Remodeling of the Tumor Microenvironment Predicts Increased Risk of Cancer in Postmenopausal Women: The Prospective Epidemiologic Risk Factor (PERF I) Study

Abstract

Background: An altered tumor microenvironment is one of the earliest signs of cancer and an important driver of the disease. We have seen previously that biomarkers reflecting tumor microenvironment modifications, such as matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M), MMP-degraded type IV collagen (C4M), and citrullinated and MMP-degraded vimentin (VICM), were higher in the serum of cancer patients than in healthy controls. However, it is not known if these biomarkers could predict an increased risk of cancer. The aim of this study was to investigate whether C1M, C4M, and VICM were elevated prior to diagnosis of solid cancers in a large prospective study.Methods: Between 1999 and 2001, 5,855 postmenopausal Danish women ages 48 to 89 years enrolled in the Prospective Epidemiologic Risk Factor study. Baseline demographics and

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

“…In support of this, a novel paradigm suggests that cancer originates following a sequence of events that include chronic inflammation and desmoplasia with associated changes in the cellular microenvironment [ 32 ]. The present data, together with the previously published PERF I data showing that C1M, C4M, and VICM were associated with increased risk of developing cancer [ 19 ], supports this notion of a role of chronic inflammation and desmoplasia as part of tumorgenesis. Thus, ECM and tissue remodeling may be associated with a pre-disposition of being diagnosed with a cancer later in life, and consequently affecting the survival, as the tumor microenvironment is more permissive of cancer development and progression.…”

“…The best predictive value of C1M was for cancer-specific mortality, the most prevalent cause of death. Interestingly, it was also recently shown in the PERF I cohort, that C1M, C4M, and VICM were elevated in those women that were subsequently diagnosed with cancer and that C1M and VICM were both independent predictors of increased risk of developing cancer [ 19 ]. It remains to be determined if the predictive value of C1M for cancer-specific mortality also applies to women given a cancer diagnosis within the same vicinity of time, as well as it remains to be determined if C4M and VICM predicts cancer-specific mortality in this cohort.…”

Matrix metalloproteinase-degraded type I collagen is associated with APOE/TOMM40 variants and preclinical dementia

“…This biomarker reflecting inflammation and remodeling potential of the body has been previously described to be associated with age-related diseases such as cancer, fibrosis, and rheumatoid arthritis. 8 – 11 The aim of our study was to systematically discover genetic factors of variation of C1M and link these variants to age-related diseases. The PERF cohort offered an ideal exploratory environment combining single nucleotide variants, demographic, and electronic hospital care history.…”

“…We have previously seen that C1M is associated with early death in postmenopausal women and with age-related pathologies such as fibrosis, cancer, and rheumatoid arthritis. 8 – 11 …”

Undervalued ubiquitous proteins

“…Metalloproteinases (MMPs) are associated with breast cancer development and "can be loosely divided into four main groups: the interstitial collagenases, gelatinases, stromelysins, and membrane-type MMPs" [55]. MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M), and citrullinated vimentin (VICM) appear important for remodelingmediated matrix and have been investigated in 5855 Danish samples in The Prospective Epidemiologic Risk Factor (PERF I) study: C1M and VICM were associated with survival in postmenopausal cancer and C1M was identified as an independent risk factor for cancer-specific mortality [56]. The expression of type IV collagenase is modulated by influenza A/Beijing/353/89 (H3N2) virus at the transcriptional level, is dependent on the epithelial cell line under investigation through matrix MMP-9 (in Vero cells), and on matrix MMP-2 in Madin-Darby canine kidney (MDCK) cells [57].…”