Explore the vast range of titles available.

Key Points G protein-coupled receptors (GPCRs) comprise the largest superfamily of receptors involved in transmembrane-initiated transduction pathways and are the most prominent family of validated pharmacological targets in biomedicine. Increasing evidence shows the role of GPCRs in mediating cancer cell proliferation, angiogenesis and metastasis. GPCRs can crosstalk (or transactivate) with other cell surface receptors involved in cancer. For example, epidermal growth factor receptor (EGFR) signalling has a crucial role in regulating the growth, survival, migration and resistance to chemotherapies in numerous human malignancies through functional crosstalk with GPCRs. Major anticancer effects are obtained by targeting both EGFR and the endothelin A subtype receptor. GPCRs and insulin/insulin-like growth factor 1 receptors cooperate in the regulation of many physiological functions as well as in the development of diverse tumours. The diabetes drug metformin prevents this cooperation; in epidemiological studies it reduced the risk of tumours in diabetic patients. G protein-coupled receptor 30 (also known as G protein-coupled oestrogen receptor) mediates rapid effects induced by oestrogens and anti-oestrogens in boths normal and cancer cells. Overexpression of this receptor has been associated with negative clinical features and poor survival rates in patients with hormone-sensitive tumours. The Gα12/13 subfamily of G proteins contributes to cancer development and progression, mainly through the activation of Rho family members which regulate cytoskeletal dynamics, transcriptional regulation, cell cycle progression and cell survival. A GPCR named Smoothened activates the Hedgehog transduction pathway, which is implicated in the development of numerous malignancies. Accordingly, Smoothened antagonists elicit potent antitumour activity by inhibiting Hedgehog-dependent signalling. Many human herpes viruses encode GPCRs which are implicated in virally induced oncogenesis. For example, the Kaposi-sarcoma-associated herpes virus encodes a GPCR that elicits transforming activity, anti-apoptotic effects, stimulation of cell growth and angiogenesis. Many G protein-coupled receptors (GPCRs) are involved in the initiation and/or progression of cancer. Here, the authors discuss recent advances regarding the involvement of GPCRs in cancer and address the implications of these findings towards the discovery of innovative drug targets for cancer prevention and treatment. G protein-coupled receptors (GPCRs) belong to a superfamily of cell surface signalling proteins that have a pivotal role in many physiological functions and in multiple diseases, including the development of cancer and cancer metastasis. Current drugs that target GPCRs — many of which have excellent therapeutic benefits — are directed towards only a few GPCR members. Therefore, huge efforts are currently underway to develop new GPCR-based drugs, particularly for cancer. We review recent findings that present unexpected opportunities to interfere with major tumorigenic signals by manipulating GPCR-mediated pathways. We also discuss current data regarding novel GPCR targets that may provide promising opportunities for drug discovery in cancer prevention and treatment.

[...]of skill to cross (i.e. steroids) or not to cross the cell membrane (i.e. growth factors), extracellular signals are transmitted to intracellular environment through a variety of transduction pathways and sensing cues. [...]conformational changes and signals originating from the ECM may lead to cell–matrix interactions in peculiar sites named focal adhesions. [...]the field is dynamic and exciting due to the chance to facilitate the translation of new therapeutic breakthroughs targeting dysregulated signaling pathways into clinical settings. [...]we are interested in research that investigates and characterizes translational signalling, even taking advantages of systems biology.

One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

G-protein-coupled receptors （GPCRs）, which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-pro- teins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses medi- ated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

[...]GPER has generated increasing attention in the scientific community and the synthesis of GPER modulators could open promising perspectives for the treatment of various diseases. [...]ERα17p decreases by about 50% the size of triple negative breast tumors xenografted in BalbC−/− nude mice, at the dose of 1.5 mg/kg body weight, three times per week during 4 weeks (Pelekanou et al., 2011). Supporting previous data, a specific GPER antibody concomitantly used with a fluorescein-labeled version of ERα17p revealed superimposed fluorescence signals in SKBr3, therefore indicating a physical interaction between ERα17p and GPER (Lappano et al., 2019). [...]docking studies showed that ERα17p interacts in the low micromolar range through its N-terminal PLMI motif with the same extracellular GPER pocket, and more specifically through hydrogen and hydrophobic contacts with the residues Gln-138, Pro-192 and Ala-209, as displayed by other ligands (Lappano et al., 2019;Kampa et al., 2023). [...]the PLMI peptide displays similar effects as ERα17p.

