Positive association of collagen type I with non-muscle invasive bladder cancer progression.

// Michael Brooks 1, * , Qianxing Mo 2, 6, * , Ross Krasnow 1 , Philip Levy Ho 3 , Yu-Cheng Lee 4 , Jing Xiao 4 , Antonina Kurtova 4 , Seth Lerner 1 , Gui Godoy 1 , Weiguo Jian 1 , Patricia Castro 5, 6 , Fengju Chen 2 , David Rowley 4, 6 , Michael Ittmann 5, 6 , Keith Syson Chan 1, 3, 4, 6, 7, 8 1 Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 2 Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 3 Department of Urology, Baylor College of Medicine, Kelsey-Seybold Clinic, Houston, Texas 77030 4 Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 5 Department of Pathology and Immunology, and Michael E. DeBakey VAMC, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 6 Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 7 Center for Cell, Gene and Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 8 Center for Drug Discovery Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030 * These authors have contributed equally to this work Correspondence to: Keith Syson Chan, email: kc1@bcm.edu Keywords: bladder cancer, type I collagen, tumor microenvironment, invasion, cancer progression Received: June 30, 2016 Accepted: September 02, 2016 Published: September 17, 2016 ABSTRACT 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.