肝癌复发转移的临床与实验研究进展与展望

Clinical and Experimental Studies on Recurrence and Metastasis of Hepatocellular Carcinoma-Progress and Prospect

90年代以来肝癌已成为我国第二位癌症杀手，为此肝癌的防治至关重要。至今，外科仍然是肝癌获得根治的最好疗法，但复发和转移是进一步改善预后的障碍。近年复发和转移的研究已成为包括肝癌在内所有实体瘤的研究热点。本文复习相关文献，并重点叙述我所的有关工作。临床方面，对亚临床期复发的再切除是进一步提高疗效的有效途径，但复发的预防则困难得多，化疗／免疫／栓塞治疗可能有助。实验研究方面，已建成裸鼠人肝癌高转移模型，研究了与侵袭性相关的分子水平变化（如c─erb—B2、p16、p21、p53、mdm2、VEGF、TGFa、EGF受体、MMP—2、ICAM—1等与侵袭性呈正相关，而nm23—H1、TIMP—2、整合素a5、Kai—1等则与侵袭性呈负相关），并探索了使用反义H─ras、抗HBx／抗CD3的双功能抗体、TNF与TK基因的基因治疗、BB94（基质金属蛋白酶抑制剂）、TNP—470（抗血管生成）等的干预治疗。预期生物治疗、基于分子生物学发现所设计的新疗法、综合干预等可能重要，而针对肿瘤血管的探索对肝癌可能有特殊意义。

Hepatocellular carcinoma(HCC) has become the second cancer killer in China since 1990s, preventionand treatment of HCC are therefore urgently needed. In clinical aspect, surgery remains the best for a curativeoutcome of HCC, unfortunately, recurrence and metastasis are ma jor obstacles for further improve prognosis.Recently, studies on recurrence and metastasis have become attractive fields in all of the solid tumors, includingHCC. This paper has briefly reviewed the related literatures, with special reference to works done in author'sinstitution. In clinical aspect, re-resection has been proved to prolong survival further in patients with subclinical recurrence, however, prevention of recurrence is difficult, postoperative chemo/immuno/embolization mighthelp. In Experimental aspect, a highly metastatic human HCC model in nude mice has been established, invasiveness related molecular events (c - erb - B2, p16, p21, p53 , mdm2, VEGF ) TGFa, EGF receptor , MMP -2, ICAM - 1 were positively related, and nm23 - H1, TIMP -- 2, Integrin a5, Kai - 1 were negativelyrelated) have been studied, and intervention using antisense H --ras, antiHBx/antiCD3 bispecific antibody,gene therapies with TNF and TK genes, BB94 (matrix metalloproteinase inhibitor), TNP - 470 (anti-angio-genic), etc. have also been tried. It is expected that biotherapy, novel approach based on molecular findings,multidisciplinary interventions might be important, and anti-angiogenic approach will of particular implicationfor HCC.