| Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of death from cancer worldwide. Hepatectomy as the optimum therapy for HCC has prolonged patients'survival. However, the further benefits obtained from curative resection are always compromised by the high post-operative recurrence rate. Anti-angiogenesis drugs represented by vascular endothelial growth factor (VEGF) /VEGFR targeted drugs are the promising therapies to prevent tumor recurrence after hepatectomy. VEGF/VEGFR targeted therapy has been an important treatment for advanced HCC. However their effect is reduced by the occurrence of resistence. Anti-placental growth factor (P1GF) therapy is effective in animal studies with less resistance. Role of P1GF in the progression of HCC is not clear. This study is aiming to explore the expression of P1GF in HCC and peritumoral liver tissues and its prognosis.Materials and MethodsPaired tumors with corresponding peritumoral liver tissues from HCC patients who underwent curative resection in Zhongshan Hospital during January 1999 and march 2008 were enrolled. [three cohort in all, including cohort 1 with 105 paired paraffin-embedded samples, cohort 2 with 32 paired paraffin-embedded and fresh samples and validation cohort with 394 paraffin-embedded samples.] Normal liver tissues without hepatitis B virus (HBV) infection (negative hepatitis B surface antigen) from 40 patients underwent liver resection for hepatic hemangioma were randomly recruited. Expression of P1GF and hypoxia-inducible factor 1a (HIF-1a) was analyzed in tissue microarrays by immohistochemistry. P1GF mRNA expression level was measured by real-time polymerase chain reaction. Relations among P1GF expression, clinicopathologic features, overall survival (OS) and time to recurrence (TTR) were evaluated. Prognosis of peritumoral P1GF was compared with that of peritumoral VEGF-A and VEGF-B.ResultsP1GF protein expression in peritumoral liver tissue (mean IOD,0.019±0.016) in cohort 1 was significantly higher than that in corresponding tumor tissue (0.007±0.011, P< 0.001). It was validated in mRNA expression level detected from cohort 2 (mean-ACT,-11.6±0.25 in tumor tissue versus-9.9±0.25 in peritumoral liver tissue, P< 0.001). P1GF expression in the peritumoral liver tissue was also higher than that in the normal liver tissue without hepatitis (mean IOD,0.019±0.016 versus 0.008±0.009, P< 0.001). P1GF expression in tumor tissue was not differed with that in the normal liver tissue (P = 0.117). P1GF mRNA expression correlated with P1GF protein expression in both tumor (r = 0.604, P = 0.006) and peritumoral area (r = 0.561, P = 0.012).Intratumoral P1GF expression was not associated with patients'OS (P = 0.079) or TTR (P = 0.958). However, high peritumoral P1GF expression, which was associated with tumor size (P = 0.002), presence of intrahepatic metastasis (P = 0.005), and TNM stage (P = 0.048), was an independent risk factor for OS (P = 0.026) and TTR (P = 0.041). Prognostic value of peritumoral P1GF expression was further validated in an independent validation cohort (n= 394).Postoperative tumor recurrence was discriminated into early and late recurrence by 24 months. Patients with high peritumoral P1GF expression tended to have an early recurrence (P = 0.011) rather than a late recurrence (P = 0.266). However, intratumoral P1GF was not associated with early recurrence (P = 0.821) or late recurrence (P = 0.538).In peritumoral tissues, P1GF expression was associated with hypoxia-inducible factor 1α(HIF-1α) (P= 0.017). In vitro, P1GF expression was upregulated in L02, a hepatic cell line, under hypoxic conditions. Intratumoral and peritumoral VEGF-B expression and intratumoral VEGF-A expression were not associated with OS and TTR. Peritumoral VEGF-A expression was a risk factor for OS (P=0.005), but not for TTR When we adopted peritumoral VEGF-A and P1GF expression into multivariate cox proportional hazards analysis, we found that peritumoral P1GF expression, but not VEGF-A expression, was an independent risk factor for patients'OS.ConclusionsHigh peritumoral P1GF expression is associated with tumor recurrence and survival after resection of HCC. P1GF could be a target of adjuvant therapy and deserves further investigations.The potential application of this workPeritumoral P1GF expression is of significant clinical implication in helping to identify a high risk subgroup of patients for whom adjuvant therapies after hepatectomy are in needed.The novelty of this work Peritumoral P1GF expression, for first time, was identified as a potential marker for prognosis in HCC patients after curative resection.
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