back to Virchow?
Section snippets
Inflammatory cells in tumour microenvironment
The inflammatory microenvironment of tumours is characterised by the presence of host leucocytes both in the supporting stroma and in tumour areas.4 Tumour-infiltrating lymphocytes may contribute to cancer growth and spread, and to the immunosuppression associated with malignant disease.
Macrophages
Tumour-associated macrophages (TAM) are a major component of the infiltrate of most, if not all, tumours.5 TAM derive from circulating monocytic precursors, and are directed into the tumour by chemoattractant cytokines called chemokines. Many tumour cells also produce cytokines called colony-stimulating factors that prolong survival of TAM. When appropriately activated, TAM can kill tumour cells or elicit tissue destructive reactions centred on the vascular endothelium. However, TAM also
Dendritic cells
Dendritic cells have a crucial role in both the activation of antigen-specific immunity and the maintenance of tolerance, providing a link between innate and adaptive immunity. Tumour-associated dendritic cells (TADC) usually have an immature phenotype with defective ability to stimulate T cells.8 In breast cancer, immature TADC are interspersed in the tumour mass, whereas mature dendritic cells are confined to the peritumoral area.8 In papillary thyroid carcinoma TADC are also immature but
Lymphocytes
Natural killer cells are rare in the tumour microenvironment.4 The predominant T-cell population has a “memory” phenotype. The cytokine repertoire of these tumour-infiltrating T cells (TIL) has not been studied systematically but in some tumours (eg, Kaposi's sarcoma, Hodgkin's disease, bronchial carcinoma, and cervical carcinoma) they produce mainly interleukins (IL) 4 and 5 and not interferon-γ.9 IL 4 and 5 are cytokines associated with the T-helper type 2 (Th2) cells whereas interferon-γ is
Tumours: wounds that do not heal
Besides inflammatory cells, tumour stroma consists of new blood vessels, connective tissue, and a fibrin-gel matrix. In his 1986 review Dvorak showed how wound healing and tumour stroma formation share many important properties (“Tumors: wounds that do not heal”11). Wound healing is usually self-limiting whereas tumours secrete a vascular permeability factor, vascular endothelial growth factor (VEGF), that can lead to persistent extravasation of fibrin and fibronectin and continuous generation
Proinflammatory cytokines
The cytokine network of several common tumours is rich in inflammatory cytokines, growth factors, and chemokines but generally lacks cytokines involved in specific and sustained immune responses.13 There is now evidence that inflammatory cytokines and chemokines, which can be produced by the tumour cells and/or tumour-associated leucocytes and platelets, may contribute directly to malignant progression. Many cytokines and chemokines are inducible by hypoxia, which is a major physiological
Mechanisms of action of inflammatory cytokines in tumour microenvironment
An inflammatory cytokine network may influence survival, growth, mutation, proliferation, differentiation, and movement of both tumour and stromal cells. Moreover, these cytokines can regulate communication between tumour and stromal cells, and tumour interactions with the extracellular matrix. We will now look in more detail at the mechanisms by which cytokines and chemokines might act to promote tumours (panel 2, figure 1).
DNA damage
TNF is a transforming agent for carcinogen-treated fibroblasts. Two weeks of exposure to the cytokine in vitro is sufficient to render cells capable of tumour formation in nude mice.36 The molecular basis may involve induction of reactive oxygen. Reactive oxygen in the form of NO is often generated by inflammatory cytokine induction of NO synthase.37 NO can directly oxidise DNA, resulting in mutagenic changes, and may damage some DNA repair proteins.37 Furthermore, inducible NO synthase has
Bypassing p53
Another link between inflammatory cytokines and DNA damage comes from recent studies of the regulation of the tumour-suppressor protein p53. In tumours, p53 is often functionally inactivated even though the p53 gene remains intact. A search for negative regulators of p53 activity highlighted an inflammatory cytokine known as migration inhibitory factor.38 Treatment of cells with this factor overcame p53 activity. It is not clear whether other cytokines can also inactivate p53 but chronic bypass
Actions as growth and survival factors
Cytokines and chemokines have the potential to stimulate tumour-cell proliferation and survival and some of them may also act as autocrine growth and survival factors for malignant cells. IL-6 is a growth factor for haematological malignancies;26 IL-1 has growth stimulating activity for gastric carcinoma that may be related to genetic predisposition39 and for myeloid leukaemias; and growth of melanomas is promoted by IL-8 and related chemokines.30
Angiogenesis
Angiogenesis is important in the evolution of both cancer and inflammatory diseases that may predispose to cancer.40 Once a tumour is established it may attain further characteristics, via mutations or hypoxia, which stimulate new blood vessels.
The inflammatory cell infiltrate, particularly TAM, may contribute to tumour angiogenesis, and there are many reports of associations between macrophage infiltration, vascularity, and prognosis.41 Moreover TNF, IL-1, and IL-6 can stimulate production of
Invasion and metastasis
Cytokines and chemokines affect various stages in the process of metastasis. TNF and CC chemokines can induce production of proteases important for invasion in both tumour cells and macrophages. Indeed, monocytes infiltrating the tumour tissue may provide cancer cells with a ready-made path for invasion (the “countercurrent invasion theory”).43 In one skin tumour model, paracrine matrix metalloproteinase-9 production by inflammatory cells was implicated in epithelial hyperproliferation,
Subversion of immunity
The prevalence of Th2 cells is common to tumours suggesting that this polarisation may be a general strategy to subvert immune responses against tumours. Inflammatory reactions are diverse, reflecting the variety of properties that can be acquired by macrophages.46 At one extreme, interferon-activated (or type I) macrophages produce high levels of proinflammatory cytokines and Th1-attracting chemokines. At the other, activated (type II) macrophages produce high levels of antagonist to IL-1
Interfering with chemotherapy
Another similarity between inflammation and cancer is raised plasma concentrations of acute-phase proteins (such as C-reactive protein and α1-acid glycoprotein). The latter binds with high affinity to, and blocks activity of, the experimental cancer drug STI57151 which normally has activity against chronic myelogenous leukaemia in mice. If acute-phase proteins do bind to and inactivate anticancer drugs there would be obvious implications for therapy.
Local inflammaton and systemic anti-inflammation: a paradox
In terms of inflammatory reactions, neoplastic disorders constitute a paradox. Tumours produce inflammatory cytokines and chemokines and are infiltrated by leucocytes. However, neoplastic disorders are associated with a defective capacity to mount inflammatory reactions at sites other than the tumour, and circulating monocytes from cancer patients are defective in their capacity to respond to chemoattractants.52
Various factors originating in the tumour microenvironment may contribute to the
Inflammatory cytokines as cancer-modifier genes
Cytokine genes are highly polymorphic and since polymorphisms are frequently in regions of DNA that regulate transcription or posttranscriptional events, they may be functionally significant. Four studies of such polymorphisms and cancer susceptibility and severity suggest that some cytokines may be cancer-modifier genes.
Systemic release of TNF and lymphotoxin contributes to the severity of non-Hodgkin lymphoma.19 In a study of 273 lymphoma patients, the TNF-308 polymorphism was associated with
TNF blockade
Two TNF antagonists (etanercept, Enbrel [Immunex]) and infliximab, Remicade [Centocor]) have been licensed for clinical trial in the treatment of rheumatoid arthritis and Crohn's disease, with over 70 000 patients now treated.57 There is clinical evidence for five actions of the anti-TNF antibody in rheumatoid arthritis joint tissue–namely, inhibition of cytokine/chemokine production, reduced angiogenesis, prevention of leucocyte infiltration, inhibition of matrix metalloproteases, and
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