Inflammatory chemokines in cancer growth and progression

https://doi.org/10.1016/j.ejca.2006.01.002Get rights and content

Abstract

Leukocyte infiltration is a cardinal feature of almost all cancers. Chemokines are generally responsible for eliciting local accumulation of inflammatory cells and they appear to play the same role in the formation of peri- and intra-tumoural infiltrates. Chronic inflammation predisposes to cancer formation and progression, and it is likely that the chemokine system contributes to this process. In part, this may be a consequence of its ability to attract mononuclear cells to cancer sites, where they provide growth or angiogenic factors that enhance cancer development. However, accumulating evidence also points to a direct effect of chemokines on cancer cells that express chemokine receptors. In particular, some chemokines can activate anti-apoptotic pathways in these cells. By either mechanism, tumour cells that secrete and/or respond to chemokines would have a selective advantage. This provides another example of cancer’s ability to co-opt host systems in order to promote tumour progression.

Introduction

For well over 100 years, pathologists have recognised that almost all cancers are accompanied by inflammatory cells. Thoughts about the function or ‘purpose’ of this infiltrate have evolved over time as biologists have gained a deeper understanding of basic mechanisms of inflammation. In the 19th century, peri-tumoural inflammatory cells were thought to be an integral part of cancer.1, 2 A little later, their presence was proposed to provide a favourable environment for cancer growth.3, 4, 5 This included the now contemporary notion that inflammatory cells might elaborate signals that promote development of new blood vessels, which are necessary for cancer progression. Still later, as experimental evidence for host anti-tumour immune responses accumulated, infiltrating cells were suggested to be evidence for the host’s attempt at immunological rejection of its cancer.6, 7, 8 Most recently, the pendulum has swung back to suggestions that tumours might recruit inflammatory cells because of their ability to provide signals that promote cancer growth.9

Understanding the molecular mechanisms that generate tumour-associated inflammatory infiltrates might help to illuminate their function. Among the predominant signals that recruit leukocytes in all inflammatory settings are chemokines. These are low molecular weight proteins that share a high degree of structural homology and the ability to attract specific types of leukocytes with picomolar potencies. More than 45 non-allelic chemokine genes have been identified in the human genome, and their combinatorial interactions with more than 20 chemokine receptors account for the variety and specificity of leukocyte types found in various inflammatory infiltrates.10 The almost universal presence of chemokines in cancers suggests that in this setting, too, the chemokine system is responsible for specific patterns of leukocyte accumulation.

However, even if there is general agreement that chemokines attract leukocytes to tumours, the function of these elicited leukocytes (and, by extension, the function of chemokines themselves) remains controversial. This review will summarise the experimental evidence that chemokines can affect the behaviour of cancers and that they and their receptors might therefore be exploitable therapeutic targets.

Section snippets

Chemokines and tumour immunity

Chemokines are potent attractants for cells involved in innate immune responses. Many chemokines can also induce activation programs in target leukocytes, some of which may be relevant to the host’s response to cancer. For example, in vitro studies have shown that macrophage-attracting chemokines, such as monocyte chemoattractant protein-1 (MCP-1, CCL2) also stimulate macrophage cytolytic activity against tumour cells.11 Given sufficient activation, these cells might have non-specific

Indirect mechanisms: tumour-associated leukocytes and stromal cells as delivery devices

One possible mechanism is an indirect one that was first proposed by Ehrlich3 and has recently been brought up-to-date and enhanced by Mantovani, Balkwill, Pollard and others.9, 39 Theirs is the notion that tumours secrete chemokines or other leukocyte attractants in order to elicit leukocytes that provide growth factors for cancer cells or angiogenic factors for the tumour-associated neovasculature. Clinical epidemiological evidence supports this idea. For example, in breast cancer, several

Direct mechanisms: chemokines may promote tumour growth

Another way that inflammatory chemokines could promote tumour growth would be through direct action on tumour cells themselves. This would require the expression of functional chemokine receptors by malignant cells. It is not surprising, perhaps, that haematopoietically derived cancer cells express a variety of chemokine receptors. The stem cell population from which they derive normally gives rise to cells that use chemokine receptors for their physiological functions, suggesting that the

Genetic considerations

The contemporary ‘gold standard’ for implicating specific molecular involvement in cancer is demonstrating a genetic basis for that molecule’s effect. Translocations and point mutations pointed to the essential contribution of BCR/ABL in chronic myelogenous leukaemia and the epidermal growth factor receptor in a subset of lung cancers. Of course, the ultimate confirmation of these observations has been the efficacy of imatinib and gefitinib in these diseases. To date, no genetic abnormalities

Conclusion

Despite demonstrations of the anti-tumour effects of chemokines in artificial models, the preponderance of evidence – clinical, genetic and experimental – indicates that the chemokine system contributes to cancer progression. This represents one molecular facet of the general pro-tumourigenic effects of inflammation. Some of the involved mechanisms are straightforward, such as recruitment to the tumour site of leukocytes that provide angiogenic factors. Other mechanisms are more surprising but

Conflict of interest statement

The author is a consultant for Novartis Pharma.

Acknowledgement

Supported by NIH grant CA53091 and the Dana-Farber/Novartis Drug Discovery Program.

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