Background: Bisphenol A (BPA) is the principal constituent of baby bottles, reusable water bottles, metal cans, and plastic food containers. BPA exerts estrogen-like activity by interacting with the classical estrogen receptors (ERα and ERß) and through the G protein-coupled receptor (GPR30/GPER). In this regard, recent studies have shown that GPER was involved in the proliferative effects induced by BPA in both normal and tumor cells. Objectives: We studied the transduction signaling pathways through which BPA influences cell proliferation and migration in human breast cancer cells and cancer-associated fibroblasts (CAFs). Methods and results: We used as a model system SKBR3 breast cancer cells and CAFs that lack the classical ERs. Specific pharmacological inhibitors and gene-silencing procedures were used to show that BPA induces the expression of the GPER target genes c-FOS, EGR-1, and CTGF through the GPER/EGFR/ERK transduction pathway in SKBR3 breast cancer cells and CAFs. Moreover, we observed that GPER is required for growth effects and migration stimulated by BPA in both cell types. Conclusions: Results indicate that GPER is involved in the biological action elicited by BPA in breast cancer cells and CAFs. Hence, GPER-mediated signaling should be included among the transduction mechanisms through which BPA may stimulate cancer progression.

Background Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. Methods In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. Results We first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. Conclusions Our data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.

G protein-coupled receptors (GPCRs) are transmembrane signal transducers that regulate a plethora of physiological and pathological processes [...].G protein-coupled receptors (GPCRs) are transmembrane signal transducers that regulate a plethora of physiological and pathological processes [...].

Background The G protein estrogen receptor GPER/GPR30 mediates estrogen action in breast cancer cells as well as in breast cancer-associated fibroblasts (CAFs), which are key components of microenvironment driving tumor progression. GPER is a transcriptional target of hypoxia inducible factor 1 alpha (HIF-1α) and activates VEGF expression and angiogenesis in hypoxic breast tumor microenvironment. Furthermore, IGF1/IGF1R signaling, which has angiogenic effects, has been shown to activate GPER in breast cancer cells. Methods We analyzed gene expression data from published studies representing almost 5000 breast cancer patients to investigate whether GPER and IGF1 signaling establish an angiocrine gene signature in breast cancer patients. Next, we used GPER-positive but estrogen receptor (ER)-negative primary CAF cells derived from patient breast tumours and SKBR3 breast cancer cells to investigate the role of GPER in the regulation of VEGF expression and angiogenesis triggered by IGF1. We performed gene expression and promoter studies, western blotting and immunofluorescence analysis, gene silencing strategies and endothelial tube formation assays to evaluate the involvement of the HIF-1α/GPER/VEGF signaling in the biological responses to IGF1. Results We first determined that GPER is co-expressed with IGF1R and with the vessel marker CD34 in human breast tumors ( n  = 4972). Next, we determined that IGF1/IGF1R signaling engages the ERK1/2 and AKT transduction pathways to induce the expression of HIF-1α and its targets GPER and VEGF. We found that a functional cooperation between HIF-1α and GPER is essential for the transcriptional activation of VEGF induced by IGF1. Finally, using conditioned medium from CAFs and SKBR3 cells stimulated with IGF1, we established that HIF-1α and GPER are both required for VEGF-induced human vascular endothelial cell tube formation. Conclusions These findings shed new light on the essential role played by GPER in IGF1/IGF1R signaling that induces breast tumor angiogenesis. Targeting the multifaceted interactions between cancer cells and tumor microenvironment involving both GPCRs and growth factor receptors has potential in future combination anticancer therapies.

Cancer cells orchestrate the surrounding tumor microenvironment ( TME ) to strike a fine balance between tissue regeneration providing them with nutrients, and tissue destruction triggered by immunogenic alarm signals. At steady state, the tenuous balance favors cancer growth. Therapies aimed at enhancing the immunogenic properties of cancer cells or the reacting immune responses can, however, revert the equilibrium to clear the host of cancer. The understanding of factors that affect this balance is progressing rapidly due to advances in high throughput technologies disclosing from previously uncharted territories new biologies referred to as “dark matter”. These advances are critical for the understanding of the true mechanisms leading to immune-mediated cancer rejection. This review focuses on cancer genetic, epigenetic and metabolic derangements that approximate those caused by intra-cellular pathogen infection, a phenomenon referred to as “ viral mimicry ” ( VM ) and other aspects of cancer/host cells interactions unexplored in the past that enhance the VM effects. On the cancer side, VM prompts alterations of cancer cell metabolism leading to the generation of aberrant cellular products recognized as foreign by the host’s immune system. The latter are defined as “ dark matter ” to emphasize the powerful effects exerted by these obscure bioproducts on the TME as the mass of invisible particles can dictate the rotational period of galaxies. On the other side, a myriad of previously unappreciated factors can influence the host responses. Thus, here we propose an extended definition of dark matter beyond the limits of cancer cell-intrinsic biology, to a broader interpretation encompassing elements that influence the cellular networks within the TME.