| Background and ObjectiveHepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer death in the world. Its incidence accounted for10.03%of the malignant tumor and its mortality account for14.56%of the malignant tumor death in our country. It occurs in China ranking second after lung cancer. The treatment of HCC involves surgical resection, liver transplantation, interventional radiologist and so on. However, only few patients (20%-30%) are suitable candidates for surgery because most of them have poor hepatic functional reserve due to pre-existing liver cirrhosis. The reasons, which restricts the application of liver transplantation,are the high cost, the lack of donor liver and so on. Therefore, in clinical practice, transarterial chemoembolization (TACE) is considered standard palliative treatment for advanced HCC. However, it often fails to induce complete lesion necrosis, which can lead to distant metastasis. HCC is a hypervascular tumor, so tumor angiogenesis is important for tumor growth and metastatic spread. Vascular endothelial growth factor (VEGF) is one of the most important angiogenesis mediators. The VEGF family consists of several members, VEGF-A, VEGF-B, VEGF-C VEGF-D and placenta growth factor (PLGF). VEGF intracellular signaling is exerted via its cognate receptors:VEGFR-1(or flt-1) and VEGFR-2(or KDR/flk-1), which are the strongest kinase activity receptors. PLGF and VEGF have their own specific functions in angiogenesis. PLGF does not affect healthy vessels but diminish angiogenesis in cancer and ischemia condition. It plays a crucial role in pathological angiogenesis. VEGFR-2was suggested to be a critical factor in the formation of new blood vessels in tumors. VEGFR-2induces vascular proliferation, migration, and survival through the Ras/Raf/MEK/ERK pathway. Thus, the VEGFR-2is considered one of the most important regulators of angiogenesis, and it is a key target in anti-angiogenic therapy. The PLGF and VEGFR-2expression levels are correlated with tumor growth, metastasis, and prognosis, and several reports have described the PLGF and VEGFR-2expression in various types of solid tumors, such as non small cell lung caner, colorectal adenocarcinoma, gastric cancer, and HCC.Therefore, in this study, we assessed the change in serum VEGFR-2levels and the plasma PLGF levels in HCC patients undergoing TACE, and the clinical and prognostic significance of the post-treatment serum VEGF concentration. The clinical usefulness of pre-treatment serum VEGFR-2level or the plasma PLGF levels as an outcome predictor in HCC patients undergoing TACE therapy.Methods1、Blood was collected1-3days before treatment and after1month of therapy from43patients with HCC undergoing TACE treatment. Plasma PLGF levels were measured by enzyme-linked immunosorbent assay (ELISA).25patients with liver cirrhosis and25healthy adults were included in this study. Pre-treatment and post-treatment plasma PLGF levels were measured. Clinicopathological features and prognosis of plasma PLGF levels in HCC patients undergoing TACE treatment were observed. The relationship between plasma PLGF levels and AFP/PLT were observed. The prognostic significance of pre-treatment plasma PLGF levels were also assessed.2、Blood was collected1-3days before treatment and after1month of therapy from69patients with HCC undergoing TACE treatment. serum VEGFR-2levels were measured by enzyme-linked immunosorbent assay (ELISA).25patients with liver cirrhosis and25healthy adults were included in this study. The relationship between serum VEGFR-2levels and AFP/PLT were observed. Pre-treatment and post-treatment serum VEGFR-2levels were measured. Clinicopathological features and prognosis of serum VEGFR-2levels in HCC patients undergoing TACE treatment were observed. The prognostic significance of serum VEGFR-2levels were also assessed.3、Statistical analysis was performed using SPSS13.0(SPSS, Chicago, IL). t test or one-way ANOVA, and nonparametric test were used to assess continuous variables. Pearson’s correlation coefficient were used to investigate the correlation between two variables. The progression-free survival (PFS) and overall survival (OS) were computed using the Kaplan-Meier method and compared by the log-rank test. The prognostic relevance of each variable to OS and PFS was analyzed using the Cox proportional hazards models. P-values<0.05were considered statistically significant for all comparisons.Results1、Plasma PLGF levels in HCC were significantly elevated as compared to those in patients with liver cirrihosis (P=0.000) and those of the normal controls (P=0.000). Significant differences were observed when plasma PLGF levels were categorized by BCLC stage(P=0.031),tumor size (P=0.009), PVTT (P=0.007) and metastasis (P=0.046). The post-treatment plasma PLGF levels were significantly higher than the pre-treatment level in patients with HCC undergoing TACE ((703.4±280.7) pg/ml versus (641.0±216.2) pg/ml, P=0.001). When the median pre-treatment plasma PLGF level (641.0pg/ml) was used as the cut-off level, patients with low plasma PLGF level had better overall survival compared with those with high plasma PLGF level (P=0.021).In multivariate cox analysis, tumor size and pre-treatment plasma PLGF level were independent and significant prognostic factors of survival of HCC patients after TACE treatment (P=0.021,P=0.023).2、Serum VEGFR-2levels in HCC were significantly elevated as compared to those in patients with liver cirrihosis (P=0.000) and those of the normal controls (P=0.000). Significant differences were only observed when serum VEGFR-2levels were categorized by liver cirrihosis (P=0.000). The post-treatment plasma PLGF levels were significantly higher than the pre-treatment level in patients with HCC undergoing TACE ((10557.9±7007.2) ng/1versus (8709.2±6509.5) ng/1, P=0.045). When the median pre-treatment serum VEGFR-2levels (8709.2ng/1) was used as the cut-off level, patients with low serum VEGFR-2levels had better overall survival compared with those with high serum VEGFR-2levels (P=0.001).In multivariate Cox analysis, pre-treatment serum VEGFR-2levels were independent and significant prognostic factors of survival of HCC patients after TACE treatment(P<0.000).Conclusions1、There were no correlation between PLGF/VEGFR-2and AFP, suggesting that they had different mechanisms of production. Plasma PLGF levels and serum VEGFR-2levels may be independent predictive factor.2、Plasma PLGF levels may be used as a tumor marker in detecting vascular invasive phenotypes of HCC.3、Plasma PLGF levels and serum VEGFR-2levels were markedly elevated in the majority of patients with HCC received TACE treatment. This suggested that ischemic injury after TACE has been found to induce the up-regulation of circulating PLGF and VEGFR-2in patients with HCC.4、High plasma PLGF levels were one of independent unfavorable prognostic factors for overall survival. It suggested that plasma PLGF may be a useful biomarker for prognostic prediction in patients with HCC treated with TACE. It was the same with serum VEGFR-2levels. |
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