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G Protein-Coupled Receptors at the Crossroad Between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts

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G Protein-Coupled Receptors at the Crossroad Between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts International Journal of Molecular Sciences Review G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts Ernestina M. De Francesco 1,2, Federica Sotgia 3, Robert B. Clarke 2, Michael P. Lisanti 3 and Marcello Maggiolini 1,* ID 1 Department of Pharmacy, Health and Nutrition Sciences, University of Calabria via Savinio, 87036 Rende, Italy; [email protected] 2 Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK; [email protected] 3 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester M5 4WT, UK; [email protected] (F.S.); [email protected] (M.P.L.) * Correspondence: [email protected]; Tel.: +39-0984-493076 Received: 30 October 2017; Accepted: 11 December 2017; Published: 14 December 2017 Abstract: G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases. In this regard, solid tumors have been demonstrated to activate an angiogenic program that relies on GPCR action to support cancer growth and metastatic dissemination. Therefore, the manipulation of aberrant GPCR signaling could represent a promising target in anticancer therapy. Here, we highlight the GPCR-mediated angiogenic function focusing on the molecular mechanisms and transduction effectors driving the patho-physiological vasculogenesis. Specifically, we describe evidence for the role of heptahelic receptors and associated G proteins in promoting angiogenic responses in pathologic conditions, especially tumor angiogenesis and progression. Likewise, we discuss opportunities to manipulate aberrant GPCR-mediated angiogenic signaling for therapeutic benefit using innovative GPCR-targeted and patient-tailored pharmacological strategies. Keywords: GPCR; tumor angiogenesis; tumor microenvironment; VEGF; HIF-1; GPER; SDF-1; sphingosine-1P 1. Introduction Over the past decade, the discovery and study of G-protein coupled receptors (GPCRs) has unveiled novel molecular mechanisms through which extracellular signals promote changes in cell functions. Encoded by more than 900 genes in the human genome, GPCRs belong to one of the largest families of membrane proteins involved in the detection of a wide panel of extracellular stimuli, including photons and ions, as well as peptides, proteins, hormones and phospholipids [1,2]. Members belonging to the GPCR superfamily regulate a broad spectrum of physiological functions, such as vision, smell, and taste, as well as neurological, cardiovascular, endocrine, and reproductive functions [1–3]. GPCRs signal through their association with G-proteins, which are membrane bound heterotrimers consisting of a guanine diphosphate (GDP)-bound α subunit with GTPase activity, Int. J. Mol. Sci. 2017, 18, 2713; doi:10.3390/ijms18122713 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 2713 2 of 26 Int. J. Mol. Sci. 2017, 18, 2713 2 of 27 GPCRs signal through their association with G-proteins, which are membrane bound heterotrimers consisting of a guanine diphosphate (GDP)-bound α subunit with GTPase activity, βγ α and a Gβγ functional monomer [[1–3].1–3]. Based on the sequence of the α subunit, G-proteins are defineddefined α α α α inin fourfour classes classes (G (Gs,αs, G Gq,α Gq, Gi,α andi, and G 12), Gα each12), each coupling coupling to more to thanmore one than receptor one receptor subtypes, subtypes, although withalthough different with affinitydifferent [2 ].affinity GPCRs [2]. are GPCRs classified are classified based on theirbased phylogenetic on their phylogenetic origin and origin sequence and homologysequence homology (Figure1). (Figure 1). Figure 1.1.G-protein G-protein coupled coupled receptors receptors (GPCRs) (GPCRs) classification. classification. The International The International Union of Pharmacology Union of (IUPHAR)Pharmacology classification (IUPHAR) (left classification column) applies (left tocolumn both vertebrates) applies to and both invertebrates vertebrates (Classand invertebrates D and E are unique(Class D to and invertebrates). E are unique The to invertebrates). GRAPH system The (middle GRAPH column) system applies (middle specifically column) applies to vertebrates. specifically to vertebrates. Typically, uponupon ligandligand binding,binding, thethe receptorreceptor undergoesundergoes aa conformationalconformational changechange transmitted to thethe