Prognostic Roles of Cross-Talk between Peritumoral Hepatocytes and Stromal Cells in Hepatocellular Carcinoma Involving Peritumoral VEGF-C, VEGFR-1 and VEGFR-3

BackgroundPeritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.MethodsTumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM. Tissue microarrays were constructed from duplicate cores of tumor tissue and surrounding peritumoral tissue from each resected specimen. Immunohistochemistry and real-time polymerase chain reaction were used to evaluate the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-1(VEGFR-1), VEGFR-2, and VEGFR-3. Macrophage infiltration was determined by CD68 staining. Correlations between the expression of these factors and overall survival (OS) and time to recurrence (TTR) were studied.ResultsThe peritumoral expression of VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were significantly higher than expression of these factors in tumors. VEGFR-1 was mostly located in peritumoral macrophages, while VEGF-C and VEGFR-3 were mostly located in peritumoral hepatocytes. HCC with high peritumoral co-expression of VEGF-C, VEGFR-1, and VEGFR-3 was associated with higher peritumoral distribution of macrophages (0.87%±0.26% versus 0.45%±0.20%), LNM (32.4% versus 12.0%), shorter TTR (10.2 months versus 34.5 months), and poor prognosis (19.4 months versus 49.3 months).ConclusionExpression of VEGF-C, VEGFR-1, and VEGFR-3 in peritumoral liver tissue is associated with a unique type of HCC that has a poorer outcome after hepatectomy.背景 肝周组织（peritumoral liver tissue）可能通过血管生成与淋巴管生成相关因子，在肝细胞癌（hepatocellular carcinoma, HCC）进展及患者生存中发挥潜在作用。但上述因子在接受根治性切除术后的肝细胞癌患者的肝细胞与基质细胞中的预后价值，仍有待探索。 方法 本研究纳入145例无淋巴结转移（lymph node metastasis, LNM）的肝细胞癌根治术后患者，以及37例伴LNM的肝细胞癌根治术后患者，收集其肿瘤组织及癌周肝组织标本。针对每例标本的肿瘤组织与癌周组织，分别取重复芯样构建组织微阵列。采用免疫组化法与实时聚合酶链反应（real-time polymerase chain reaction）检测血管内皮生长因子-A（vascular endothelial growth factor-A, VEGF-A）、VEGF-C、血管内皮生长因子受体-1（VEGFR-1）、VEGFR-2及VEGFR-3的表达水平；通过CD68染色检测巨噬细胞浸润情况。分析上述因子的表达与患者总生存期（overall survival, OS）及复发时间（time to recurrence, TTR）的相关性。 结果 癌周组织中VEGF-A、VEGF-C、VEGFR-1、VEGFR-2及VEGFR-3的表达水平显著高于肿瘤组织。其中VEGFR-1主要表达于癌周巨噬细胞，而VEGF-C与VEGFR-3主要表达于癌周肝细胞。癌周组织同时高表达VEGF-C、VEGFR-1及VEGFR-3的肝细胞癌患者，其癌周巨噬细胞浸润比例更高（0.87%±0.26% vs 0.45%±0.20%）、伴淋巴结转移比例更高（32.4% vs 12.0%）、复发时间更短（10.2个月 vs 34.5个月）且预后更差（19.4个月 vs 49.3个月）。 结论 癌周肝组织中VEGF-C、VEGFR-1及VEGFR-3的表达，与一类具有术后肝切除预后不良特征的独特肝细胞癌亚型相关。