Introduction

A complex cellular network within and between cells coordinates the balance of growth promoting- and growth-inhibiting mechanisms. In cancer cells, however, these control mechanisms are altered and the cells acquire the ability to grow in an unrestricted manner, migrate from their original sites, invade nearby tissues and form metastases at distant organ sites. When a primary tumor and its metastases invade and disrupt tissues with vital functions, they can become lethal.

Cancer is believed to be a genetic disease because alterations are detected within specific genes — either in (pro)oncogenes or tumor suppressor genes.1 Increased expression of or activating mutations within (pro)oncogenes or the loss of expression or function of tumor suppressing genes due, for example, to gene silencing through DNA methylation or inactivating mutations may be crucial determinants for the onset of oncogenesis.

In general, more than one activating or inactivating event must occur in an oncogene or tumor suppressor gene for the initiation and progression of cancer. Key molecular mechanisms of cancer involve (trans)activation of receptor tyrosine kinase signaling pathways, small GTPases, including Ras activating the MAP kinase cascades and Rho family GTPases (Rho, Rac, cdc42), focal adhesion kinase, the Wnt signaling cascade, TGF-p, regulation of cell cycle control (Kip family p21, p27, cyclins, cyclin-dependent kinases), transcriptional activation (e.g. CREB, STATs, NF-kB), and the inactivation of tumor suppressor genes (Rb, p53, APC, PTEN).1 See Figure 5.1. After malignant transformation occurs, microenvironmental factors such as cell adherence to the extracellular matrix, host-tumor interactions, degradation of matrix components, migration, and invasion become essential for tumor progression to the metastatic phenotype.2,3

GPCRs are known to play an essential role in the coordination of cellular communication and more particularly they can activate signaling pathways that control expression and proliferation of genes4 including those mentioned above. Therefore, aberrant GPCR signaling through activating mutations within the GPCRs or due to overexpression of GPCRs or their ligands may lead to transformations that may be able to contribute to the onset or progression of oncogenesis.5-7 Increasing evidence suggests that some GPCRs are implicated in the pathogenesis of cancer and are therefore to be viewed as potential targets for the development of antitumor agents.

This chapter discusses the different GPCR families with respect to their potential contributions to the onset or progression of cancer. Although numerous in vitro GPCRs, in particular those linked to the Gq/phospholipase C (PLC) signaling pathway, induce proliferation, we focus only on those receptors shown to be able to induce tumorigenesis in vivo or for which altered GPCR expression has been detected within tumors. Although no detailed studies exclusively address the contributions of GPCRs to cancers, we try to cite examples of different GPCR families that are potentially linked to cancer.

GPCRs that negatively regulate tumor formation or progression are also described since they may also be considered potential drug targets for the treatment of certain cancers. It is beyond the scope of this chapter to address the mechanisms by which GPCRs induce cancer in full detail. For a more detailed description of

FIGURE 5.1 GPCR-mediated signaling pathways in cancer. Aberrant GPCR signaling through activating mutations within the GPCRs or due to overexpression of GPCRs or their ligands may lead to transformations that may contribute to the onset or progression of oncogenesis. Key molecular mechanisms of cancer that may be activated by GPCRs involve (trans)activation of receptor tyrosine kinase signaling pathways, activation of small GTPases, including Ras activating the MAP kinase cascades and Rho family GTPases (Rho, Rac, cdc42), focal adhesion kinase, and transcriptional activation (e.g., CREB, STATs, NF-kB). PI3K = phosphoinositide-3 kinase. PLC-b = phospholipase C-b. DAG = diacylglycerol. F ak = focal adhesion kinase; MAPK, mitogen-activated protein kinase; TF, transcription factors.

FIGURE 5.1 GPCR-mediated signaling pathways in cancer. Aberrant GPCR signaling through activating mutations within the GPCRs or due to overexpression of GPCRs or their ligands may lead to transformations that may contribute to the onset or progression of oncogenesis. Key molecular mechanisms of cancer that may be activated by GPCRs involve (trans)activation of receptor tyrosine kinase signaling pathways, activation of small GTPases, including Ras activating the MAP kinase cascades and Rho family GTPases (Rho, Rac, cdc42), focal adhesion kinase, and transcriptional activation (e.g., CREB, STATs, NF-kB). PI3K = phosphoinositide-3 kinase. PLC-b = phospholipase C-b. DAG = diacylglycerol. F ak = focal adhesion kinase; MAPK, mitogen-activated protein kinase; TF, transcription factors.

signaling pathways responsible for initiation and progression of cancer, readers are referred to a recent review by Gutkind and colleagues.1

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