title: The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome.
abstract: The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.
authors.affiliation: Centre for Immunology, St Vincent's Hospital and University of New South Wales, Australia. a.bauskin@cfi.unsw.edu.au
authors.forename: Asne R
authors.initials: AR
authors.lastname: Bauskin
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Simon
authors.initials: S
authors.lastname: Junankar
authors.forename: Krishan K
authors.initials: KK
authors.lastname: Rasiah
authors.forename: Sarah
authors.initials: S
authors.lastname: Eggleton
authors.forename: Mark
authors.initials: M
authors.lastname: Hunter
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Dave
authors.initials: D
authors.lastname: Smith
authors.forename: Tamara
authors.initials: T
authors.lastname: Kuffner
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Pankhurst
authors.forename: Heiko
authors.initials: H
authors.lastname: Johnen
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.forename: Wade
authors.initials: W
authors.lastname: Barret
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Stricker
authors.forename: John J
authors.initials: JJ
authors.lastname: Grygiel
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000096:biosynthesis* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D011498:Protein Precursors