Disseminated Tumor Cells Homing Into Liver: A Possible Mechanism Of Hepatocellular Carcinoma Recurring Observed In Animals

It is widely accepted that the clonality of recurrent hepatocellular carcinoma (HCC)following curative treatment arises from multicentric occurrence (MO) or intrahepaticmetastasis (IM). The two different mechanisms are responsible for its high frequencyof recurrence. De novo tumor may develop synchronously or metachronously in theremnant cirrhotic liver associated with hepatitis virus infection, where therepreexisted multiple independent nodules ignored before treatment. On the other hand,the malignant cells may disseminate from a single primary tumor to form satellitetumor nodules through portal venous system.However, the two mechanisms fail to elucidate the HCC recurrence in transplants ofstrictly selected patients because liver replacement eradicates both HCCs and cirrhotichepatic parenchyma to meet truly radical therapy. Immunosuppressant could promotetumor growth but it has no carcinogenesis. In this study, we established stableorthotopic liver transplantation for HCC in rats. The recurrent patterns were observedand recorded. We further discriminated the origin of recurrent HCC from recipient ordonor through ISH for Y chromosome in gender discordant rats. In term of theseresults, we make an attempt to propose a possible new mechanism different from MOand IM, which also contributes to the recurrence following curative resection.Part 1. Tumor recurrence pattern after liver transplantation for HCC on ananimal model.The objective of this study was to develop an animal model and further to evaluate thebiology of hepatocellular carcinoma recurrence after liver transplantation.Diethylnitrosamine (DENA) of 100 parts per million in drinking water wasadministered daily for 90 days or 120 days to 130 male inbred SD rats. Normalfemale SD rats were taken as donor. Orthotopic liver transplantation was performedaccording to Kamada cuff techniques in 98 rats more than 30 days after thewithdrawal of DENA. No immunosuppressant was postoperatively administered. Allrats were stratified by tumor size into three experimental groups in laparotomies: 1st 3第二军医大学临床博士学位论文 英文摘要group less than 1.0cm in diameter(n=25), 2nd group less than 1.5cm but more than1.0cm in diameter(n=41) and 3rd group more than 1.5cm in diameter(n=32). 26of them died in operation and 70 rats lost their lives within 30 days following livertransplantation for various reasons. The mean survival times of three groups were81.3±33.2 days,67.6±24.9 days,54.4±24.9 days separately. 10 rats in natural historysurvived by 29.4±12.9 days calculated by 150 days after DENA administration. Therecurrence rate in 1st, 2nd and 3rd group were 12.0%, 12.2%, 12.5%, respectively.There was no significant difference among them. The overall HCC recurrence ratewas 35.7%(10/28). The recurrent sites were pure transplant 7.1%(2/28), transplantand lung 10.7% (3/28),transplant and abdorminal cavity 3.6%(1/28),pureabdorminal cavity 7.1%(2/28),pure lung 7.1%(2/28). The overall recurrence ratewas 60.0% (6/10) in transplant. Of them, three grafts were discarded because therecipients have been dead when laparotomy. Thirteen lesions were obtained in otherthree available transplants. Pathological examination showed that multiple tumorsdiffusely located in each transplant and no recurrent HCC in cavity directly invadeddonor livers macroscopically. The results showed that the animal model mimics livertransplantation on patients. But the deteriorated physical conditions of rats with HCCdiethylnitrosamine-induced lead to higher death rates than we expected. Enough longsurvival time allows HCC recurrence in experimental rats. Multiple patterns of HCCrecurrence could be observed. Transplant itself is the most frequent HCC recurrentsite.Part 2. Determination of the clonal origin of recurrent HCC in transplanted liver The objective of this study was to detect the origin of he...