Chemokines in neoplastic progression

https://doi.org/10.1016/j.semcancer.2003.10.004Get rights and content

Abstract

Chemokines and their receptors have emerged as attractive targets regulating the migration of tumor cells in vivo, a process known as cancer metastasis. The control of metastasis is critical to the control of cancer progression. Two chemokine receptors and their ligands stand out as likely targets for therapeutics: CCR7/CCL21 for lymph node metastases, and CXCR4/CXCL12 for lung, liver, bone marrow, and brain metastases. The most widely expressed chemokine receptor among cancers is likely to be CXCR4.

Introduction

The chemokines represent a large superfamily of small peptides that currently number 42 in the human and that bind 18 receptors, which belong to the Class A subfamily of G-protein-coupled receptors [1]. While it is possible that other chemokine receptors may yet be identified, it is likely that we have completed the identification of chemokine ligand genes. Some of these may still yield some divisions, for example, CCL27 is a chemokine whose gene includes many exons and that, depending on which exons are read in a particular combination, may yield several protein forms of the chemokine (although only one form is secreted). Nevertheless, this situation allows us to take the ‘global view’ of the chemokines and start asking questions relating to the potential role of this superfamily in various human ailments. Chemokines are already well known to participate in immune responses, infectious diseases (specially important roles in HIV infection though CCR5 and CXCR4 reviewed elsewhere in these series), development on various systems and organs, and, more recently, cancer metastasis. The latter will be the subject of the present review. We will aim to establish the rationale for the discoveries, and will review the scientific and clinical evidence that now points to a major role for chemokines and their receptors in metastasis.

Section snippets

Metastasis and cancer

Firstly, it is important to put metastasis in context in the disease we call cancer. Cancer is, at its core, the result of a disregulation of cell proliferation. Cells are programmed to respond to signals that control their growth and differentiation. Growth is a critical element of the life of a cell. Unfortunately, this is a highly complicated process where many genes and signaling pathways participate. For this reason, it is not uncommon that, if there is a defect in the regulation of

The molecular basis of metastasis

From the previous discussion it is apparent that controlling metastasis should be a major goal if we seek to improve the life expectancy of cancer patients. However, until recently, we did not have much information of the molecules controlling metastasis. In fact, the prevailing view was that metastasis occurred simply because some tumor cells somehow ‘escape’ from the primary tumor, and as they reach major circulatory systems like the lymph or blood, they would be able to travel great

The chemokines and their role in cancer metastasis

The chemokines were originally discovered and studied mostly from the perspective of inflammation and immunology. It soon became apparent that chemokines are very important in the development of inflammatory responses. In contrast, important chemokine discoveries in other areas were more accidental and surprising. Such is the case of the CCR5 and CXCR4 receptors which were found to be receptors for HIV [4]. By 1999, discovery in the chemokine superfamily was almost complete and several very

CCR7 and CXCR4 are key receptors in metastasis of many cancers

We can now discuss what has been the outcome of many other studies following our original report. The importance of our study centered on the fact that we (a) performed a comprehensive chemokine receptor survey and (b) showed that at least in the case of breast cancer and melanoma, the expression of chemokine receptors in cancer was not random. The question arises: how generally applicable are these observations to other cancers? Many other reports have now addressed this question. But before

The big picture

We can summarize the discussion above as follows. Firstly, the expression of chemokine receptors in cancer cells is not random. There are now many reports supporting this conclusion. Secondly, there are several receptors that are very commonly expressed in cancer cells. At the top of this list is CXCR4. A distant second is CCR7. These two receptors together account the most compelling data on chemokine receptors and cancer metastasis, both in exploratory research and in clinical data. Taking

Homing versus growth

From the discussion above we can conclude that CXCR4 inhibitors (be them antibodies or small molecules) would be highly compelling potential therapeutics to inhibit metastasis in the early stages of cancer development. But metastasis is a complex phenomenon that may include not only the ability of tumor cells to home on a particular location, but also to become established and grow. In this context, it is possible that the effects of CXCL12 on CXCR4 tumor cells may include growth promotion

Conclusion

We can conclude that chemokines and their receptors are likely to play an important role in cancer metastasis. Metastasis, in turn, is a phenomenon we must understand in order to control cancer effectively. Molecular mechanisms controlling metastasis are likely to be an area of intense research in the next few years. We should, however, be optimistic that chemokines and their receptors (mainly CXCL12/CXCR4) are likely to be important targets for the development of inhibitors with potential

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