Abstract
Complete surgical tumor resection (R0) for treatment of intrahepatic cholangiocarcinoma (ICC) is potentially curative, but the prognosis remains dismal due to frequent tumor recurrence and metastasis after surgery. Adjuvant therapies may improve the outcome, but clinical studies for an adjuvant approach are difficult and time-consuming for rare tumor entities. Therefore, animal models reflecting the clinical situation are urgently needed to investigate novel adjuvant therapies. To establish a mouse model of resectable cholangiocarcinoma including the most frequent genetic alterations of human ICC, we electroporated Sleeping Beauty-based oncogenic transposon plasmids into the left liver lobe of mice. KRas-activation in combination with p53-knockout in hepatocytes resulted in formation of a single ICC nodule within 3-5 weeks. Lineage tracing analyses confirmed the development of ICC by transdifferentiation of hepatocytes. Histologic examination demonstrated that no extrahepatic metastases were detectable during primary tumor progression. However, formation of tumor satellites close to the primary tumor and vascular invasion were observed, indicating early invasion into normal tissue adjacent to the tumor. After R0-resection of the primary tumor, we were able to prolong median survival, thereby observing tumor stage-dependent local recurrence, peritoneal carcinomatosis, and lung metastasis. Adjuvant gemcitabine chemotherapy after R0-resection significantly improved median survival of treated animals. We have developed a murine model of single, R0-resectable ICC with favorable characteristics for the study of recurrence patterns and mechanisms of metastasis after resection. This model holds great promise for preclinical evaluation of novel multimodal or adjuvant therapies to prevent recurrence and metastasis after R0-resection.
Highlights
Biliary tract cancers (BTC) are characterized by aggressive adenocarcinomas that are clinically classified into gallbladder carcinomas as well as distal, perihilar, and intrahepatic cholangiocarcinomas (ICC)
Since KRas-activation and p53-alteration can be frequently found in BTC,[26,27] predominantly in the ICC subtype,[28,29] we investigated this genetic setup in mice
Intrahepatic cholangiocarcinoma is representative of tumor entities where resection of the primary tumor is the only option for cure, but frequent disease recurrence limits survival.[35]
Summary
Engin G€urlevik,1* Bettina Fleischmann-Mundt,1* Nina Armbrecht,[1] Thomas Longerich,[2] Norman Woller,[1] Arnold Kloos,[1] Dirk Hoffmann,[3] Axel Schambach,[3] Thomas C. Curative resection of the developed single ICC nodules prolonged survival of the animals with the subsequent observation of tumor stage-dependent local recurrence and distant metastases. Since these recurrence patterns reflect the clinical situation in humans, we were able to establish for the first time a clinically relevant and reliable animal model for investigations of novel adjuvant therapies after R0resection of ICC
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