Asporin is a stromally expressed marker associated with prostate cancer progression

Abstract

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.

Biomarker-based outcome prediction in prostate adenocarcinoma depends on theTMPRSS2-ERGstatus

“…For example, Asporin (ASPN) and Biglycan (BGN) [25] are both known to be associated with PCa progression [26] and poor prognosis [27]. Our results confirm these previous observations but highlight that they have only prognostic value for T2E-negative cases.…”

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…Stromal-specific secreted molecules identified in embryonic rat and human prostate tissues have been shown to be re-expressed in cancer-associated fibroblasts (CAFs) and can modulate tumour growth [4,5]. In addition, stromal markers have been shown to correlate with disease progression and may be predictors of aggressive prostate tumour subtypes [6].…”

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

“…For example, Asporin (ASPN) and Biglycan (BGN) 30 are both known to be associated with PCa progression 31 and poor prognosis. 32 Our results confirm these previous observations but highlight that they have only prognostic value for T2Enegative cases.…”