The tumor microenvironment (TME) is a complex and dynamic system that includes various cell types, extracellular matrix components, and signaling molecules. Among the signaling molecules present in the TME, chemokines play a crucial role in regulating the recruitment and activity of immune cells, stromal cells, and cancer cells. Chemokines are small, secreted proteins that bind to specific G protein-coupled receptors (GPCRs) on the surface of target cells. The interaction between chemokines and their receptors regulates cell migration, proliferation, survival, and differentiation.
In the TME, several chemokine receptors are highly expressed on immune cells, stromal cells, and cancer cells. The expression of these receptors is often associated with poor prognosis, tumor progression, and resistance to therapy. In this answer, we will discuss some of the chemokine receptors that are highly expressed in the TME and their functional roles in cancer.
CXCR4
CXCR4 is a GPCR that binds to the chemokine CXCL12 (also known as stromal cell-derived factor 1 or SDF-1). CXCR4 is highly expressed in various types of cancer, including breast, prostate, lung, and pancreatic cancer. CXCL12 is secreted by stromal cells, such as fibroblasts and endothelial cells, and promotes the recruitment of CXCR4-expressing cancer cells to the TME. CXCR4/CXCL12 signaling also regulates the activity of immune cells, such as T cells, dendritic cells, and natural killer cells, in the TME. CXCR4 expression is associated with metastasis, angiogenesis, and therapy resistance in cancer.
CCR2
CCR2 is a GPCR that binds to the chemokines CCL2 (also known as monocyte chemoattractant protein-1 or MCP-1) and CCL7. CCR2 is highly expressed on monocytes and macrophages, which are important components of the TME. CCL2 is secreted by tumor cells, stromal cells, and immune cells, and promotes the recruitment of CCR2-expressing monocytes to the TME. Once in the TME, monocytes differentiate into tumor-associated macrophages (TAMs) and promote tumor growth and invasion. CCR2/CCL2 signaling is also involved in the regulation of angiogenesis and immune suppression in the TME. CCR2 expression is associated with poor prognosis and therapy resistance in cancer.
CXCR2
CXCR2 is a GPCR that binds to the chemokines CXCL1 (also known as growth-regulated oncogene-alpha or GRO-alpha), CXCL2 (also known as GRO-beta), and CXCL8 (also known as interleukin-8 or IL-8). CXCR2 is highly expressed on neutrophils and myeloid-derived suppressor cells (MDSCs), which are important immune cells in the TME. CXCR2 ligands are secreted by cancer cells, stromal cells, and immune cells, and promote the recruitment and activation of CXCR2-expressing neutrophils and MDSCs in the TME. CXCR2/CXCL1 signaling is involved in the regulation of angiogenesis, immune suppression, and tumor growth in the TME. CXCR2 expression is associated with poor prognosis and therapy resistance in cancer.
CCR5
CCR5 is a GPCR that binds to the chemokines CCL3 (also known as macrophage inflammatory protein-1 alpha or MIP-1 alpha), CCL4 (also known as MIP-1 beta), and CCL5 (also known as regulated upon activation, normal T cell expressed and secreted or RANTES). CCR5 is highly expressed on T cells, macrophages, and cancer cells. CCR5 ligands are secreted by stromal cells, such as fibroblasts and endothelial cells, and promote the recruitment and activation of CCR5-expressing immune cells and cancer cells in the TME. CCR5/CCL5 signaling is involved in the regulation of angiogenesis, immune suppression, and tumor growth in the TME. CCR5 expression is associated with poor prognosis and therapy resistance in cancer.
CX3CR1
CX3CR1 is a GPCR that binds to the chemokine CX3CL1 (also known as fractalkine). CX3CR1 is highly expressed on monocytes, macrophages, and some T cells. CX3CL1 is expressed by stromal cells, such as endothelial cells and fibroblasts, and promotes the recruitment and activation of CX3CR1-expressing immune cells in the TME. CX3CR1/CX3CL1 signaling is involved in the regulation of immune surveillance, angiogenesis, and tumor growth in the TME. CX3CR1 expression is associated with better prognosis and improved immune response in cancer.
In conclusion, chemokine receptors play a critical role in the regulation of cell migration, proliferation, survival, and differentiation in the TME. Several chemokine receptors, such as CXCR4, CCR2, CXCR2, CCR5, and CX3CR1, are highly expressed in the TME and are associated with poor prognosis, tumor progression, and therapy resistance in cancer. Targeting these receptors and their ligands may represent a promising strategy for cancer therapy.
