GPCR Markers for Cancer Research

• What Are GPCRs?
• GPCRs in Cancer Research
• Neurohormonal GPCRs
• GPCR and Oncoviruses
• Rhodopsin-Like GPCRs
• Frizzled GPCRs and Wnt Signaling
• Adhesion GPCRs
• GPCRs and Chemokines
• GPR132: A Potential Tumor Suppressor
• GPCR Antibody Products
• References

G protein-coupled receptors (GPCRs) allow for the communication between the environment and the cell’s interior - they transduce extracellular stimuli into intracellular signals. GPCRs play an essential role in different physiological functions and have been well documented in many forms of cancer, contributing to cancer proliferation, angiogenesis, invasion, and metastasis. GPCRs are suitable biomarkers for the early diagnosis of cancer. 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. Read on to explore the role of some selected GPCR markers in cancer research development and treatment.

What Are GPCRs?

G protein-coupled receptors (GPCRs) are also known as seven-transmembrane domain (7TM) receptors. They belong to a vast family of signaling proteins that mediate cellular responses to most hormones, metabolites, chemokines, and neurotransmitters.

With more than 800 identified members, the human GPCRs gene family remains the largest in mammals, including humans. Among the plethora of functions assigned to these proteins, one could mention mood and affective behavior, cardiovascular regulation, immunity and inflammation, olfaction, and pain ¹. Among the 800 family members, only four proton-sensing receptors GPR132 (G2A), GPR4, GPR65 (TDAG8), and GPR68 (OGR1), are known to regulate acidity (pH) in the cellular environment ¹. Except for protons, these receptors have no other known ligand and are hence called “orphan”.

The GPCRs that are known so far fall into six classes based on sequence and function:

• Class A: Rhodopsin-like receptors
• Class B: Secretin family
• Class C: Metabotropic glutamate receptors
• Class D: Fungal mating pheromone receptors
• Class E: cAMP receptors
• Class F: Frizzled (FZD) and Smoothened (SMO) receptors

GPCRs constitute the most significant and druggable therapeutic target category, in fact, any pharmaceutical drug in development targets a transmembrane receptor, mainly a GPCR ^2,3. Finding new ways to modulate GPCR signaling to increase their efficacy and at the same time blocking the adverse effects remains an important and tremendous challenge in pharmaceutical development.

GPCRs in Cancer Research

GPCRs are attractive drug targets due to their relevance in a plethora of disease conditions ⁴. Despite a considerable body of information, GPCRs have not presented themselves as a valid “genetic driver” in cancer. Hence, GPCRs have remained neglected or at least understudied as molecular targets in oncology.

The past decades have experienced a changed perception towards the role of GPCRs in cancers. Today we know that aberrant GPCR expression may contribute to oncogenesis mechanisms, including metastasis, therapy resistance, and immune evasion. Yet surprisingly, few GPCR-based therapies have found their way to the oncologist at the clinic. Despite recent advancements in the structural and functional knowledge of GPCRs, only eight FDA-approved drugs target GPCRs for cancer therapy (Table 1) ⁵. Current and future research aim to discover the potential benefits of targeting GPCRs and their signaling circuits for the new era of precision medicine and cancer immunotherapies.

Table 1. FDA-approved GPCR drugs against different cancers.

Receptor	Drug	Cancer Therapy	Approval
Dopamine receptor D1 (DRD1)	Cabergoline	Neuroendocrine tumors, pituitary tumors	1996
Somatostatin receptor (SSTR)	Lanreotide	Pancreatic cancer	2007
Gonadotropin-releasing factor hormone receptor (GnRH)	Degarelix	Prostate cancer	2008
C-X-C chemokine receptor 4 (CXCR4)	Plerixafor	Multiple myeloma	2008
Smoothened receptor (SMO)	Vismodegib (Erivedge)	Locally advanced and metastatic basal cell carcinoma	2012
Estrogen receptor (ER)	Raloxifene	Breast cancer	2014
Smoothened receptor (SMO)	Sonidegib	Locally advanced and metastatic basal cell carcinoma	2015
C–C Chemokine receptor 4 (CCR4)	Mogamulizumab	T cell lymphoma	2018

