Positive association of collagen type I with non-muscle invasive bladder cancer progression
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Michael Brooks1,*, Qianxing Mo2,6,*, Ross Krasnow1, Philip Levy Ho3, Yu-Cheng Lee4, Jing Xiao4, Antonina Kurtova4, Seth Lerner1, Gui Godoy1, Weiguo Jian1, Patricia Castro5,6, Fengju Chen2, David Rowley4,6, Michael Ittmann5,6, Keith Syson Chan1,3,4,6,7,8
1Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
2Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
3Department of Urology, Baylor College of Medicine, Kelsey-Seybold Clinic, Houston, Texas 77030
4Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
5Department of Pathology and Immunology, and Michael E. DeBakey VAMC, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
6Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
7Center for Cell, Gene and Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
8Center for Drug Discovery Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
*These authors have contributed equally to this work
Keith Syson Chan, email: [email protected]
Keywords: bladder cancer, type I collagen, tumor microenvironment, invasion, cancer progression
Received: June 30, 2016 Accepted: September 02, 2016 Published: September 17, 2016
PURPOSE: Non-muscle invasive bladder cancers (NMIBC) are generally curable, while ~15% progresses into muscle-invasive cancer with poor prognosis. While efforts have been made to identify genetic alternations associated with progression, the extracellular matrix (ECM) microenvironment remains largely unexplored. Type I collagen is a major component of the bladder ECM, and can be altered during cancer progression. We set out to explore the association of type I collagen with NMIBC progression.
EXPERIMENTAL DESIGN: The associations of COL1A1 and COL1A2 mRNA levels with progression were evaluated in a multi-center cohort of 189 patients with NMIBCs. Type I collagen protein expression and structure were evaluated in an independent single-center cohort of 80 patients with NMIBCs. Immunohistochemical analysis was performed and state-of-the-art multi-photon microscopy was used to evaluate collagen structure via second harmonic generation imaging. Progression to muscle invasion was the primary outcome. Kaplan-Meier method, Cox regression, and Wilcoxon rank-sum were used for statistical analysis.
RESULTS: There is a significant association of high COL1A1 and COL1A2 mRNA expression in patients with poor progression-free survival (P=0.0037 and P=0.011, respectively) and overall survival (P=0.024 and P=0.012, respectively). Additionally, immunohistochemistry analysis of type I collagen protein deposition revealed a significant association with progression (P=0.0145); Second-harmonic generation imaging revealed a significant lower collagen fiber curvature ratio in patients with invasive progression (P = 0.0018).
CONCLUSIONS: Alterations in the ECM microenvironment, particularly type I collagen, likely contributes to bladder cancer progression. These findings will open avenues to future functional studies to investigate ECM-tumor interaction as a potential therapeutic intervention to treat NMIBCs.
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