heterotrimer, whose whose tri-dimensional tri-dimensional rearrangem rearrangementent determines determines the the exchange exchange of ofGTP GTP for for GDP GDP on α βγ onthe theα subunitsubunit and and the thedissociation dissociation of the of theGβγ G monomer.monomer. Overlapping Overlapping with with GTP GTP recruitment, recruitment, the α βγ thetransition transition from from“off” “off”to “on” to state “on” allows state the allows Gα and the G βγ andsubunit G tosubunit interact towith interact and regulate with and the regulateactivity of the a activity vast repertoire of a vast of repertoire transduction of transduction effectors, effectors,such as calcium, such as calcium,adenylyl adenylylcyclase, cyclase,phospholipase phospholipase C, phosphodiesterases, C, phosphodiesterases, and protein and kinases protein [4,5]. kinases These [4,5 ].second These messengers second messengers activate activateadditional additional intracellular intracellular pathways pathways such suchas the as themitogen-activated mitogen-activated protein protein kinase kinase (MAPK), phosphoinositide-3 kinase (PI3K)-Akt, small GTP-bindingGTP-binding proteins (Ras and Rho GTPases),GTPases), whichwhich ultimately engageengage transcription transcription factors, factors, leading leading to geneto gene expression expression changes changes [5,6]. [5,6]. Additionally, Additionally, many sevenmany trans-membraneseven trans-membrane receptors receptors (7TMRs) (7TMRs) are orphan are GPCRsorphan withGPCRs unidentified with unidentified ligands and ligands potential and ligand-independentpotential ligand-independent properties, properties, suggesting suggesting that GPCR-mediated that GPCR-mediated action may action include may unexpected include biologicalunexpected functions, biological conceivably functions, unrelated conceivably with unre the classicallated with paradigm the classical of a signal paradigm conveyed of a through signal theconveyed cell membrane through [7the]. In cell addition membrane to their [7]. participation In addition in to an their extraordinary participation number in an of extraordinary physiological processes,number of some physiological of which yetprocesses, to be defined, some GPCRsof which are yet implicated to be defined, in the onsetGPCRs and are evolution implicated of several in the pathologicalonset and evolution conditions, of includingseveral pathological inflammatory conditions, and degenerative including diseases, inflammatory metabolic and imbalances, degenerative and cancerdiseases, [8– metabolic11]. Not surprisingly, imbalances, the and manipulation cancer [8–11]. of aberrant Not surprisingly, GPCR transduction the mani pathwayspulation of holds aberrant great therapeuticGPCR transduction potential pathways [12]. Indeed, holds GPCR-targeting great therapeuti agents,c potential totaling [12]. almostIndeed, one GPCR-targeting third of all currently agents, marketedtotaling almost drugs, one are third excellent of all candidates currently formarketed the treatment drugs, are of a excellent widespread candidates array of for diseases the treatment [12–14]. of a widespread array of diseases [12–14]. Int. J. Mol. Sci. 2017, 18, 2713 3 of 27 For instance, GPCRs as drug targets to halt the anomalous formation of new blood vessels may be a strategy to normalize the dysregulated vascularization, which distinguishes various ischemic and inflammatory conditions and cancer [15]. Neoangiogenesis is an essential physiological and developmental process tightly regulated by a highly coordinated balance between pro- and anti-angiogenic factors. Alterations in this fine-tuned equilibrium could arguably lead to the increased production of pro-angiogenic mediators and the loss of inhibitory factors, which ultimately drive an aberrant vascularization [16–18]. For example, during cancer progression, an excessive vascular growth with abnormal vessel remodeling and tortuosity is actively stimulated by the release in the tumor microenvironment of angiogenic mediators such as vascular endothelial growth factor (VEGF) [19–21]. Several 7TMRs are reported to trigger VEGF release to boost the formation of new blood vessels, particularly during cancer evolution toward an aggressive and metastatic cancer phenotype [22,23], suggesting that GPCRs may serve as novel drug candidates in combination therapies aimed at combatting tumor angiogenesis. In addition to their role in the production of angiogenic factors, 7TMRs also function as receptor for angiogenic ligands,
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