The Prognostic Value of the Combination of Low VEGFR-1 and High VEGFR-2 Expression in Endothelial Cells of Colorectal Cancer.

Nicky D’Haene,Sarah Bouri,Françoise Hulet,Justine Allard,Yves-Rémi Van Eycke,Myriam Remmelink,Christine Decaestecker,Calliope Maris,Caroline Koopmansch,Sandrine Rorive,Isabelle Salmon

doi:10.3390/ijms19113536

Abstract

Research on tumor angiogenesis has mainly focused on the vascular endothelial growth factor (VEGF) family and on methods to block its actions. However, reports on VEGF receptor (VEGFR) expression in tumor-associated endothelial cells (ECs) are limited. Thus, we evaluated VEGF, VEGFR-1 and VEGFR-2 expression in ECs of colorectal cancer (CRC) using immunohistochemistry. VEGF, VEGFR-1 and -2 expression in ECs was quantitatively evaluated by digital image analysis in a retrospective series of 204 tumor tissue samples and related to clinical variables. The data show that the VEGF, VEGFR-1 and VEGFR-2 expression in ECs is heterogeneous. Multivariate analysis including a set of clinicopathological variables reveals that high EC VEGFR-1 expression is an independent prognostic factor for overall survival (OS). The combination of low VEGFR-1 and high VEGFR-2 expression in ECs outperforms models integrating VEGFR-1 and VEGFR-2 as separate markers. Indeed, this VEGFR-1_VEGFR-2 combination is an independent negative prognostic factor for OS (p = 0.012) and metastasis-free survival (p = 0.007). In conclusion, this work illustrates the importance of studying the distribution of VEGF members in ECs of CRC. Interestingly, our preliminary data suggest that high VEGFR-1 and low VEGFR-2 expression in ECs appear to be involved in the progression of CRC, suggesting that targeting EC VEGFR-1 could offer novel opportunities for CRC treatment. However, a prospective validation study is needed.

Highlights

Angiogenesis, which refers to the formation of new blood vessels, plays an essential role in tumor growth and metastasis to another organ [1,2].Research on tumor angiogenesis has mainly focused on vascular endothelial growth factor (VEGF)
VEGF receptor (VEGFR) are mostly expressed in endothelial cells (ECs) [14], only one study has focused on the prognostic value of VEGFR expression in colorectal cancer (CRC) endothelial cells
We quantitatively evaluated the immunohistochemical expression of the VEGF, VEGFR-1 and VEGFR-2 in ECs of a retrospective CRC series

Summary

Introduction

Angiogenesis, which refers to the formation of new blood vessels, plays an essential role in tumor growth and metastasis to another organ [1,2]. Different angiogenic factors have been explored as potential biomarkers of prognosis and of prediction of tumor response to therapy in CRC. Different studies have shown that tumor blood vessels differ from their normal counterparts in several important ways (i.e., in structure and function and in space and time). Many studies have assessed the expression of the VEGF family members and their prognostic value in CRC. VEGFRs are mostly expressed in endothelial cells (ECs) [14], only one study has focused on the prognostic value of VEGFR expression in CRC endothelial cells. To the best of our knowledge, no study has analyzed the prognostic value of VEGFR-1 and VEGFR-2 expression in ECs of CRC. We further characterize CRC ECs by studying the expression of these two receptors and evaluating their prognostic value. We quantitatively evaluated the immunohistochemical expression of the VEGF, VEGFR-1 and VEGFR-2 in ECs of a retrospective CRC series

Study Population

Discussion

Materials and Methods

Immunohistochemistry

Quantitative Image Analysis

Statistical Analyses