The first study of GPCRs and cancer was published in 1986 when a new human oncogene called MAS was noted for its tumorigenicity in nude mice ⁶. This protein was found to be very hydrophobic with seven potential transmembrane domains. In this respect, the structure of the MAS protein was a novelty among cellular oncogene products. For this reason, MAS constituted an entirely new functional class of oncogenes carrying no oncogenic mutations ⁶. The MAS1 proto-oncogene-like GPCR binds the neuroregulatory peptide angiotensin and is expressed in the testis, breast, cervical, lung, and pancreatic cancers ⁷.

Figure 1. Immunohistochemical staining of human testis with anti-MAS1L polyclonal antibody (Cat. No. HPA017983) shows strong positivity in basal cells of ductus seminiferous.

The first example of a classical GPCR neurotransmitter receptor with transforming properties was the serotonin 5HT1C-receptor (HTR1C) that, when expressed in mouse fibroblasts, generated sarcomas (tumors) ⁸. The identification of activating mutations in the thyrotropin receptor gene (TSHR) in hyperfunctioning thyroid adenomas provided more evidence that mutant GPCRs could initiate a neoplastic disease ⁹. The muscarinic acetylcholine (mAChRs) family of the GPCR rhodopsin-like receptors subtypes (CHRM1 (Cat. No. HPA014101), CHRM2, and CHRM3) reveals oncogenic potential. Ligand-stimulation of mAChRs linked to phosphatidylinositol hydrolysis can act as conditional oncogenes showing the transforming ability of mouse fibroblast ¹⁰.

Like other oncogenes, tumor-generating mutations also occur among GPCRs, such as for the α-adrenergic receptor 1B (ADRA1B, Cat. No. HPA074416) inducing tumor generation in nude mice ¹¹. These early studies presented a new and unexpected role for GPCRs as capable of oncogenic transformation. More recently, another interesting example of a mutated GPCR turned tumorigenic is the cysteinyl-leukotriene receptor 2 (CysLTR2, Cat. No. HPA046528), which has a single mutation in transmembrane helix 3 (mutant CysLTR2-L129Q), causing uveal melanomas in humans ¹².

Neurohormonal GPCRs

The two members of the bombesin family of regulatory peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB), are strongly implicated in cancer development ^13,14. The GRP receptor (GRPR) has higher selectivity for GRP over NMB, whereas the NMB receptor (NMBR) has the reverse pattern.

These GPCR-ligands are highly expressed/produced in different tumors where they act as autocrine or paracrine growth factors. GRPR and NMBR are frequently overexpressed in colorectal tumors, gliomas and lung carcinomas, ovarian epithelial cancers, and neuroendocrine tumors of the gut and lung ^15,16. Many of the growth stimulatory effects of these GPCRs are mediated through the transactivation of the tyrosine kinase receptors like the EGF and HER2 receptors, belonging to an entirely different class of transmembrane proteins with kinase activity ¹⁷.

Another category of neurohormonal GPCRs involved in cancer is the category of somatostatin receptors SSTR1 and SSTR2, expressed in both small cell (SCLC) and non-small cell lung cancer (NSCLC) ¹⁸. Radiolabeled SSTR2 analogs are utilized for radiographic imaging of tumors, which, in combination with PET-CT, provides improved lung cancer detection. SSTR2 analogs are also an interesting candidate for targeted chemotherapy and radiotherapy ^19,20.

Figure 2. Immunohistochemical staining of human stomach with anti-SSTR1 polyclonal antibody (Cat. No. HPA031506) shows moderate to strong positivity in luminal membrane in glandular cells, in brown.

