Chemokines and chemokine receptors: new insights into cancer-related inflammation

Abstract

Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future.

Figure 1. Repertoire of chemokines and chemokine receptors expressed in cancer tissues

Close interactions occur between cancer cells and cells of the tumor microenvironment, including endothelial cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), myeloid cells and tumor-associated neutrophils (TAN). Cancer cells produce a variety of chemokines that can modulate the biological properties not only of these cells but also those of associated stromal cells. Similarly, the cells of the tumor microenvironment also provide a source of chemokines that can alter the functions of cancer cells.

Figure 2. Multiple chemokines affect angiogenesis, proliferation, invasion, apoptosis, and senescence

Chemokines can modulate cancer cell proliferation, apoptosis, senescence and invasion and participate in tumor angiogenesis as well as leukocyte infiltration. Cancer cells are shown in red. Recent findings suggest that CXCR7 could be involved in the control of proliferation. CXCR7 could also inhibit apoptosis, whereas CCL2 impedes autophagic death. Senescence is also tightly regulated by CXCR2 and its ligands CXCL1 and CXCL8. Decoy receptors such as DARC and D6 could regulate angiogenesis negatively. Other chemokines such as CXCL1, CXCL8 and their receptor CXCR2 promote angiogenesis. CXCL1 is induced by prostaglandin E2 (PGE2), whereas CXCL8 is negatively regulated by prolylhydroxylase 2 (PHD2). Homing of cancer cells to specific metastatic sites is tightly controlled by chemokines CXCL1,8, 12, CCL5, CCL19, 21, 25, 27 and chemokine receptors CCR5, 7, 9, 10 and CX3CR1. CXCL12 levels are induced by Src (a non-receptor cytoplasmic tyrosine kinase) and in turn can modulate metastasis. CCR7, whose expression is controlled by Notch1 and interstitial flow, plays an active role in metastasis. Several reports have indicated the central role played by TGFβ, which can induce CXCL12 expression, but are also induces CCL2, 5, CXCR2 and CXCR4 expression. In turn, these chemokines and chemokine receptors promote inflammatory cell infiltration. By contrast, TGFβ down-regulates CXCL1, 5, 8, CCL9 and CCR1 levels, which acts to further modulate leukocyte infiltration.

Figure 3. Current and future intervention points for chemokine- and chemokine receptor-based therapies in cancer

The chemokines or chemokine receptors currently targeted in clinical trials are shown in black. Novel candidates for therapeutic targets, based on recent studies of their actions in different stages of cancer development, are shown in red,

Box 1 Figure I. Chemokines and chemokine receptor families[RE3]

Most chemokines can interact with multiple receptors, and a single receptor can interact with multiple chemokines. This is the case for most CC (red) and CXC (green) chemokines. Decoy receptors (black) can also bind multiple chemokines. On the other hand, a minority of receptors (blue) have only one ligand.