This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bauskin, A. R. Articles by Breit, S. N. Search for Related Content PubMed PubMed Citation Articles by Bauskin, A. R. Articles by Breit, S. N.

The Propeptide Mediates Formation of Stromal Stores of PROMIC-1: Role in Determining Prostate Cancer Outcome

¹ Centre for Immunology, St Vincent's Hospital and University of New South Wales; ² Cancer Research Program, Garvan Institute of Medical Research and Departments of ³ Anatomical Pathology, ⁴ Urology, and ⁵ Medical Oncology, St Vincent's Hospital; ⁶ Oncology Research Centre, Prince of Wales Hospital and Department of Medicine, University of New South Wales; and ⁷ Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia

Requests for reprints: Samuel N. Breit or Asne R. Bauskin, Centre for Immunology, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia. Phone: 612-8382-3200; Fax: 612-8382-2390; E-mail: s.breit{at}cfi.unsw.edu.au or a.bauskin{at}cfi.unsw.edu.au.

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–ß 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 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 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.

Key Words: prostate cancer • cytokine • extracellular matrix • secretion • MIC-1

This article has been cited by other articles:

				S. Lakhal, N. P. Talbot, A. Crosby, C. Stoepker, A. R. M. Townsend, P. A. Robbins, C. W. Pugh, P. J. Ratcliffe, and D. R. Mole Regulation of growth differentiation factor 15 expression by intracellular iron Blood, February 12, 2009; 113(7): 1555 - 1563. [Abstract] [Full Text] [PDF]

				T. Kempf, E. Bjorklund, S. Olofsson, B. Lindahl, T. Allhoff, T. Peter, J. Tongers, K. C. Wollert, and L. Wallentin Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction Eur. Heart J., December 1, 2007; 28(23): 2858 - 2865. [Abstract] [Full Text] [PDF]

				K. S. Selander, D. A. Brown, G. B. Sequeiros, M. Hunter, R. Desmond, T. Parpala, J. Risteli, S. N. Breit, and A. Jukkola-Vuorinen Serum Macrophage Inhibitory Cytokine-1 Concentrations Correlate with the Presence of Prostate Cancer Bone Metastases Cancer Epidemiol. Biomarkers Prev., March 1, 2007; 16(3): 532 - 537. [Abstract] [Full Text] [PDF]

				T. Kempf, R. Horn-Wichmann, G. Brabant, T. Peter, T. Allhoff, G. Klein, H. Drexler, N. Johnston, L. Wallentin, and K. C. Wollert Circulating Concentrations of Growth-Differentiation Factor 15 in Apparently Healthy Elderly Individuals and Patients with Chronic Heart Failure as Assessed by a New Immunoradiometric Sandwich Assay Clin. Chem., February 1, 2007; 53(2): 284 - 291. [Abstract] [Full Text] [PDF]

				K. K. Rasiah, J. G. Kench, M. Gardiner-Garden, A. V. Biankin, D. Golovsky, P. C. Brenner, R. Kooner, G. F. O'Neill, J. J. Turner, W. Delprado, et al. Aberrant neuropeptide y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis. Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 711 - 716. [Abstract] [Full Text] [PDF]

				M. Mimeault and S. K. Batra Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies Carcinogenesis, January 1, 2006; 27(1): 1 - 22. [Abstract] [Full Text] [PDF]

				D. A. Brown, C. Stephan, R. L. Ward, M. Law, M. Hunter, A. R. Bauskin, J. Amin, K. Jung, E. P. Diamandis, G. M. Hampton, et al. Measurement of Serum Levels of Macrophage Inhibitory Cytokine 1 Combined with Prostate-Specific Antigen Improves Prostate Cancer Diagnosis Clin. Cancer Res., January 1, 2006; 12(1): 89 - 96. [Abstract] [Full Text] [PDF]