Serum PlGF and EGF are independent prognostic markers in non-metastatic colorectal cancer

Sebastian Schölch,Martin Schneider,Andreas Bogner,Jürgen Weitz,Balázs Győrffy,Christoph Reissfelder,Mohammad Rahbari,Ulrich Bork,Nuh N Rahbari

doi:10.1038/s41598-019-47429-5

Abstract

The aim of this study was to determine the prognostic value of circulating angiogenic cytokines in non-metastatic colorectal cancer (CRC) patients. Preoperative serum samples of a training (TC) (n = 219) and a validation cohort (VC) (n = 168) were analyzed via ELISA to determine PlGF, EGF, VEGF, Ang1, PDGF-A, PDGF-B, IL-8 and bFGF levels. In addition, survival was correlated with PlGF and EGF expression measured by microarray and RNAseq in two publicly available, independent cohorts (n = 550 and n = 463, respectively). Prognostic values for overall (OS) and disease-free survival (DFS) were determined using uni- and multivariate Cox proportional hazard analyses. Elevated PlGF is predictive for impaired OS (TC: HR 1.056; p = 0.046; VC: HR 1.093; p = 0.001) and DFS (TC: HR 1.052; p = 0.029; VC: HR 1.091; p = 0.009). Conversely, elevated EGF is associated with favorable DFS (TC: HR 0.998; p = 0.045; VC: HR 0.998; p = 0.018) but not OS (TC: p = 0.201; VC: p = 0.453). None of the other angiogenic cytokines correlated with prognosis. The prognostic value of PlGF (OS + DFS) and EGF (DFS) was confirmed in both independent retrospective cohorts. Serum PlGF and EGF may serve as prognostic markers in non-metastatic CRC.

Highlights

With an estimated 1.4 million new cases and 700.000 deaths worldwide, colorectal cancer (CRC) is among the three most frequent malignant diseases[1]
Univariate analysis and arithmetic means for vascular endothelial growth factor (VEGF), Ang[1], PDGF-A, PDGF-B, Interleukin 8 (IL-8) and basic fibroblast growth factor (bFGF) are given in Supplementary Tables 1–3
Higher serum Placental growth factor (PlGF) levels were observed in patients with age > 70 in validation cohort (VC) (Odds Ratio (OR) 0.425; 95% Confidence Interval (CI): 0.215–0.840; p = 0.014), BMI > 25 in VC and neoadjuvant chemotherapy

Summary

Introduction

With an estimated 1.4 million new cases and 700.000 deaths worldwide, colorectal cancer (CRC) is among the three most frequent malignant diseases[1]. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family and a key molecule in angiogenesis and vasculogenesis[10,11]; its molecular mechanisms of action remain incompletely understood[12]. PlGF contributes to immune escape mechanisms by suppressing anti-tumor immunity within solid malignancies[16]. Another tumor-promoting mechanism of PlGF is its binding capacity to vascular endothelial growth www.nature.com/scientificreports/. Epidermal growth factor receptor (EGFR) is a member of the HER/ERBB family of receptor tyrosine kinases and responsible for downstream activation of several oncogenic mechanisms including angiogenesis, endothelial cell invasion, proliferation and migration. Epidermal growth factor (EGF) is the main activator of EGFR and its downstream signaling cascade[19,20]

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