Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma

Abstract

Angiogenesis is important for tumor growth, and is regulated by angiogenetic factors such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether or not expression of VEGF receptors (VEGFRs) is related to the proliferation of tumor cells in hepatocellular carcinoma (HCC). We simultaneously stained proliferation marker Ki-67 antigen and either VEGFR1 (Flt-1) or VEGFR2 (Flk-1) on paraffin-embedded tissue sections from 50 cases of surgically resected human HCC. Based on the staining pattern of VEGFRs, we classified the cases into 4 categories; receptor double-negative, Flt-1 single-positive, Flk-1 single-positive, receptor double-positive. Interestingly, the Ki-67 index was significantly lower in receptor doublenegative cases in comparison to that in either Flt-1 singlepositive or Flk-1 single-positive cases (P=0.0491, P=0.0196, respectively). Moreover, the index was also significantly lower in receptor double-positive cases in comparison to either Flt-1 single-positive or Flk-1 single-positive cases (P=0.0026, P<0.0001, respectively). We further investigated 35 cases showing a Ki67 index >10% to determine the expression of VEGFRs on Ki-67 antigen-positive proliferating cells. Surprisingly, the histological grade of HCC and the expression pattern of VEGFRs showed a characteristic relation; the well-differentiated HCC cases were all distributed in the Flk-1-positive group (7/7), moderately differentiated HCC cases were distributed in either the Flt-1 or Flk-1 single-positive group (20/21), and poorly differentiated HCC cases were predominantly distributed in either the receptor doublenegative or double-positive group (6/7). These findings suggest that the expression pattern of VEGFRs influences the histological differentiation of HCC.

The ratio of serum placenta growth factor to soluble vascular endothelial growth factor receptor-1 predicts the prognosis of hepatocellular carcinoma

“…It is little understood how expression of sVEGFR1 gene is regulated, although sVEGFR1 gene is abundant in all identified VEGFR1 cDNAs from human endothelial cell (27). The expression of VEGFR1 has been shown to be up-regulated and correlated to microvascular density and histological differentiation of HCC (28). Since high sVEGFR1 group had a more advanced tumor stage than low sVEGFR1 group in this study, serum of sVEGFR1 at least partly might be derived from tumor tissues.…”

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

“…This factor is synthesized essentially during hypoxic stress [4] and promotes the growth, migration, morphogenesis of vascular endothelial cells and increases vascular permeability [5,6] . Furthermore, the VEGF/VEGF receptor system is thought to be closely related to the histological grade of hepatocellular carcinoma [7] and strongly expressed in well differentiated HCC [8] . Several other potent angiogenic factors have been reported to be involved in HCC angiogenesis, notably basic fibroblast growth factor (bFGF) [9,10] , angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) [11] .…”

VEGFR-1 Activation-Induced MMP-9-Dependent Invasion in Hepatocellular Carcinoma

“…In this study, we confirmed that VEGFR-1 activation in HCC cell lines can regulate the expression of MMP-9, which might be a novel mechanism for HCC invasion. HCC usually expresses high level of VEGF/ VEGFR compared with the peritumoral tissue [16,[30][31] . Among VEGFRs, VEGFR-1, expressed in cancer cells, is particularly interesting due to its direct tumor activation via an autocrine stimulatory pathway [4,7,32].…”