Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy

Soleyman-Jahi, Saeed; Sadeghi, Fatemeh; Khoshbin, Amin Pastaki; Khani, Leila; Roosta, Venus; Zendehdel, Kazem

doi:10.3389/fonc.2019.01014

Cited by 32 publications

(31 citation statements)

References 142 publications

(293 reference statements)

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“…The data support that the studied radiometal Ghrelin inverse agonists could be used for the imaging of functional expression of Ghrelin receptors in vivo that these radiotracers have the potential to gain a deeper understanding on Ghrelin and its receptors in vivo in health and disease, in particular, in cancer [ 31 ]. The Ghrelin binding, constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) has been imaged and quantified by the developed novel compounds, structurally based on the potent inverse agonist KK-(D-1-Nal)-FwLL-NH 2 that were evaluated for receptor binding and efficacy in vitro .…”

Section: Discussionmentioning

confidence: 61%

“…Although widely studied as a promising drug target, our knowledge about Ghrelin signaling, behavior, dynamic interactions with its receptor and functional receptor expression in vivo is still limited and basic bioscientific research is warranted to further evaluate the safety and benefits of Ghrelin drug treatment in patients with cancer [31][32][33]. In vivo imaging of the Ghrelin receptor should help to improve our understanding of its mode of action and might become a powerful tool for diagnosis and drug development [26,34].…”

Section: Research Papermentioning

confidence: 99%

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Development of a ghrelin receptor inverse agonist for positron emission tomography

et al. 2021

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Imaging of Ghrelin receptors in vivo provides unique potential to gain deeper understanding on Ghrelin and its receptors in health and disease, in particular, in cancer. Ghrelin, an octanoylated 28-mer peptide hormone activates the constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) with nanomolar activity. We developed novel compounds, derived from the potent inverse agonist K-(D-1-Nal)-FwLL-NH 2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1glutaric acid-4,7-acetic acid (NODAGA), palmitic acid and/or diethylene glycol (PEG2) to allow radiolabeling and improve pharmacokinetics, respectively. All compounds were tested for receptor binding, potency and efficacy in vitro, for biodistribution and-kinetics in rats and in preclinical prostate cancer models on mice. Radiolabeling with Cu-64 and Ga-68 was successfully achieved. The Cu-64-or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH 2 radiotracer were specifically accumulated by the GHS-R1a in xenotransplanted human prostate tumor models (PC-3, DU-145) in mice. The tumors were clearly delineated by PET. The radiotracer uptake was also partially blocked by K-(D-1-Nal)-FwLL-NH 2 in stomach and thyroid. The presence of the GHS-R1a was also confirmed by immunohistology. In the arterial rat blood plasma, only the original compounds were found. The Cu-64 or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH 2 radiolabeled inverse agonists turned out to be potent and safe. Due to their easy synthesis, high affinity, medium potency, metabolic stability, and the suitable pharmacokinetic profiles, they are excellent tools for imaging and quantitation of GHS-R1a expression in normal and cancer tissues by PET. These compounds can be used as novel biomarkers of the Ghrelin system in precision medicine.

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Section: Discussionmentioning

confidence: 61%

Section: Research Papermentioning

confidence: 99%

Development of a ghrelin receptor inverse agonist for positron emission tomography

et al. 2021

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“…Ghrelin is an endogenous peptide hormone mainly produced in the stomach. Previous research has shown that ghrelin can be a promising therapeutic option for cancer cachexia [ 49 ]. In addition, the KD genes were also enriched in functions related to cell growth, development and metabolism, such as “Biosynthetic process”, “Negative regulation of biological process” and “Cellular macromolecule metabolic process”.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel prognostic biomarkers by integrating multi-omics data in gastric cancer