Figure 3. Immunofluorescent staining of human cell line A-431 with anti-SSTR2 polyclonal antibody (Cat. No. HPA007264) shows localization to cytosol, in green. Microtubules are shown in red and nuclei in blue.

GPCR and Oncoviruses

Oncoviruses are cancer-causing viruses. The human hepatitis B (HBV) and C (HCV), the human papillomaviruses (HPV), the Epstein–Barr virus (EBV), and the Kaposi sarcoma herpesvirus (KSHV) are the most important human oncoviruses currently known. Interestingly, some virally encoded and constitutively activated GPCRs promote and sustain tumorigenesis.

An example of GPCR and oncovirus is the “hijacked” GPCR known as KSHV-vGPCR (or ORF74). ORF74 is a highly constitutively active GPCR encoded and expressed by the HHV herpesvirus 8 (HHV8). ORF74 is involved in the pathogenesis of Kaposi’s sarcoma (a tumorous skin lesion in immunocompromised patients, including those with progressed HIV/AIDS) ²¹.

As for the “classical” oncogenes belonging to the kinase category, most were originally identified in retroviruses. The dawn of these studies opened a new door to establish the link between GPCRs and cancers.

Figure 4. Staining with anti-C2ORF74 polyclonal antibody (Cat. No. HPA026826). (A) Immunohistochemical staining of human stomach shows strong cytoplasmic positivity in parietal cells. (B) Immunofluorescent staining of human cell line U-251 MG shows positivity in centrosome and nucleus but excluded from the nucleoli.

Rhodopsin-Like GPCRs

The neuropeptide Y (NPY) is a neuropeptide that can also regulate the growth of various tumors. The NPY receptors belong to the class A or rhodopsin-like GPCR ²². Neuroblastoma and Ewing’s sarcoma (two pediatric tumor types) produce high levels of NPY. The hypoxic condition of the tumor microenvironment of these solid cancers upregulates and promotes the Y2R/Y5R NPY signaling axis ²³. By stimulating the cognate receptors, Y2R and Y5R, NPY promotes the survival, migration, and angiogenesis of these neoplasias.

Another category of rhodopsin-like GPCRs involved in cancer is the tachykinin receptors, including the substance P receptor/NK1R/TACR1. Substance P induces tumor cell proliferation, angiogenesis, and cancer cell migration. Moreover, tumor cells frequently overexpress TACR1 (Cat. No. HPA074573). Interestingly, the TACR1 antagonist, aprepitant, shows promising anti-tumorigenic activity ²⁴.

Figure 5. Immunohistochemical staining of human skin with anti-TACR1 polyclonal antibody (Cat. No. HPA074573) shows strong cytoplasmic positivity in epidermal cells in the basal layer.

Frizzled GPCRs and Wnt Signaling

The frizzled group of GPCRs is evolutionarily conserved and serves to transduce signals from the Wnt-type lipoprotein growth factors. Several cancers display dysregulated Wnt signaling pathways. Originally defined as a Wnt target gene, potentiating the canonical Wnt/β-Catenin signaling, the Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5 or GPR49, Cat. No. HPA012530) represents an exquisitely specific and almost “generic” marker of normal stem cells in several tissues, including the intestine ²⁵.

LGR5 has been proposed as an independent prognostic marker and as a therapeutic target for colorectal cancer, although, in this context, its role appears very complex ²⁶.

Figure 6. Immunohistochemical staining of human colon with anti-LGR5/GPCR49 polyclonal antibody (Cat. No. HPA012530) shows cytoplasmic positivity in glandular cells, in brown.

Adhesion GPCRs

The adhesion G protein-coupled receptors (aGPCRs) constitute a large yet poorly understood family of seven-transmembrane proteins. There is ample evidence for the implication of tumor-associated adhesion-GPCRs in tumorigenesis. These receptors affect the growth of tumor cells, angiogenesis, tumor cell migration, invasion, and metastasis, either positively or negatively ²⁷.

