Asporin is a stromally expressed marker associated with prostate cancer progression.
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.
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Annie
A
Rochette
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Nadia
N
Boufaied
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Eleonora
E
Scarlata
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Lucie
L
Hamel
Department of Pathology, Division of Urology, McGill University and The McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Fadi
F
Brimo
Department of Oncology, University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Hayley C
HC
Whitaker
Department of Oncology, University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Antonio
A
Ramos-Montoya
Department of Oncology, University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
David E
DE
Neal
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Alice
A
Dragomir
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Armen
A
Aprikian
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Simone
S
Chevalier
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Axel A
AA
Thomson
D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005333:Fetus / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C439889:ASPN protein, human; D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53