Excessive matrix metalloprotease-mediated degradation of interstitial tissue (type I collagen) independently predicts short-term survival in an observational study of postmenopausal women diagnosed with cancer

Abstract

Extensive tissue remodeling mediated by matrix metalloproteases (MMPs) is an important part of cancer. The aim of this study was to investigate whether serum biomarkers reflecting MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M) and citrullinated vimentin (VICM) were predictive of cancer-specific mortality. Between 1999 and 2001, 5855 Danish postmenopausal women participated in The Prospective Epidemiologic Risk Factor (PERF I) study. Demographics and serum samples were collected at enrolment. Cancer diagnosis, and cause and time of death were obtained from Danish registries. C1M, C4M and VICM were measured by ELISA. Hazard ratios (HR) and Kaplan-Meier curves were applied to assess mortality at 3 and 12 years of follow-up for women diagnosed with cancer within 3 years from blood sampling. Within 3 years from blood sampling, 250 women had been diagnosed with cancer. C1M and VICM were associated with survival over time at 3 years of follow-up. Only C1M was predictive of mortality at 3 years follow-up: the adjusted HR was 2.65 [95% CI: 1.08-6.51]. In conclusion, C1M and VICM are associated with survival in postmenopausal women with cancer, and C1M is an independent risk factor for cancer-specific mortality. Thus, quantification of tissue remodeling is important in cancer.

Keywords: ECM; MMP; cancer; mortality; type I collagen.

Figure 1. Cohort and study design

Overview of women included and excluded from analysis. *Excluded were those diagnosed with a benign neoplasm: ICD10 codes D10-D36; neoplasms of uncertain or unknown behavior: ICD10 codes D37-D48; skin cancer: ICD-10 codes C44, D040-D049 (i.e. not including malignant melanoma); dysplasia: ICD-10 code N87; non-solid tumors: ICD-10 codes C81-C96 (a.k.a. malignant neoplasms stated or presumed to be primary, of lymphoid, hematopoietic and related tissue). External CoD: ICD-10 codes V01-Y98; Cancer CoD: ICD10 codes C00-D48. CoD =cause of death.

Figure 2. Independent predictive value of C1M, C4M and VICM for cancer-specific mortality at 3 and 12 years follow-up

Hazard ratios (HR) with 95% confidence intervals (95% CI) for cancer-specific mortality in quartiles (Q1–Q4) of C1M, C4M and VICM are shown. Values are adjusted for age, BMI, smoking status, alcohol consumption, exercise level, educational level, hypertension, hyperlipidemia, use of HRT, and history of cancer.

Figure 3. Percentage of women surviving cancer at 3 and 12 years follow-up, by C1M, C4M and VICM biomarker levels at baseline

Kaplan-Meier survival curves illustrated the percent survival over time for women with baseline biomarker levels in the upper quartile (Q4) vs the lower quartile (Q1). A log-rank test was used to determine differences between the survival curves. Curves considered significantly different if p<0.05.