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

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.

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

“…There was no significant association of the expression levels of VEGFR 1-3 and overall survival. Nonetheless, these results are in line with previous studies on other gastrointestinal malignancies [ 35 , 36 ]. This might in part be explained by the fact that well- to moderately differentiated GEP-NENs have a favorable overall survival even in the presence of distant metastases and that there was no significant correlation between tumor grading and the expression of VEGFRs.…”

Sorafenib inhibits vascular endothelial cell proliferation stimulated by anaplastic thyroid cancer cells regardless of BRAF mutation status

“…These effects are mediated by the phosphorylation of VEGFR on vascular endothelial cells. Indeed, VEGFR expression on cancer cells has been reported (28,30), which enables accelerating proliferation via autocrine growth factor signaling cascades. However, VEGFR expression was not detected in the ATC cell lines used in the present study, suggesting that the VEGF-VEGFR autocrine cascade may be limited in ATC.…”

Changes in the Expression Profile of VEGF-A, VEGF-B, VEGFR-1, VEGFR-2 in Different Grades of Endometrial Cancer

“…They also emphasized the value of determining changes in their expression, while stressing that it would be reasonable to simultaneously assess the level of both receptors. This will allow to determine the relationship between receptors and increase the sensitivity and precision of the assay [ 45 ]. In turn, Kopparapu et al observed a higher level of VEGF-A , VEGFR-1 , VEGFR-2 in all bladder cancer samples compared to the control.…”