It might be possible to evaluate the appearance of immune responses to cryosurgery by monitoring serum cytokine levels.

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.

VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.

This study on the expression of VEGF might be useful to estimate the liver condition and the clinicopathological features of HCC.

Hepatoma cells might be able to survive under continuous oxidative stress through expression of VEGF.