Asporin is a stromally expressed marker associated with prostate cancer progression

• Published in: British journal of cancer Vol. 116; no. 6; pp. 775 - 784
• Main Authors: Rochette, Annie, Boufaied, Nadia, Scarlata, Eleonora, Hamel, Lucie, Brimo, Fadi, Whitaker, Hayley C, Ramos-Montoya, Antonio, Neal, David E, Dragomir, Alice, Aprikian, Armen, Chevalier, Simone, Thomson, Axel A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-03-2017; Nature Publishing Group
• Subjects: 692/4028/67/1857; 692/699/2768/589/466; Adult; Aged; Animals; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cells, Cultured; Cohort Studies; Culture Media, Conditioned - pharmacology; Drug Resistance; Epidemiology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fetus - metabolism; Fetus - pathology; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Follow-Up Studies; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunoenzyme Techniques; Male; Medical research; Mice; Mice, Knockout; Middle Aged; Molecular Diagnostics; Molecular Medicine; Multivariate analysis; Neoplasm Grading; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Oncology; Prognosis; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Real-Time Polymerase Chain Reaction; Retinoblastoma Protein - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stromal Cells - metabolism; Stromal Cells - pathology; Surveillance; Survival Rate; Tumor Microenvironment; Tumor Suppressor Protein p53 - physiology; Urology; Canada; Montreal Quebec Canada; Quebec Canada; prostate cancer; tumour stroma; stromal markers; asporin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.15

Background:
Prostate cancer shows considerable heterogeneity in disease progression and we propose that markers expressed in tumour stroma may be reliable predictors of aggressive tumour subtypes.
Methods:
We have used Kaplan–Meier, univariate and multivariate analysis to correlate the expression of Asporin (
ASPN
) mRNA and protein with prostate cancer progression in independent cohorts. We used immunohistochemistry and H scoring to document stromal localisation of ASPN in a tissue microarray and mouse prostate cancer model, and correlated expression with reactive stroma, defined using Masson Trichrome staining. We used cell cultures of primary prostate cancer fibroblasts treated with serum-free conditioned media from prostate cancer cell lines to examine regulation of
ASPN
mRNA in tumour stromal cells.
Results:
We observed increased expression of
ASPN
mRNA in a data set derived from benign
vs
tumour microdissected tissue, and a correlation with biochemical recurrence using Kaplan–Meier and Cox proportional hazard analysis. ASPN protein localised to tumour stroma and elevated expression of ASPN was correlated with decreased time to biochemical recurrence, in a cohort of 326 patients with a median follow up of 9.6 years. Univariate and multivariate analysis demonstrated that ASPN was correlated with progression, as were Gleason score, and clinical stage. Additionally, ASPN expression correlated with the presence of reactive stroma, suggesting that it may be a stromal marker expressed in response to the presence of tumour cells and particularly with aggressive tumour subtypes. We observed expression of ASPN in the stroma of tumours induced by p53 inhibition in a mouse model of prostate cancer, and correlation with neuroendocrine marker expression. Finally, we demonstrated that
ASPN
transcript expression in normal and cancer fibroblasts was regulated by conditioned media derived from the PC3, but not LNCaP, prostate cancer cell lines.
Conclusions:
Our results suggest that ASPN is a stromally expressed biomarker that correlates with disease progression, and is observed in reactive stroma. ASPN expression in stroma may be part of a stromal response to aggressive tumour subtypes.