Chemokines make a critical contribution to a diverse range of physiological and pathological processes including embryogenesis, immune system development and function, inflammation, tumourigenesis and cancer metastasis.
A complex network of chemokines and their receptors influences the development of primary tumours and cancer metastases. New information about the biological role of chemokines in these cancer related processes is providing insights into host–tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Chemokines are chemotactic cytokines that cause the directed migration of leukocytes, and are induced by inflammatory cytokines, growth factors and pathogenic stimuli.
Chemokine signalling results in the transcription of target genes that are involved in cell invasion, motility, interactions with the extracellular matrix (ECM) and survival.Chemokine signalling can coordinate cell movement during inflammation, as well as the homeostatic transport of haematopoietic stem cells (HSCs), lymphocytes and dendritic cells. Directed migration of cells that express the appropriate chemokine receptor occurs along a chemokine gradient — allowing cells to move towards high local concentrations of chemokines. (Fig. 1)
Figure 1 | Diagram of a chemokine gradient in a cancer. An inflammatory cytokine induces chemokine production by an epithelial tumour cell. A macrophage that expresses the corresponding receptor binds the chemokine and undergoes rapid cytoskeletal rearrangement. This is followed by induction of a transcriptional programme that favours cell migration — for example, induction of matrix metalloproteinases (MMPs) — and cell survival. The cell migrates towards a higher concentration of chemokine. As the chemokine concentration increases, the chemokine receptor can be downregulated. Alternatively, the chemokine-receptor profile of the cell might change under the influence of other inflammatory cytokines or local conditions. This might help to retain the cell at the site of inflammation or to direct it elsewhere.
Epithelial tumour cells produce inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), and chemokines, such as CCL2 and CXCL12. Leukocytes bearing the appropriate chemokine receptors are attracted to the malignant cells, and are themselves stimulated to produce more chemokines and inflammatory cytokines. Autocrine and paracrine networks are established that attract more leukocytes, especially T-helper 2 (TH2) lymphocytes, type-2 macrophages and pre-dendritic cells. The inflammatory leukocytes contribute to tumour growth and progression by producing proteases, angiogenic factors, growth factors and immunosuppressive cytokines.
The significance of chemokine-receptor expression on cancer cells. a | Cancer cells in a primary tumour have metastatic potential, but do not always express chemokine receptors. b | Some cancer cells acquire chemokine-receptor expression by gene mutation, gene fusion or local conditions, such as hypoxia. c | If local levels of the specific chemokine ligand are low, chemokine-receptor-expressing cancer cells can now respond to high levels of ligand at sites of metastasis and migrate towards the chemokine gradient. Alternatively, the acquisition of chemokine receptor might make tumour cells more likely to invade and spread. d | Chemokine ligand at the metastatic site can deliver anti-apoptotic and proliferative signals, and induce tumour-necrosis factor-alpha. This cytokine can initiate a pro-tumour inflammatory network in the surrounding stroma. Hence, the chemokine ligand encourages the tumour cells to survive and grow.