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Ghrelin is a peptide hormone which, when acylated, regulates appetite, energy balance and a range of other biological processes. Ghrelin predominately circulates in its unacylated form (unacylated ghrelin; UAG). UAG has a number of functions independent of acylated ghrelin, including modulation of metabolic parameters and cancer progression. UAG has also been postulated to antagonise some of the metabolic effects of acyl-ghrelin, including its effects on glucose and insulin regulation. In this study, Rag1-/- mice with high-fat diet-induced obesity and hyperinsulinaemia were subcutaneously implanted with PC3 prostate cancer xenografts to investigate the effect of UAG treatment on metabolic parameters and xenograft growth. Daily intraperitoneal injection of 100 μg/kg UAG had no effect on xenograft tumour growth in mice fed normal rodent chow or 23% high-fat diet. UAG significantly improved glucose tolerance in host Rag1-/- mice on a high-fat diet, but did not significantly improve other metabolic parameters. We propose that UAG is not likely to be an effective treatment for prostate cancer, with or without associated metabolic syndrome.

Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. Here, the long-term effects of a 23% Western high-fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1 −/− ) suitable for engraftment with human-derived tissue xenografts, and the effect of diet-induced hyperinsulinaemia on human prostate cancer cell line xenograft growth, were investigated. Rag1 −/− and NOD/SCID HFD-fed mice demonstrated diet-induced impairments in glucose tolerance at 16 and 23 weeks post weaning. Rag1 −/− mice developed significantly higher fasting insulin levels (2.16 ± 1.01 ng/ml, P  = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, P  = 0.01) compared to low-fat chow-fed mice (0.71 ± 0.12 ng/ml and 2.91 ± 0.42 HOMA-IR). This was not observed in the NOD/SCID strain. Hepatic steatosis was more extensive in Rag1 −/− HFD-fed mice compared to NOD/SCID mice. Intramyocellular lipid storage was increased in Rag1 −/− HFD-fed mice, but not in NOD/SCID mice. In Rag1 −/− HFD-fed mice, LNCaP xenograft tumours grew more rapidly compared to low-fat chow-fed mice. This is the first characterisation of the metabolic effects of long-term Western HFD in two mouse strains suitable for xenograft studies. We conclude that Rag1 −/− mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia.

It is now appreciated that long non-coding RNAs (lncRNAs) are important players in orchestrating cancer progression. In this study we characterized GHSROS , a human lncRNA gene on the opposite DNA strand (antisense) to the ghrelin receptor gene, in prostate cancer. The lncRNA was upregulated by prostate tumors from different clinical datasets. Transcriptome data revealed that GHSROS alters the expression of cancer-associated genes. Functional analyses in vitro showed that GHSROS mediates tumor growth, migration and survival, and resistance to the cytotoxic drug docetaxel. Increased cellular proliferation of GHSROS -overexpressing PC3, DU145, and LNCaP prostate cancer cell lines in vitro was recapitulated in a subcutaneous xenograft model. Conversely, in vitro antisense oligonucleotide inhibition of the lncRNA reciprocally regulated cell growth and migration, and gene expression. Notably, GHSROS modulates the expression of PPP2R2C , the loss of which may drive androgen receptor pathway-independent prostate tumor progression in a subset of prostate cancers. Collectively, our findings suggest that GHSROS can reprogram prostate cancer cells toward a more aggressive phenotype and that this lncRNA may represent a potential therapeutic target.

Background: The benefits of exercise for patients with cancer are well-established, however, for patients with bone metastases, exercise as adjuvant therapy is underutilised due to concerns for safety, efficacy and other barriers such as the method of delivery. This scoping review explores these barriers by reviewing the results of clinical trials conducted on participants with bone metastases. Methods: A thorough literature search was undertaken using PubMed, Scopus, NIH Clinical Trials and Google Scholar databases. Articles that involved an exercise intervention and patients with bone metastases were included. Data were pooled, charted, analysed and reported according to PRISMA-ScR standards. Results: A total of 26 trials were reviewed with interventions that included aerobic and resistance training. Only three serious adverse events occurred, not likely related to bone metastases. Nine trials (34.6%) involved unsupervised exercise sessions. Remote exercise delivery had an average of 80.3% compliance, rivalling in-person and mixed supervision. The results of this review reaffirm that exercise helps improve functional capacity, muscle strength, lean mass and cardiovascular function, and is safe in patients with bone metastases irrespective of in-person or remote delivery. Conclusions: Exercise therapy, whether delivered in person or remotely, is safe and efficacious for patients with bone metastases.

