Prostate-specific antigen (PSA) is the main diagnostic tool when it comes to prostate cancer but it possesses serious limitations. Therefore, there is an urgent need for more sensitive and specific biomarkers for prostate cancer prognosis and patient follow-up. Recent advances led to the discovery of many novel diagnostic/prognostic techniques and provided us with many worthwhile candidates. This paper briefly reviews the most promising biomarkers with respect to their implementation in screening, early detection, diagnostic confirmation, prognosis, and prediction of therapeutic response or monitoring disease and recurrence; and their use as possible therapeutic targets. This review also examines the possible future directions in the field of prostate cancer marker research.

IGF-1 is one of the key molecules in cancer biology; however, little is known about the role of the preferential expression of the premature IGF-1 isoforms in prostate cancer. We have examined the role of the cleaved COO-terminal peptide (PEc) of the third IGF-1 isoform, IGF-1Ec, in prostate cancer. Our evidence suggests that endogenously produced PEc induces cellular proliferation in the human prostate cancer cells (PC-3) in vitro and in vivo, by activating the ERK1/2 pathway in an autocrine/paracrine manner. PEc overexpressing cells and tumors presented evidence of epithelial to mesenchymal transition, whereas the orthotopic injection of PEc-overexpressing, normal prostate epithelium cells (HPrEC) in SCID mice was associated with increased metastatic rate. In humans, the IGF-1Ec expression was detected in prostate cancer biopsies, where its expression correlates with tumor stage. Our data describes the action of PEc in prostate cancer biology and defines its potential role in tumor growth, progression and metastasis.

ObJECTIvE: preferential IgF-1Ec expression has been firmly associated with skeletal muscle repair mechanisms, post-infarction remodeling of the myocardium, the pathophysiology of endometriosis and prostate cancer biology. Therefore, we have studied the possible biological significance of synthetic Ec peptide, a putative cleavage product of IgF-1Ec in pC-3 cells and C2C12 myoblasts. DESIgN: We had previously designed and synthesized commercially peptides corresponding to the human Ec and its mouse igf1 counterpart as well as synthetic peptides that correspond to parts of the hEc. Using proliferation and mitogenic signaling assays, we tested their effect on pC-3 cells and C2C12 myoblasts at different doses and in different culture conditions. RESUlTS: human Ec, hEc, was documented as exerting progression but not competence growth factor actions, activating ERK1/2 without affecting akt phosphorylation in pC-3 cells. a narrow concentration range of hEc (5-50nm) stimulated the growth of pC-3 cells grown in culture media supplemented with 10% FbS. hEc did not stimulate the growth of pC-3 cells cultured with media containing 0.5% FbS or in mouse C2C12 myoblasts under any culture conditions. The activity of hEc was blocked by a neutralizing anti-human IgF-1Ec antibody but not by a neutralizing anti-human IgF-1 receptor antibody. The synthetic mouse Ec was inactive in human pC-3 cells; however, it stimulated significantly the proliferation of mouse C2C12. by analyzing the bioactivity of synthetic hEc fragments, we documented that hEc's active core is located in the last 4aa of its C-terminal end. CONClUSION: The hEc peptide is an important progression factor for human pC-3 prostate cancer cells.

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BackgroundEc peptide (PEc), resulting from the proteolytic cleavage of the IGF-1Ec isoform, is involved in prostate cancer progression and metastasis, whereas in muscle tissue, it is associated with the mobilization of satellite cells prior to repair. Our aim is to determine the physiological conditions associated to the IGF-1Ec upregulation and PEc secretion in prostate tumors, as well as, the effect of tumor PEc on tumor repair.MethodsIGF-1 (mature and isoforms) expression was examined by qRT-PCR, both in prostate cancer cells co-incubated with cells of the immune response (IR) and in tumors. PEc secretion was determined by Multiple Reaction Monitoring.The effect of PEc, on mesenchymal stem cell (MSC) mobilization and repair, was examined using migration and invasion assays, FISH and immunohistochemistry (IHC). The JAK/STAT signaling pathway leading to the IGF1-Ec expression was examined by western blot analysis. Determination of the expression and localization of IL-6 and IGF-1Ec in prostate tumors was examined by qRT-PCR and by IHC.ResultsWe documented that IL-6 secreted by IR cells activates the JAK2 and STAT3 pathway through IL-6 receptor in cancer cells, leading to the IGF-1Ec upregulation and PEc secretion, as well as to the IL-6 expression and secretion. The resulting PEc, apart from its oncogenic role, also mobilizes MSCs towards the tumor, thus promoting tumor repair.ConclusionsIL-6 leads to the PEc secretion from prostate cancer cells. Apart from its oncogenic role, PEc is also involved in the mobilization of MSCs resulting in tumor repair.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0003-z) contains supplementary material, which is available to authorized users.