Additionally, some adhesion-GPCRs are considered to be potential biomarkers for specific types of cancers. ADGRG1/GPR56 is upregulated in some colorectal cancer tissues but shows anti-metastatic properties in melanoma via inhibition of cell-extracellular matrix signaling ^28,29.

Another member of the adhesion GPCRs family involved in cancer is the glioma marker ADGRL4 (AMAb91268), which promotes glioblastoma through hypoxia signaling and is considered a target for anti-cancer therapy ³⁰.

GPCRs and Chemokines

Chemokines are small soluble cytokines that guide the migration of other cell types, particularly immune cells. The chemokines have a plethora of important roles in cancer, not least in association with metastasis and tumor immunity ³¹. Most chemokines act through GPCRs and play critical roles in tumor growth, angiogenesis, invasion, and leukocyte infiltration into the tumor. One example includes CCL2 (Cat. No. HPA019163), a chemokine secreted from tumors acting through its receptor CCR2 to promote prostate tumor growth and stimulate tumor angiogenesis ^32,33.

Most solid tumors undergoing metastasis do so via lymph nodes. One example is the chemokine (C-C motif) ligand 1 CCL1 (Cat. No. HPA049861) that attracts CCR8-positive distal tumor cells towards the lymph node ³⁴. Strategies to block the ligand interactions with these GPCRs would be of great therapeutic value.

Chemokine/chemokine receptor signaling is also known to regulate tumor immunity. Hypoxia in the ovarian cancer tumor causes the induction of CCL28 (Cat. No. HPA077434). The upregulated CCL28 accelerated tumor growth by binding to its cognate GPCR, CCR10 (Cat. No. HPA013819), and activation of the immunosuppressive regulatory T-cells (Tregs) ³⁵.

GPR132: A Potential Tumor Suppressor

The early GPCR-derived oncogene G2A, also known as GPR132 (Cat. Nos. HPA029694, HPA029695), is a member of the proton-sensing GPCRs subfamily. This GPCR induces a full range of phenotypes characteristic of oncogenic cellular transformation of mouse fibroblasts and tumorigenicity ^36,37. Inhibition of GPR132 is a potentially novel treatment for reducing cancer metastasis. Loss of GPR132 in mice inhibits breast cancer metastasis, and lower GPR132 expression in patients with breast cancer correlates with better metastasis-free survival ³⁸.

Figure 7. Immunohistochemical staining of a human lymph node with anti-GPR132 antibody (Cat. No. HPA029695) shows strong cytoplasmic positivity in non-germinal center cells.