Recent evidence suggests that numerous long non-coding RNAs (lncRNAs) are dysregulated in cancer, and have critical roles in tumour development and progression. The present study investigated the ghrelin receptor antisense lncRNA growth hormone secretagogue receptor opposite strand (GHSROS) in breast cancer. Reverse transcription-quantitative polymerase chain reaction revealed that GHSROS expression was significantly upregulated in breast tumour tissues compared with normal breast tissue. Induced overexpression of GHSROS in the MDA-MB-231 breast cancer cell line significantly increased cell migration in vitro, without affecting cell proliferation, a finding similar to our previous study on lung cancer cell lines. Microarray analysis revealed a significant repression of a small cluster of major histocompatibility class II genes and enrichment of immune response pathways; this phenomenon may allow tumour cells to better evade the immune system. Ectopic overexpression of GHSROS in the MDA-MB-231 cell line significantly increased orthotopic xenograft growth in mice, suggesting that in vitro culture does not fully capture the function of this lncRNA. This study demonstrated that GHSROS may serve a relevant role in breast cancer. Further studies are warranted to explore the function and therapeutic potential of this lncRNA in breast cancer progression.

PurposeTrisomy 21 (T21), more commonly known as Down syndrome (DS) is a genetic condition where every cell in the body has an additional copy of chromosome 21. Despite improvements in our management of DS-associated health risks, we still do not understand how T21 impacts human bone health. This is a critical area of research owing to increased life expectancy of people with DS, and the predisposition of individuals with DS to early-onset osteoporosis and osteopenia.MethodsWe have conducted a scoping review using the methodological framework of Arksey and O’Malley (2005) which analysed the existing data on bone growth, development, maintenance and repair in T21 using the Medical Subject Headings (MeSH) terms: Trisomy 21, Down syndrome, Down’s syndrome, bone development, bone growth, bone maintenance, fracture risk, osteoporosis, bone mineral density, bone strength, bone mineral content, bone formation, bone repair, osteoblast, osteoclast, osteocyte, osteomacs. A total of 31 papers were identified. After screening, 16 articles were included in full-text review.ResultsThere was a total of eleven in vivo animal model studies identified and included in the scoping review. Of those eleven, ten revealed a difference in bone growth and development in animal models of DS, and two found that bone maintenance and repair in animal models of DS is reduced with both studies reporting an osteoporotic bone phenotype in male and female mice. All five studies that included human participants reported impacts on bone growth and development with reduced bone growth rates and delayed bone maturation in individuals with DS. At the time of review, there were no human studies directly investigating bone maintenance and repair in individuals with DS.ConclusionWe found documented evidence that T21 impacts bone growth and development, maintenance and repair in both animal models and human studies.

It is now appreciated that long non-coding RNAs (lncRNAs) are important players in the orchestration of cancer progression. In this study we characterized GHSROS, a human lncRNA gene on the opposite DNA strand (antisense) to the ghrelin receptor gene, in prostate cancer. The lncRNA was upregulated by prostate tumors from different clinical datasets. Consistently, transcriptome data revealed that GHSROS alters the expression of cancer-associated genes. Functional analyses in vitro showed that GHSROS mediates tumor growth, migration, and survival and resistance to the cytotoxic drug docetaxel. Increased cellular proliferation of GHSROS-overexpressing PC3, DU145, and LNCaP prostate cancer cell lines in vitro was recapitulated in a subcutaneous xenograft model. Conversely, in vitro antisense oligonucleotide inhibition of the lncRNA reciprocally regulated cell growth and migration, and gene expression. Notably, GHSROS modulates the expression of PPP2R2C, the loss of which may drive androgen receptor pathway-independent prostate tumor progression in a subset of prostate cancers. Collectively, our findings suggest that GHSROS can reprogram prostate cancer cells toward a more aggressive phenotype and that this lncRNA may represent a potential therapeutic target. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE86097 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103320

Ghrelin is a peptide hormone which, when acylated, regulates appetite, energy balance and a range of other biological processes. Ghrelin predominately circulates in its unacylated form (unacylated ghrelin; UAG). UAG has a number of functions independent of acylated ghrelin, including modulation of metabolic parameters and cancer progression. UAG has also been postulated to antagonise some of the metabolic effects of acyl-ghrelin, including its effects on glucose and insulin regulation. In this study, Rag1-/- mice with high-fat diet-induced obesity and hyperinsulinaemia were subcutaneously implanted with PC3 prostate cancer xenografts to investigate the effect of UAG treatment on metabolic parameters and xenograft growth. Daily intraperitoneal injection of 100 g/kg UAG had no effect on xenograft tumour growth in mice fed normal rodent chow or 23% high-fat diet. UAG significantly improved glucose tolerance in host Rag1-/- mice on a high-fat diet, but did not significantly improve other metabolic parameters. We hypothesise that UAG is not likely to be an effective treatment for prostate cancer, with or without associated metabolic syndrome.