Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma

Abstract

Tumor cells express vascular endothelial growth factor (VEGF) that can activate VEGF receptors (VEGFRs) on or within tumor cells to promote growth in an angiogenesis‐independent fashion; however, this autocrine VEGF pathway has not been reported in hepatocellular carcinoma (HCC). Sorafenib, an angiogenic inhibitor, is the only drug approved for use in advanced HCC patients. Yet the treatment efficacy is diverse and the mechanism behind it remains undetermined. Our aims were to study the molecular mechanisms underlying autocrine VEGF signaling in HCC cells and evaluate the critical role of autocrine VEGF signaling on sorafenib treatment efficacy. By immunohistochemistry, we found robust nuclear and cytoplasmic staining for active, phosphorylated VEGF receptor 1 (pVEGFR1) and phosphorylated VEGF receptor 2 (pVEGFR2), and by western blotting we found that membrane VEGFR1 and VEGFR2 increased in HCC tissues. We showed that autocrine VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2 in HCC cells, which was both pro‐proliferative through a protein lipase C‐extracellular kinase pathway and self‐sustaining through increasing VEGF, VEGFR1, and VEGFR2 mRNA expressions. In high VEGFR1/2‐expressing HepG2 cells, sorafenib treatment inhibited cell proliferation, reduced VEGFR2 mRNA expression in vitro, and delayed xenograft tumor growth in vivo. These results were not found in low VEGFR1/2‐expressing Hep3B cells. In an advanced HCC population on sorafenib treatment for postoperative recurrence, we found that the absence of VEGFR1 or VEGFR2 expression in resected tumor tissues before sorafenib treatment was associated with poorer overall survival. Conclusion: Autocrine VEGF signaling directly promotes HCC cell proliferation and affects the sorafenib treatment outcome in vitro and in vivo, which may enable better stratification for clinical treatment decisions. (Hepatology 2014;60:1264–1277)

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

“…Peng et al [134] showed that tumor expression of VEGFR (phosphorylated VEGFR-1 and VEGFR-2) could affect the outcome of patients treated with sorafenib for advanced HCC [134] . Using immunohistochemistry analyzes, low pVEGFR-1 and pVEGFR-2 expressions in previously resected HCC specimens; a subsequent treatment with sorafenib was associated with worse outcome and poorer OS.…”

“…Using immunohistochemistry analyzes, low pVEGFR-1 and pVEGFR-2 expressions in previously resected HCC specimens; a subsequent treatment with sorafenib was associated with worse outcome and poorer OS. The authors postulated that high autocrine VEGF signaling activity in tumor tissue could be predictive of response and outcome in patients treated with sorafenib [134] . These results could be hampered somewhat by the retrospective feature of the analysis, the small number of patients included and the low feasibility in clinical practice.…”

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer

“…The PLCγ1-ERK1/2 pathway is well recognized as an important pathway that modulates cell proliferation in some malignant tumors [27][28]. To determine whether this pathway was the mechanism underlying HOP regulation of GC cell growth, we evaluated the expression of PLCγ1 and ERK1/2 by western blotting.…”

Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment

“…Our analysis also identified CRP as one of the independent prognostic markers which led to construction of a pretreatment scoring system based on CRP, AFP, albumin and major vascular invasion for the stratification of the prognosis of patients with advanced HCC treated by sorafenib. Several candidate biomarkers or genetic signatures have been reported for predicting the prognosis [35][36][37][38][39], but they are costly and not readily available. In contrast, the serum CRP level is examined routinely in clinical practice, and it does not require invasive tissue collection.…”