Chemokine Receptors

The family of chemokines is involved in the control and regulation of the immune system by directing the migration and activation of leukocytes during homeostasis through interactions with their respective GPCRs.3,70 However, chemokines appear also to be involved in the leukocyte infiltration of tumors, a characteristic of cancer, and to influence metastatic potential and site-specific spread of tumor cells.3,71

In addition to their chemotactic properties, chemokines and their receptors play a part in other signaling pathways relevant to oncogenesis, including tumor cell growth, survival, protease induction, and angiogenesis. Local production of chemokines directs the infiltration of macrophages and lymphocytes, expressing respective chemokine receptors in human carcinomas of breast, cervix, and pancreas, as well as sarcomas and gliomas.72 In ovarian cancer, several chemokines are found at pico- to nanomolar levels in ascites (accumulations of fluid in the peritoneum resulting from cancer) including CCL2, CCL3, CCL4, CCL5, CCL8, CCL22 and CXCL2, CXCL12.73

Increased expression of chemokines often correlates with tumor-promoting macrophages and lymphocytes, whereas in some cases chemokines are associated with tumor-inhibiting macrophages and lymphocytes. The role of chemokines in malignant tumors appears complex as some chemokines, through activation of their receptors, show antitumor activity by stimulating immune cells or by inhibiting neovascularization. For example, CXCL10 is suggested to have tumor inhibitory functions since it was shown to limit tumor growth and the establishment of metastasis in different tumor cell systems.74

Cancer cells also express chemokine receptors.75,76 CXCR4 appears to be the most widely expressed chemokine receptor in many tumors, including breast, ovarian, and lung cancer.71,77 Its corresponding ligand (CXCL12) is strongly expressed in lung, liver, bone marrow, and lymph nodes, suggesting that the CXCL12-CXCR4 axis is responsible for the primary metastatic destination of breast cancer cells.

In normal breast, ovarian, and prostate tissue, epithelial expression of CXCR4 is either limited or absent. Expression of CXCR4 appears to be regulated by autocrine action of vascular endothelial growth factor (VEGF), upregulated by NF-kB, or regulated by hypoxia-inducible factors and indirectly by genes regulating these factors. It is clear that cancer cells with increased expression of CXCR4 are more likely to form metastases.78

CCR7 is highly expressed in breast cancer, and its CCL21 ligand strongly expressed in lymph nodes and may be responsible for lymph node metastasis.

Expression of CXCR4 or CCR7 into nonmetastasizing cells allowed these cells to metastasize to lung and lymph nodes, respectively, showing the importance of these receptors in directing organ-specific metastasis in vivo.79-80

Melanomas and the cells derived from them have been found to express a number of chemokines including CXCL8, CXCL1-3, CCL5, and CCL2 that have been implicated in tumor growth and progression.8182 Recent studies have demonstrated organ-specific patterns of melanoma metastasis that correlate with expression of specific chemokine receptors including CXCR3, CXCR4, CCR7, and CCR10.

A role of CXCR3 in melanoma cell metastasis to lymph nodes has been demonstrated recently.83 Mouse B16F10 cells were shown to constitutively express CXCR3. Induced expression of CXCL9 and CXCL10 facilitated metastasis, while specific antibodies against CXCL9 and CXCL10 and suppression of CXCR3 expression by antisense RNA attenuated metastasis. Through activation of RhoA and Racl, inducing a reorganization of the actin cytoskeleton, triggering cell chemotaxis and activation of p44/42 and p38 MAPKs in melanoma cells, CXCR3 may contribute to cell motility during invasion and to regulation of cell proliferation and survival.82 CXCL1/GROa has been shown to transform melanocytes that have the ability to form tumors in nude mice, most likely via CXCR2 leading to activation of NF-kB, ultimately controlling the transcription of genes that control cell proliferation.8485

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