A prospective cohort study of TIMP1 as prognostic biomarker in gastric and colon cancer

Abstract

Background: Tissue inhibitor metalloproteinase 1 (TIMP1) inhibits proteins which has proteolytic activity, but in cancer it contributes for tumoral invasion and metastization. The authors investigated the expression of TIMP1 in different digestive cancer types. The aim of this study was to test TIMP1 as a serum marker since in clinical practice there is a lack of biomarkers to monitor the response to treatments or to detect early relapses.Methods: It was performed a prospective study with recent diagnosed patients with gastrointestinal cancers. Patients with esophageal, gastric, colon, rectal, hepatocarcinoma, and cholangiocarcinoma at any stage, that did not perform any type of treatment, were included. Enzyme-linked immunosorbent assays and chemiluminescence were used to quantify levels of TIMP1. The differences of the Kaplan-Meier survival curves were tested for statistical significance with the log rank test, and the 95% confidence intervals were calculated. Multivariate analysis was done using the COX proportional hazard model and a forward stepwise method. Statistical analyses were done using the IBM SPSS Statistics version 26.0. P value inferior to 0.05 was considered significant.Results: A total of 190 patients were recruited: 54.7% males, median age of 68 years old, 57.9% with colorectal cancer followed by esophagogastric disease with 22.6%. TIMP1 level were increased in 29.5%. In colon cancer, patients with higher levels of TIMP1 are associated with worse progression free survival (PFS) (P=0.007) and overall survival (OS) (P=0.036). No relationship was seen with Rat sarcoma virus (RAS), B-raf (BRAF) and Microsatellite instability status (MSI). In gastric cancer, patients with higher levels of TIMP1 are associated with worse OS (P=0.020), with no difference in PFS.Conclusions: Higher TIMP1 levels in gastric and colon cancer patients are associated with worse prognosis. Further studies are needed: higher number of patients and sequential measurements of TIMP1 during patient treatments.

A new biomarker panel for differential diagnosis of cholangiocarcinoma: Results from an exploratory analysis

“…26 Such a mode of action supports the contribution of TIMP-1 to tumor invasion and metastasis reported for gastrointestinal cancers, with increased expression levels associated with poor survival outcomes (i.e., overall survival and progression-free survival) in gastric and colon cancers. 39 Although TIMP-1 and MMP-2 are both involved in extracellular matrix turnover and remodeling, and TIMP-1 can directly bind and inhibit activity of MMP-2, 26 both biomarkers differ in specificity and sensitivity towards CCA diagnosis. This effect can be caused by the complex interaction network between different MMPs, TIMPs, and further molecules functioning within the tumor microenvironment.…”

The anoikis-related gene signature predicts survival accurately in colon adenocarcinoma

“…Mariana Toricelli found that Timp1 confers cell survival through activation of the PDK1 pathway and that Timp1 and AKT cooperate to confer resistance to anoikis in metastatic melanoma cells 48 . TIMP1 stimulates cell proliferation and has anti-apoptotic functions 49 . In colorectal cancer, upregulation of TIMP1 in tumor tissue compared with normal tissue 50 is considered to be an independent prognostic factor for disease free survival 51 .…”