GPCR Antibody Products

Product Name	Alternative Gene Names	Cat. No.	Clonality	Validated Applications	Seq Identity Mouse / Rat
Anti-ACKR2	CCBP2, CCR10, CCR9	HPA013819	Polyclonal	IHC*	56% / 56%
Anti-ADGRG2	EDDM6, GPR64,HE6	HPA001478	Polyclonal	IHC*	78% / 78%
Anti-ADGRG2	EDDM6, GPR64,HE6	HPA050029	Polyclonal	IHC*, WB*	76% / 75%
Anti-ADGRG4	GPR112, PGR17	HPA035324	Polyclonal	IHC	79% / 27%
Anti-ADGRL4	ELTD1, ETL	AMAb91268	Monoclonal	IHC, WB	53% / 55%
Anti-ADGRE5	CD97, TM7LN1	HPA013707	Polyclonal	IHC*	49% / 51%
Anti-ADGRG5	GPR114, PGR27	HPA007133	Polyclonal	IHC*, ICC-IF	61% / 61%
Anti-ADGRG6	FLJ14937, GPR126	HPA017346	Polyclonal	IHC	55% / 53%
Anti-ADRA1B	-	HPA074416	Polyclonal	ICC-IF	96% / 94%
Anti-C2orf74	LOC339804	HPA026826	Polyclonal	IHC, ICC-IF	50% / 47%
Anti-CCL1	I-309, P500, SCYA1	HPA049861	Polyclonal	IHC	36% / 37%
Anti-CCL2	GDCF-2, HC11, MCAF	HPA019163	Polyclonal	IHC, ICC-IF	65% / 60%
Anti-CCL28	CCK1, MEC, SCYA28	HPA077434	Polyclonal	IHC	87% / 94%
Anti-CCR7	CD197, CDw197, CMKBR7	HPA031383	Polyclonal	ICC-IF	83% / 85%
Anti-CCR7	CD197, CDw197, CMKBR7	HPA074467	Polyclonal	ICC-IF	88% / 88%
Anti-CCR8	CMKBRL2, CY6, GPR-CY6	HPA042383	Polyclonal	IHC	50% / 58%
Anti-CHRM1	-	HPA014101	Polyclonal	IHC*	98% / 97%
Anti-CXCR3	CD183, CMKAR3, GPR9	HPA045942	Polyclonal	IHC*	67% / 67%
Anti-CXCR5	BLR1, CD185, MDR15	HPA042432	Polyclonal	IHC*	47% / 42%
Anti-CYSLTR2	CysLT(2), CYSLT2R	HPA046528	Polyclonal	IHC	35% / 37%
Anti-FPR2	FMLP-R-II, FMLPX, FPR2A	HPA029154	Polyclonal	IHC	63% / 63%
Anti-GPBAR1	GPCR, GPCR19, GPR131	HPA062890	Polyclonal	IHC*	82% / 75%
Anti-GPR4	-	HPA014278	Polyclonal	IHC	96% / 96%
Anti-GPR27	SREB1	HPA029395	Polyclonal	WB, ICC-IF	91% / 91%
Anti-GPR39	-	HPA022111	Polyclonal	IHC	55% / 54%
Anti-GPR132	G2A	HPA029694	Polyclonal	IHC	54% / 54%
Anti-GPR132	G2A	HPA029695	Polyclonal	IHC	36% / 42%
Anti-GPR143	OA1	HPA003648	Polyclonal	IHC*	55% / 55%
Anti-GPR162	A-2, GRCA	HPA055135	Polyclonal	IHC*, WB, ICC-IF	97% / 94%
Anti-GPR17	-	HPA029766	Polyclonal	IHC*	92% / 92%
Anti-GPR37L1	ETBR-LP-2	HPA064454	Polyclonal	IHC*	77% / 81%
Anti-GPR65	hTDAG8, TDAG8	HPA054454	Polyclonal	ICC-IF	61% / 63%
Anti-KNG1	BDK, BK, KNG	HPA001616	Polyclonal	IHC*, WB	62% / 61%
Anti-KNG1	BDK, BK, KNG	HPA001645	Polyclonal	IHC*, WB*	59% / 58%
Anti-LGR5	FEX, GPR49, GPR67, HG38	HPA012530	Polyclonal	IHC	88% / 87%
Anti-LRP6	ADCAD2	HPA029925	Polyclonal	IHC*	96% / 97%
Anti-MAS1L	dJ994E9.2, MAS-L, MRG	HPA017983	Polyclonal	IHC, ICC-IF	25% / 23%
Anti-NMUR2	NMU2R	HPA045836	Polyclonal	IHC	56% / 53%
Anti-SSTR1	-	HPA031506	Polyclonal	IHC	98% / 98%
Anti-SSTR2	-	HPA007264	Polyclonal	IHC, WB*, ICC-IF	98% / 96%
Anti-TACR1	NK1R, SPR, TAC1R	HPA074573	Polyclonal	IHC	100% / 100%
Anti-TACR2	NK2R, NKNAR, SKR, TAC2R	HPA076573	Polyclonal	ICC-IF	81% / 78%
Anti-TACR3	NK3R	HPA009418	Polyclonal	IHC	60% / 55%
Anti-TBXA2R	-	HPA077366	Polyclonal	ICC-IF	82% / 75%

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