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-h h 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 f f20-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 V V 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. (Cancer Res 2005; 65(6): 2330-6)

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…The premature proprotein is produced preferentially by cancer cells over normal tissues, and the preprocessed or mature GDF-15 forms have been suggested to be differentially deposited in extracellular matrix (ECM). 15 Current data supports the assertion, that it is the propeptide that mediates interactions of pro-GDF-15 with ECM. 15 Therefore, the tissue availability of GDF-15 depends on ECM degradation, histological composition and architecture or presence of enzymes capable of conversion of pro-GDF-15 to GDF-15, implying a regulation similar to TGF-b.…”

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

“…MIC-1 is often secreted in an unprocessed propeptide form that regulates the balance between extracellular matrix stores and circulating mature MIC-1 (Bauskin et al, 2005). The absence of propeptide in xenograft animal tumour models is associated with a 20-fold increase in serum MIC-1 (Bauskin et al, 2005).…”

“…MIC-1 is often secreted in an unprocessed propeptide form that regulates the balance between extracellular matrix stores and circulating mature MIC-1 (Bauskin et al, 2005). The absence of propeptide in xenograft animal tumour models is associated with a 20-fold increase in serum MIC-1 (Bauskin et al, 2005). In low-grade localised prostate cancer, the level of proMIC-1 stromal stores was the best predictor of future disease relapse when compared with other clinicopathological variables (Bauskin et al, 2005).…”

“…The absence of propeptide in xenograft animal tumour models is associated with a 20-fold increase in serum MIC-1 (Bauskin et al, 2005). In low-grade localised prostate cancer, the level of proMIC-1 stromal stores was the best predictor of future disease relapse when compared with other clinicopathological variables (Bauskin et al, 2005). The mechanisms surrounding the processing and extracellular storage of MIC-1 may represent one explanation for the observed differences in plasma MIC-1 between different tumour variables.…”

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

“…It is expressed in activated macrophages (1), placenta and prostate, and to a lesser extent in the liver, kidney and brain (4,5). Significant amounts of MIC-1 are released into the circulation suggesting that it can also act as an endocrine factor (6).…”