Liu

Cheng

et al. 2021

BMC Cancer

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Background Gastric cancer is a fatal gastrointestinal cancer with high morbidity and poor prognosis. The dismal 5-year survival rate warrants reliable biomarkers to assess and improve the prognosis of gastric cancer. Distinguishing driver mutations that are required for the cancer phenotype from passenger mutations poses a formidable challenge for cancer genomics. Methods We integrated the multi-omics data of 293 primary gastric cancer patients from The Cancer Genome Atlas (TCGA) to identify key driver genes by establishing a prognostic model of the patients. Analyzing both copy number alteration and somatic mutation data helped us to comprehensively reveal molecular markers of genomic variation. Integrating the transcription level of genes provided a unique perspective for us to discover dysregulated factors in transcriptional regulation. Results We comprehensively identified 31 molecular markers of genomic variation. For instance, the copy number alteration of WASHC5 (also known as KIAA0196) frequently occurred in gastric cancer patients, which cannot be discovered using traditional methods based on significant mutations. Furthermore, we revealed that several dysregulation factors played a hub regulatory role in the process of biological metabolism based on dysregulation networks. Cancer hallmark and functional enrichment analysis showed that these key driver (KD) genes played a vital role in regulating programmed cell death. The drug response patterns and transcriptional signatures of KD genes reflected their clinical application value. Conclusions These findings indicated that KD genes could serve as novel prognostic biomarkers for further research on the pathogenesis of gastric cancers. Our study elucidated a multidimensional and comprehensive genomic landscape and highlighted the molecular complexity of GC.

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“…Indeed, ghrelin has been shown to have a strong anti-inflammatory effect in many organs in both experimental and human models of diseases [66,67], which may help pancreatic beta cells to proliferate and be more functional. All of these factors, coupled with its ability to stimulate growth hormone [68], mean that it is therefore logical that ghrelin would be able to stimulate pancreatic beta cell proliferation. Studies have shown that ghrelin can stimulate GLP-1 [69], which in turn increases pancreatic beta cell mass via a large variety of mechanisms [47].…”

Section: Body Weight Gain Blood Glucose and Glucose Tolerancementioning

confidence: 99%

Exogenous Ghrelin Increases Plasma Insulin Level in Diabetic Rats

et al. 2020

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Ghrelin, a 28-amino acid peptide, is a strong growth hormone secretagogue and a regulator of food intake. In addition, ghrelin is thought to play a role in insulin secretion and in glucose homeostasis. A lot of contradictory data have been reported in the literature regarding the co-localization of ghrelin with other hormones in the islet of Langerhans, its role in insulin secretion and attenuation of type 2 diabetes mellitus. In this study, we investigate the effect of chronic ghrelin treatment on glucose, body weight and insulin level in normal and streptozotocin-induced diabetic male Wistar rats. We have also examined the distribution pattern and co-localization of ghrelin with insulin in pancreatic islet cells using immunohistochemistry and immune-electron microscopy and the ability of ghrelin to stimulate insulin release from the CRL11065 beta cell line. Control, non-diabetic groups received intraperitoneal injection of normal saline, while treated groups received intraperitoneal injection of 5 µg/kg body weight of ghrelin (amino acid chain 24–51) on a daily basis for a duration of four weeks. Our results show that the administration of ghrelin increases the number of insulin-secreting beta cells and serum insulin level in both normal and diabetic rats. We also demonstrated that ghrelin co-localizes with insulin in pancreatic islet cells and that the pattern of ghrelin distribution is altered after the onset of diabetes. Moreover, ghrelin at a dose of 10−6 M and 10−12 M increased insulin release from the CRL11065 beta cell line. In summary, ghrelin co-localizes with insulin in the secretory granules of pancreatic beta cells and enhances insulin production.

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Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy

Cited by 32 publications

References 142 publications

Development of a ghrelin receptor inverse agonist for positron emission tomography

Development of a ghrelin receptor inverse agonist for positron emission tomography

Identification of novel prognostic biomarkers by integrating multi-omics data in gastric cancer

Exogenous Ghrelin Increases Plasma Insulin Level in Diabetic Rats

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