Kisspeptin is an antimetastatic agent in some cancers that has also been associated with lymphoid cell apoptosis, a phenomenon favoring metastases. Our aim was to determine the association of kisspeptin with lymphocyte apoptosis and the presence of metastases in colorectal cancer patients. Blood was drawn from 69 colon cancer patients and 20 healthy volunteers. Tissue specimens from healthy and pathological tissue were immunohistochemically analyzed for kisspeptin and endothelial monocyte activating polypeptide II (EMAP-II) expression. Blood EMAP-II and soluble Fas ligand (sFasL) levels were examined by an enzyme-linked immunosorbent assay method. The kisspeptin and EMAP-II expression and secretion levels in the DLD-1 and HT-29 colon cancer cell lines were examined by quantitative real-time polymerase chain reaction, Western analysis and enzyme-linked immunosorbent assay, whereas lymphocyte viability was assessed by flow cytometry. The effect of kisspeptin on the viability of colon cancer cells was examined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. Exogenous, synthetic and naturally produced, kisspeptin induces through the G-protein-coupled receptor 54 (GPR54; also known as the kisspeptin receptor) the EMAP-II expression and secretion in colon cancer cell lines, inducing in vitro lymphocyte apoptosis, as verified by the use of an anti-EMAP-II antibody. These results were reversed with the use of kisspeptin inhibitors and by kisspeptin-silencing experiments. Tumor kisspeptin expression was associated with the tumor EMAP-II expression (p < 0.001). Elevated kisspeptin and EMAP-II expression in colon cancer tissues was associated with lack of metastases (p < 0.001) in colon cancer patients. These data indicate the antimetastatic effect of tumor-elevated kisspeptin in colon cancer patients that may be mediated by the effect of kisspeptin on EMAP-II expression in colon cancer tumors in patients with normal serum EMAP-II levels. These findings provide new insight into the role of kisspeptin in the context of metastases in colon cancer patients.

The Ec peptide (PEc) of insulin-like growth factor 1 Ec (IGF-1Ec) induces human mesenchymal stem cell (hMSC) mobilization and activates extracellular signal-regulated kinase 1/2 (ERK 1/2) in various cells. The aim of the present study was to examine the effects of PEc on the mobilization and differentiation of hMSCs, as well as the possibility of its implementation in combination with transforming growth factor β1 (TGF-β1) for cartilage repair. The effects of the exogenous administration of PEc and TGF-β1, alone and in combination, on hMSCs were assessed using a trypan blue assay, reverse transcription-quantitative polymerase chain reaction, western blot analysis, Alcian blue staining, wound healing assays and migration/invasion assays. It was determined that PEc is involved in the differentiation process of hMSCs towards hyaline cartilage. Treatment of hMSCs with either PEc, TGF-β1 or both, demonstrated comparable cartilage matrix deposition. Furthermore, treatment with PEc in combination with TGF-β1 was associated with a significant increase in hMSC mobilization when compared with treatment with TGF-β1 or PEc alone (P<0.05). Thus, PEc appears to facilitate in vitro hMSC mobilization and differentiation towards chondrocytes, enhancing the role of TGF-β1.

Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk - the probability that a drug will eventually receive regulatory approval - has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources, and, as a result, an overall reduction in R&D productivity. We propose a Machine Learning (ML) approach that provides a more accurate and unbiased estimate of drug development risk than traditional models.