Orphan GPCRs

RDC-1, defined as a GPCR, appears to be highly expressed in tumor endothelial cells of both brain and peripheral vasculature and is therefore considered a tumor endothelial marker.173 Other GPCRs including GPCR mas, GPR35, TDAG8, GPR4, G2A, and D-GPCR are linked to signaling pathways that control proliferation or are reported to be upregulated in certain cancers.174-177 GPR54, also known as hOT7T175 and AXOR12, is the receptor for the peptide derived from the KISS1 gene, which is known as metastin or kisspentin-54. KISS1 is a suppressor gene that inhibits metastasis in both in vivo melanoma and breast cancer carcinoma models.178


It is apparent that GPCRs are able to modulate signaling pathways that control cell proliferation. Activating mutations within the GPCRs or overexpression of GPCRs or their ligands may lead to transformation and may contribute to the onset or progression of oncogenesis.5

Mutational alterations of key amino acids, for example, in the C-terminal region of the third intracellular loop or conserved DRY motif, may render the GPCR consti-tutively active179 and confer oncogenic properties to the receptor. Spontaneous mutations may acquire an agonist-independent transformation capability, subvert the normal function of these receptors, and result in disease states associated with uncontrolled cell growth including neoplasia.10180 As discussed in this chapter, several constitutively active mutations in GPCRs have been linked to carcinomas including activating mutations in the TSH (thyroid insular carcinoma),39 MCR1 (melanoma), LH (testicular carcinoma),35 and smoothened receptors (basal cell carcinoma).138 Constitutive activity is without doubt also a hallmark of many virally encoded receptors such as ORF74 encoded by KSHV. Transgenic expression of ORF74 induces an angioproliferative disease resembling KS, indicating that ORF74 acts as a viral oncogene.

Besides the inherited or acquired (spontaneously activated) GPCR mutants, GPCRs and their respective ligands may be upregulated in certain disease states, thus enhancing their oncogenic potential. Clear examples include the upregulation of chemokine receptor CXCR4 and its corresponding ligand CXCL12 (breast cancer), LPA and its cognate receptors (ovarian and prostate cancer), CCK2R (colon cancer), PAR-1 (breast cancer, melanoma), endothelin receptors (melanoma and ovarian cancer), and metabotropic mGluR1 (melanoma). Activation of some GPCRs, including adenosine A3, dopamine D2, cannabinoid CB1, peptidergic somatostatin SSTR, bombesin and LH receptors were shown to inhibit tumor progression, suggesting that these receptors may represent targets to counteract aberrant proliferation. The use of cytotoxic conjugates targeting the peptidergic receptors appears promising.

In order to effectively target GPCRs in certain cancers, one should determine the molecular basis by which GPCRs play a role in the onset or progression of the disease. A thorough investigation of the ways mutant or overexpressed GPCRs or their ligands affect tumorigenic pathways is essential and will provide novel targets for future therapeutic intervention. Important for the aforementioned constitutively active receptors is the use of inverse agonists, whereas in case of GPCR overexpression or upregulation of endogenous ligands, neutral antagonists are recommended as therapeutic agents targeting these receptors.

The completion of the sequencing of the human genome and genome studies has already improved our understanding of how cancer initiates or progresses and will continue to do so. The use of microarrays helps us dissect genetic events in specific cancer cells. Expression profiles of DNA allow us to predict hereditary cancer, assist in identifying specific disease markers that may serve as new pharmacological targets for therapeutic intervention, and enable us to type the various stages and progression of the disease. Certain orphan GPCRs have been shown to play important roles in tumor biology and thus appear potential targets for drug development. Collections of large datasets, including tumor banks and family, twin, and case-controlled studies, are expected to provide more information on new drug targets with respect to cancer treatment. Because GPCRs have proven to be successful drug targets based on their functionality and membrane localization, and because their role in cancer is becoming apparent, GPCRs are emerging targets for therapeutic intervention in cancer patients.

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