title: Plasma macrophage-stimulating protein and hepatocyte growth factor levels are associated with prostate cancer progression.
abstract: Hepatocyte growth factor (HGF) is a well-known multifunctional growth factor, and evidence has accumulated indicating that the HGF/MET (HGF receptor) signaling axis is involved in the progression of cancer. Macrophage-stimulating protein (MSP) is also known as a growth factor which activates not only macrophages but also cancer cells and osteoclasts through the activation of the specific Receptor d'origine nantais (RON). Pro-HGF and pro-MSP lack biological activity and, therefore, require proteolytic activation for conversion to an active two-chain form by HGF activator (HGFA). Although, there are several studies on HGF/MET signaling with castration-resistant prostate cancer (CRPC) and bone metastasis, reports on plasma protein are rare. In addition, the MSP/RON signaling axis in PC is not well understood. Here, we analyzed associations between PC progression and plasma HGF and MSP levels. We tested plasma samples from 58 patients with PC: 36 with castration-resistant (CR) PC and 22 with pretreatment for PC as control. We used enzyme-linked immunosorbent assay (ELISA) kit to determine plasma levels of HGF, MSP and HGFA, and examined correlations with clinicopathological characteristics such as Gleason grade and bone metastasis. PCR was used to evaluate HGF and MSP-related molecules in PC cell lines. Plasma levels of HGF, MSP and HGFA in the CRPC group were higher than in the control group (HGF: P < 0.001; MSP: P = 0.008; HGFA: P < 0.001). HGF and MSP levels were significantly correlated (P = 0.003). In the CRPC group, plasma HGF and MSP levels and Gleason score were not correlated; however, high plasma MSP level correlated with bone metastasis. (P = 0.016). In cell lines, PC3 expressed significantly more HGF, MET and RON than did LNCaP (P < 0.001), and both cell lines expressed MSP. Plasma concentrations of HGF, MSP and HGFA are significantly elevated in patients with CRPC. Also, as plasma MSP levels are significantly associated with bone metastasis in CRPC patients, MSP may be a candidate for serum marker of bone metastasis. Our results show the importance of the HGF/MET and MSP/RON signaling systems in CRPC.
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Sugie
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan. syoichiro_mukai@med.miyazaki-u.ac.jp.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Mukai
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
authors.forename: Toyoharu
authors.initials: T
authors.lastname: Kamibeppu
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Tsukino
authors.affiliation: Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kamoto
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary*; D002478:Cells, Cultured; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins / Q000097:blood*; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D012189:Retrospective Studies; D012697:Serine Endopeptidases / Q000097:blood; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C066855:HGF protein, human; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C081092:HGF activator; D012697:Serine Endopeptidases
keywords: Bone metastasis; CRPC; HGF; HGFA; MSP