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

Oncotarget. 2016 Dec 13;7(50):82609-82619. doi: 10.18632/oncotarget.12089.


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.

Keywords: bladder cancer; cancer progression; invasion; tumor microenvironment; type I collagen.

Publication types

  • Multicenter Study

MeSH terms

  • Aged
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • Collagen Type I / analysis*
  • Collagen Type I / genetics
  • Collagen Type I / ultrastructure
  • Disease Progression
  • Disease-Free Survival
  • Extracellular Matrix / chemistry*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / ultrastructure
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Oligonucleotide Array Sequence Analysis
  • Proportional Hazards Models
  • RNA, Messenger / genetics
  • Registries
  • Retrospective Studies
  • Second Harmonic Generation Microscopy
  • Texas
  • Time Factors
  • Tumor Microenvironment*
  • Urinary Bladder Neoplasms / chemistry*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology


  • Biomarkers, Tumor
  • COL1A2 protein, human
  • Collagen Type I
  • RNA, Messenger
  • collagen type I, alpha 1 chain