Department of Surgery and Centre for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Ann Surg. 2010 Jun;251(6):1154-61. doi: 10.1097/SLA.0b013e3181d96e3d.
We aimed to explore the precise molecular mechanism of early and invasive tumor growth in a small-for-size graft after liver transplantation and to identify the distinct molecular signature linked to acute-phase injury and late-phase tumor invasiveness.
Acute phase small-for-size liver graft injury plays an important role in tumor recurrence after liver transplantation. For prevention of such recurrence, understanding of its underlying mechanism will be important in developing novel therapeutic strategies.
An orthotopic rat liver transplantation model was applied using whole grafts and small-for-size (50%) grafts. The recipients were injected with hepatoma cell lines via the portal vein to mimic tumor recurrence after liver transplantation. Tumor invasive properties were compared between the tumor developed from small and whole graft. Gene signatures of acute phase graft injury (days 1 and 3) and late phase tumor recurrence (days 14 and 21) were screened using cDNA microarray analysis and further confirmed by quantitative RT-PCR. The potential gene candidate CXCL10 was singled out for further functional studies to investigate its role in tumor progression.
A number of genes linked to inflammatory responses and tumor invasiveness were found over-expressed in small-for-size liver grafts and/or tumors developed in small liver grafts by cDNA microarray screening. Real-time RT-PCR also confirmed that the gene CXCL10 was over-expressed not only in small-for-size graft at the early phase, but also in tumor from small-for-size graft at the late phase after liver transplantation. In vitro functional studies further confirmed that CXCL10 promoted tumor-invasion-related properties and tumor-associated macrophage activation.
CXCL10 over-expression, the distinct gene signature of acute-phase graft injury and tumor invasiveness in small-for-size liver grafts, may contribute to early tumor recurrence after liver transplantation. CXCL10 and its downstream signals may be potential therapeutic targets in the prevention of tumor recurrence after liver transplantation using small-for-size graft.
我们旨在探索肝移植后小体积供肝中早期侵袭性肿瘤生长的精确分子机制，并确定与急性期损伤和晚期肿瘤侵袭相关的独特分子特征。
急性小体积肝移植损伤在肝移植后肿瘤复发中起重要作用。为了预防这种复发，了解其潜在机制对于开发新的治疗策略非常重要。
应用原位大鼠肝移植模型，使用全肝和小体积（50%）肝进行实验。通过门静脉向受体注射肝癌细胞系，模拟肝移植后肿瘤复发。比较小体积和全体积供肝所形成肿瘤的侵袭特性。通过 cDNA 微阵列分析筛选急性移植物损伤（第 1 天和第 3 天）和晚期肿瘤复发（第 14 天和第 21 天）的基因特征，并通过实时定量 RT-PCR 进一步验证。选择潜在的基因候选物 CXCL10 进行进一步的功能研究，以研究其在肿瘤进展中的作用。
通过 cDNA 微阵列筛选，发现许多与炎症反应和肿瘤侵袭性相关的基因在小体积肝移植和/或小体积肝移植中形成的肿瘤中过度表达。实时 RT-PCR 也证实，基因 CXCL10 不仅在肝移植后早期小体积移植物中过度表达，而且在小体积移植物中的肿瘤中也过度表达。体外功能研究进一步证实，CXCL10 促进肿瘤侵袭相关特性和肿瘤相关巨噬细胞的激活。
CXCL10 的过度表达、小体积肝移植中急性期移植物损伤和肿瘤侵袭性的独特基因特征，可能导致肝移植后早期肿瘤复发。CXCL10 及其下游信号可能是预防小体积肝移植后肿瘤复发的潜在治疗靶点。
