Molecular Imaging Study In Prostate Cancer With Ghrelin And Its Receptor GHSR

Prostate cancer is the leading malignancy in male. Early detection with PSA screening can decrease the mortality of prostate cancer, as well as the incidence of complication of advanced prostate cancer. In the other hand, how to balance the active control and overtreatment for prostate cancer is still a clinical dilemma. New strategies in prostate cancer diagnosis have been increasing in the past few decades, for more precise risk assessment and more effective treatment decision.Ghrelin is a 28 amino acid peptide hormone, which was determined to be the endogenous ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin plays an important role in the stimulation of GH secretion through binding with GHSR along with other functions including appetite regulation. Ghrelin’s receptor GHSR, is a member of the G protein-coupled receptor (GPCR) family, which are widely distributed in different regions of the brain, pituitary gland and other peripheral tissues. Different expression levels of the GHSR have also been reported in normal human tissues and in various types of tumors. This heterogeneity in tissue distribution of GHSR provides the feasibility to use Ghrelin analogue as molecular imaging strategies targeting the GHSR in human tumor.In this study, the expression of Ghrelin and its receptor GHSR in prostate cancer cell line and human prostate cancer tissue was detected. A Ghrelin analogue was synthesized and labelled with fluorescent mark. The feasibility of Ghrelin analogue in the differential diagnosis of prostate tumor was assessed in the human prostate cancer cell line PC-3 and human prostate tissue ex vivo. The effect of Ghrelin on the proliferation of PC-3 cells was evaluated in the avian embryo CAM (chorioallantoic membrane) model in vivo.The expression of Ghrelin and GHSR was detected in the human prostate cancer cell line PC-3 and human prostate tissue at the level of mRNA and protein. In androgen-indepent prostate cancer cell and human prostate tissue, upregulated expression was detected.18-mer or 19-mer Ghrelin analogue could be synthesized by solid phase peptide synthesis while maintained its affinity to GHSR. This kind of ligand-receptor binding of Ghrelin and GHSR was followed by internalization, which could help increase the signal/background ratio in in vivo imaging. In ex vivo analysis, Ghrelin was able to distinguish benign tissue from cancer or pre-cancer in human prostate tissues. Green fluorescent protein (GFP) expressing PC-3 cells was obtained with the transfection of GFP plasmid. PC-3-GFP CAM model was constructed and observed in real time. The inhibit effect of Ghrelin on the proliferation of PC-3 cells was observed.This study reveals Ghrelin receptor targeting as a potentially useful strategy for molecular imaging of prostatic neoplasms, while the validity and safety of Ghrelin analogue requires further in vivo research.This is an active project of Lawson Health Research Institute, the University of Western Ontario, Study No.16840E.