Elsevier

The Lancet

Volume 357, Issue 9255, 17 February 2001, Pages 539-545
The Lancet

Review
Inflammation and cancer: back to Virchow?

https://doi.org/10.1016/S0140-6736(00)04046-0Get rights and content

Summary

The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing. This article reviews the links between cancer and inflammation and discusses the implications of these links for cancer prevention and treatment. We suggest that the inflammatory cells and cytokines found in tumours are more likely to contribute to tumour growth, progression, and immunosuppression than they are to mount an effective host antitumour response. Moreover cancer susceptibility and severity may be associated with functional polymorphisms of inflammatory cytokine genes, and deletion or inhibition of inflammatory cytokines inhibits development of experimental cancer. If genetic damage is the “match that lights the fire” of cancer, some types of inflammation may provide the “fuel that feeds the flames”. Over the past ten years information about the cytokine and chemokine network has led to development of a range of cytokine/chemokine antagonists targeted at inflammatory and allergic diseases. The first of these to enter the clinic, tumour necrosis factor antagonists, have shown encouraging efficacy. In this article we have provided a rationale for the use of cytokine and chemokine blockade, and further investigation of non-steroidal anti-inflammatory drugs, in the chemoprevention and treatment of malignant diseases.

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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