G-protein-coupled receptors and cancer

G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors that regulate many cell functions, including cell proliferation, survival and motility, and have recently emerged as key players in tumour growth, angiogenesis and metastasis.Although some endocrine tumours arise from constitutively-active mutant forms of GPCRs and G proteins, the aberrant overexpression of GPCRs and their autocrine and paracrine activation by agonists released by tumour or stromal cells represents the most frequent tactic used by cancer cells to stimulate GPCRs and their signalling networks.Prostaglandin E2 (PGE2) resulting from cyclooxygenase 2 (COX2) activity, the release of chemokines such as stromal cell-derived factor 1 (SDF1; also known as CXCL12) and interleukin 8 (IL8; also known as CXCL8), lipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), and neuropeptides such as gastrin-releasing peptide (GRP) and endothelin are all implicated in stromal–cancer-cell interactions that promote tumour growth, neovascularization and metastatic spread.Tumour cell proliferation is regulated by many neuropeptides, PGE2, thrombin, S1P, LPA and IL8, which signal through their cognate receptors to stimulate Gαs, Gαi, Gαq and Gα12 thereby initiating the activity of a signalling network that includes second-messenger-generating systems, small GTPases of the Ras and Rho families, and mitogen-activated protein kinase (MAPK) cascades that regulate the nuclear expression of growth-promoting genes.Tumour cells that express CXCR4 receptors are guided towards gradients of the chemoattractant SDF1, which is released by organs that serve as secondary sites for cancer cell colonization.IL8 that is released from cancer cells and endothelial cells promotes angiogenesis by acting on CXCR2 receptors to supply nutrients to the tumour. Other GPCR agonists, such as chemokines, PGE2 and S1P also contribute to tumour-induced angiogenesis through the regulation of extracellular matrix degradation and endothelial cell permeability, proliferation and migration.Many GPCRs represent suitable biomarkers for the early diagnosis of cancer, and the pharmacological inhibition of GPCRs and their downstream targets might provide an opportunity for the development of new, mechanism-based strategies for cancer prevention and treatment.