title: Positive association of collagen type I with non-muscle invasive bladder cancer progression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Krasnow
authors.affiliation: Department of Urology, Baylor College of Medicine, Kelsey-Seybold Clinic, Houston, Texas 77030, USA.
authors.forename: Philip Levy
authors.initials: PL
authors.lastname: Ho
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Kurtova
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Lerner
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Gui
authors.initials: G
authors.lastname: Godoy
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Jian
authors.affiliation: Department of Pathology and Immunology, and Michael E. DeBakey VAMC, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Castro
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rowley
authors.affiliation: Department of Pathology and Immunology, and Michael E. DeBakey VAMC, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Urology, Baylor College of Medicine, Kelsey-Seybold Clinic, Houston, Texas 77030, USA.|Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Center for Cell, Gene and Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.|Center for Drug Discovery Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Keith Syson
authors.initials: KS
authors.lastname: Chan
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D024042:Collagen Type I / Q000032:analysis* / Q000235:genetics / Q000648:ultrastructure; D000090602:Collagen Type I, alpha 1 Chain; D018450:Disease Progression; D018572:Disease-Free Survival; D005109:Extracellular Matrix / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics; D012042:Registries; D012189:Retrospective Studies; D000073798:Second Harmonic Generation Microscopy; D013781:Texas; D013997:Time Factors; D059016:Tumor Microenvironment; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger
keywords: bladder cancer; cancer progression; invasion; tumor microenvironment; type I collagen