Premium
Adjuvant gemcitabine therapy improves survival in a locally induced, R0‐resectable model of metastatic intrahepatic cholangiocarcinoma
Author(s) -
Gürlevik Engin,
FleischmannMundt Bettina,
Armbrecht Nina,
Longerich Thomas,
Woller Norman,
Kloos Arnold,
Hoffmann Dirk,
Schambach Axel,
Wirth Thomas C.,
Manns Michael P.,
Zender Lars,
Kubicka Stefan,
Kühnel Florian
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26468
Subject(s) - medicine , intrahepatic cholangiocarcinoma , gemcitabine , metastasis , primary tumor , adjuvant therapy , kras , oncology , adjuvant , cancer , pathology , colorectal cancer
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. Conclusion : 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. (H epatology 2013;53:1031–1041)