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.
Highlights
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
Several 7TMRs are reported to trigger vascular endothelial growth factor (VEGF) release to boost the formation of new blood vessels, 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
We comprehensively report the most recent findings on the GPCRs involved in vasculogenesis through the activation of developmental pathways, as well as on the most clinically relevant GPCRs involved in the regulation of angiogenesis both in normal and pathological conditions such as sphingosine 1P receptor (S1P1) and thrombin receptor (PAR1)
Summary
The discovery and study of G-protein coupled receptors (GPCRs) has unveiled novel molecular mechanisms through which extracellular signals promote changes in cell functions. Several 7TMRs are reported to trigger VEGF release to boost the formation of new blood vessels, 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 function as receptor for angiogenic ligands, directly mediating endothelial cell function. We discuss the opportunities to translate these major findings in a clinical setting
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