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G-protein-coupled receptors and cancer

Key Points

  • 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.

Abstract

G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.

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Figure 1: Diversity of G-protein-coupled receptor signalling.
Figure 2: G-protein-coupled receptors stimulating Gαq, Gαi and Gα12 pathways contribute to cancer cell proliferation.
Figure 3: EP2, a Gαs-coupled receptor involved in colon cancer progression.
Figure 4: Hedgehog and Wnt signalling: emerging roles for G proteins.
Figure 5: G-protein-coupled receptors have a central role in tumour metastasis.
Figure 6: G-protein-coupled receptors in tumour-induced angiogenesis.

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Acknowledgements

We truly regret that we could not cite the seminal work of many of our colleagues owing to space limitations. The authors are supported by funding from the Intramural Research Program of the US National Institutes of Health (NIH) and National Institute of Dental and Craniofacial Research (NIDCR).

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GPCR database

Glossary

Chemokines

The chemokines are small molecular weight (8–10 kDa) secreted proteins that direct the migration of leukocytes to sites of inflammation, and are also important for the trafficking of haematopoietic stem cells, lymphocytes and dendritic cells. More than 50 chemokines have been identified so far; these are classified into four families, CXC, CC, C and CX3C.69 They bind and activate their cognate GPCRs, which are classified based on their ligands as CXCR (1–5), CCR (1–11), XCR1 and CX3CR169.

ERK

A kinase in the MAPK family of proteins that links mitogenic signalling to the activation of nuclear gene expression through the phosphorylation of transcription factors.

Kaposi sarcoma

KS is the most frequent tumour arising in HIV-infected patients, and remains a significant cause of morbidity among the world's AIDS population. KS is a highly angiogenic tumour, with spindle cells, probably of endothelial origin, representing the most prominent cell type.

Nuclear hormone receptors

Transcription factors such as oestrogen and androgen receptors that are activated by a ligand and bind their target DNA sequence, thereby promoting gene expression.

Orphan receptor

A general designation for GPCRs for which ligands have not yet been identified.

'Red hair colour' phenotype

Characterizes those individuals that have red hair, a fair complexion, an inability to tan and a tendency to freckle caused by an allelic variant of MC1R, which increases the susceptibility to melanoma and other cancers.

Hedgehog family

This family of proteins binds to the membrane protein patched, leading to the activation of smoothened, which regulates the Gli family of transcription factors. This signalling pathway is integral to embryonic development, and mutations of this system have been linked to many cancers, including basal-cell carcinoma.

Wnt pathway

The Wnt signalling pathway, which is highly conserved throughout species, regulates cell proliferation, migration, adhesion and differentiation, and has a central role in embryonic development and tissue homeostasis, whereas aberrant Wnt signalling has been implicated in developmental abnormalities and cancer.

Pertussis toxin

An exotoxin produced by Bordetella pertussis that ADP-ribosylates the Gαi, Gαo and Gαt subunits, rendering them incapable of transducing a signal. This toxin has widespread experimental use to characterize the contributions of the Gαi family to various biological systems.

Angiogenic factors

These factors induce the migration, adhesion and proliferation of endothelial cells, therefore resulting in the formation of new blood vessels.

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Dorsam, R., Gutkind, J. G-protein-coupled receptors and cancer. Nat Rev Cancer 7, 79–94 (2007). https://doi.org/10.1038/nrc2069

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