Regulation of Breast Cancer Metastasis by Atypical Chemokine Receptors 55Commentary on Feng Et Al., P

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Regulation of Breast Cancer Metastasis by Atypical Chemokine Receptors 55Commentary on Feng et al., p. 2962 Xiaoyun Cheng1, 2 and Mien-Chie Hung1, 2 , 3

The interaction between chemokines and their G-protein-coupled receptors plays an important role in promoting metastasis ofdifferent kinds ofhuman cancers. However, the expression ofan atypical chemokine receptor, CCX-CKR, which serves as a decoy receptor to attract chemokines, inhibits the growth and metastasis ofbreast cancer by sequestration ofchemokines.

In this issue of Clinical Cancer Research, Feng and colleagues (1) cellular transport of chemoattractants (2). The authors have report that CCX-CKR, a novel chemokine decoy receptor, is a previously shown that both DARC and D6 play a negative role negative regulator of growth and metastasis in breast cancer. in breast cancer (6, 7), and in this issue, they further examine Chemokines are small proteins known mostly to be involved the effect of CCX-CKR in breast cancer. CCX-CKR has been in cell migration, but they have also been found to be involved found to bind CCL19, CCL21, CCL25, and CXCL13, which are in other activities such as angiogenesis, proliferation, and involved in migration to secondary lymphoid organs, thymo- apoptosis (2, 3). They, in cooperation with their receptors, have cyte migration, and leukocyte migration (2, 8). Additionally, also been implicated in the progression of many different CCX-CKR-expressing cells are able to efficiently uptake CCL19 cancers, affecting survival, proliferation, and metastasis. One and mediate its degradation (2, 3). However, many questions well-studied example is the chemokine CXCL12 and its regarding the functionality and expression of CCX-CKR still receptor, CXCR4, which have been shown to be involved in remain. Although the importance of secreted chemokines in many cancers. CXCL12 is expressed in organs, such as lung, attracting migrating cells bearing specific chemokine receptors liver, bone, and lymph nodes, where metastases are commonly is well established, how these atypical receptors work is still located (4). Additionally, CXCR4 has been reported to be poorly understood. As mentioned above, it has been proposed required for HER2-mediated metastasis (5). Other chemokine- that atypical receptors may work in several ways: (a) to compete receptor pairings, such as CCR7-CCL19, CCR9-CCL25, and for ligand binding and hence inhibit the migration of cells CXCR5-CXCL13, have also been shown to play a role in cancer. bearing typical receptors; (b) to internalize and degrade ligands ‘‘Silent’’ or atypical chemokine receptors comprise a three- and therefore deplete chemokine levels in a particular member subfamily of chemokine receptors: Duffy antigen microenvironment to reduce the recruitment of cells to that receptor for chemokines (DARC), D6, and ChemocentryX site; (c) in the transcytosis of chemokines to, in turn, transfer chemokine receptor (CCX-CKR). Among them, CCX-CKR is the ligands across certain barriers; or (d) to retain or present most recently discovered. These receptors differ from other chemokines (2). chemokine receptors in that the signaling elements of In this issue of Clinical Cancer Research, Feng and colleagues traditional chemokines are not conserved, and they are able report for the first time that CCX-CKR is a negative regulator of to bind a broader spectrum of chemokines. To date, there are growth and metastasis in breast cancer (1). Overexpression of no known signaling cascades activated by them (3). It has been CCX-CKR in breast cancer cells inhibited the proliferation and suggested that they might act as decoy receptors to compete for invasion in vitro, as well as the tumor growth and lung metastasis ligand binding, to control the availability of ligands in a in vivo. In their 98-case breast cancer study, a significant particular environment, or that they might mediate trans- correlation between CCX-CKR expression and lymph node metastasis was observed. Higher CCX-CKR expression was negatively correlated with lymph node metastasis; furthermore, Authors’ Affiliations: 1Department ofMolecular and Cellular Oncology, The CCX-CKR was found to be associated with longer patient University ofTexas M. D. Anderson Cancer Center, Houston, Texas; 2Cancer survival. In a multivariated analysis by the Cox risk proportion Biology Program,The University ofTexas, Graduate School ofBiomedical Sciences model, CCX-CKR status was determined to be an independent 3 at Houston, Houston,Texas; and Center for Molecular Medicine, Graduate Institute prognostic factor for disease-free survival in breast patients. ofCancer Biology, China Medical University and Hospital,Taichung 404,Taiwan Received 2/13/09; accepted 2/16/09; published OnlineFirst 4/21/09. Feng and colleagues also showthat CCX-CKR can decrease Commentary on Feng et al., p. 000. CCL19, CCL21, CCL25, and CXCL13 protein levels in xenograft Requests for reprints: Mien-Chie Hung, Department ofMolecular and Cellular tumors and significantly inhibit tumor growth and lung Oncology, Unit 108,The University ofTexas M. D. Anderson Cancer Center, 1515 metastasis, and that mRNA expression of the ligands in CCX- Holcombe Boulevard, Houston,TX 77030. Phone: 713-792-3668; Fax: 713-794- in vitro 3270; E-mail: [email protected]. CKR-transfected cells is not significantly changed , F 2009 American Association for Cancer Research. suggesting that CCX-CKR mediated the internalization and doi:10.1158/1078-0432.CCR-09-0141 degradation of chemokine proteins, similar to those shown in

