Abstract 5143: The role of VEGFR2 in lung cancer differs between adenocarcinoma and squamous cell carcinoma cell lines

Abstract

Abstract Vascular endothelial growth factor A (VEGFA) is a cytokine implicated in proliferation, migration and cell survival that mediates its effects through its major receptor, VEGFR2. VEGFA is highly induced by hypoxia and is a crucial regulator of angiogenesis in both healthy and tumor tissues. For this reason, many efforts have been made to target the VEGFA/VEGFR2 pathway for the treatment of cancer. In lung cancer, an anti-VEGFA therapy (bevacizumab) was approved, in combination with platinum-based chemotherapy, as first line treatment in unresectable advanced non-small cell lung cancer (NSCLC). The expression of VEGFA has been widely reported in NSCLC, supporting the idea that VEGFA is produced by tumor cells and activates its receptors on endothelial cells, leading to vascularization of the tumor. However, it is known that NSCLC cells also express VEGFR2, although its role in tumor progression or response to treatment has not been evaluated. The aim of the present work was to study the biological role of the autocrine/paracrine VEGFA loop in NSCLC cells, paying special attention to the differences between the two main histological subtypes. To this purpose, we assessed the expression and activation of the VEGFA-VEGFR2 pathway in NSCLC cell lines, analyzing the effect of VEGFR2 inhibition/overexpression in both adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cell lines. Human NSCLC cell lines were examined for the expression of VEGFA and VEGFR2 by real time PCR and Western blotting. All cell lines expressed VEGFA. Two out of ten ADC cell lines (NCI-H441 and NCI-H358), and two out of eleven SCC cell lines (EPLC-272H and LOU-NH91) showed detectable levels of VEGFR2. Addition of exogenous VEGFA to VEGFR2-positive cells induced phosphorylation of the receptor and activation of its intracellular signaling pathway. To better understand the role of VEGFR2 in NSCLC, we used lentiviruses to inhibit or retroviruses to overexpress this protein in VEGFR2-positive cell lines. Changes in VEGFR2 levels had no effect in proliferation or migration in the ADC cell lines. However, in the SCC cell lines, the inhibition of the receptor increased proliferation and decreased migration. When the receptor was overexpressed in the SCC cell lines, the opposite effects were observed. In conclusion, VEGFR2 is expressed by some NSCLC cell lines and its activation may have different effects depending on the histology of the cells. Specifically, in SCC cells the activation of VEGFR2 decreases cell growth. These data illustrate the importance of the different histologies in the study of the VEGFA biology in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2011-5143