Fig. 1. A, activation ofthe chemokine receptors on supporting cells in the microenvironment ofbreast cancer results in an enhanced angiogenesis in primary tu mor and promotes metastasis. Certain organs, such as lymph node, have high levels ofchemokines. Breast cancer cells with typical chemokine receptors passi ng through those organs with large amounts ofthe chemokines will be attracted to leave the circulation and enter the organs to develop the metastasis. B, atypical chemokine receptor-expressing breast cancer cells are capable ofdepleting extracellular chemokines; consequently, angiogenesis in the primary tumor and metastasis are inhibit ed.When breast cancer cells with atypical chemokine receptors pass through those organs with large amounts ofchemokines, the atypical chemokine receptor will disrupt the chem okine-chemokine receptor axis and reduce metastasis. previous publications (1). It should be mentioned that those CCR7, CCR9, and CXCR5 are also coexpressed with the ligands are not expressed predominantly by tumor cells, but by atypical receptors like CCX-CKR. Can CCX-CKR also deplete stromal cells and endothelial cells in the microenvironment; the chemokines at the secondary sites, e.g., in lymph node thus, it would be interesting to see whether CCX-CKR in tumor and lung? If so, can it serve the chemokine-chemokine cells might affect the ligand secretion from stromal and receptor axis at the secondary site, and therefore reduce the endothelial cells. Moreover, the authors demonstrate that, over recruitment of migrating cells to the secondary sites? time, CCX-CKR-expressing cells are capable of depleting large Additionally, because atypical chemokine receptors cannot quantities of extracellular chemokines; consequently, intra- transduct signals, can the expression of atypical receptors tumoral neovascularity was inhibited in CCX-CKR-transfected inhibit the adherence and growth of the tumor cells in the xenografts (Fig. 1). The correlation is interesting, and it would metastatic site and therefore reduce the formation of the also be worthwhile to further provide a causal relationship secondary tumor? Will the combination of CCX-CKR and between the depletion of extracelluar chemokines and the typical chemokine receptors be a better prognostic factor for decreased neovascularity. This issue is important, as it has been breast cancer patients? Is CCX-CKR expressed in human reported that activation of the CCR7 receptor on fibroblast-like tumors other than breast cancer, and, if so, does it contribute synoviocytes (FLSs) by CCL19 results in an enhanced VEGF in the same way? And, finally, is it possible that CCX-CKR secretion (9), yet VEGF expression was not changed in the might be a newtherapeutic avenue for cancer treatment? supernatant of CCX-CKR transfectants in this study. Answering all of these questions will increase our understand- The results presented by Feng and colleagues raise many ing of howCCX-CKR regulates the chemotactic networksand interesting questions (1). For example, it remains to be human tumors, and whether it may be a potential cancer determined why the expression of CCX-CKR inhibits angio- intervention in the near future. genesis. Howis the expression of CCX-CKR itself regulated? What is the relationship between the expression of CCX-CKR and typical chemokine receptors? Coexpression of the typical Disclosure of Potential Conflicts of Interest and atypical chemokine receptors in the motile cells raises the interesting question of whether the typical receptors like No potential conflicts of interest were disclosed.

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Xiaoyun Cheng and Mien-Chie Hung

Clin Cancer Res 2009;15:2951-2953.

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