RESUMEN
BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.
Asunto(s)
Aurora Quinasa A , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Fosfohidrolasa PTEN , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Animales , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Colangiocarcinoma/etiología , Colangiocarcinoma/patología , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Ratones , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/etiología , Neoplasias de los Conductos Biliares/metabolismo , Humanos , Ratones Noqueados , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Conductos Biliares Extrahepáticos/patología , Modelos Animales de Enfermedad , Colangitis/patología , Colangitis/etiología , Colangitis/metabolismo , Colangitis/genética , Transducción de SeñalRESUMEN
Aim: The differential diagnosis of intrinsic nonfibrotic conditions that may lead to portal hypertension include hepatoportal sclerosis (HPS), nodular regenerative hyperplasia (NRH), and sinusoidal obstruction syndrome (SOS). In this article, we characterize the clinical features and outcome of these lesions when they manifest as portal hypertension. Methods: Data was collected through retrospective patient medical records. Results: Patients (HPS: 28, NRH: 17, SOS: 11) were identified more frequently in recent years. All groups presented with signs and symptoms of portal hypertension. All patients had complex medical histories. An elevated serum alkaline phosphatase occurred in all groups and an elevated bilirubin with SOS. Imaging of the liver with HPS and NRH suggested cirrhosis, which was not seen with SOS. 11%, 12%, and 9% of patients in the HPS, NRH, and SOS respectively, underwent transjugular intrahepatic portosystemic shunt placement to manage the complications of portal hypertension, while 43%, 24%, and 36% of patients respectively, received a liver transplant. Conclusions: Patients with HPS, NRH, and SOS had complex medical histories, likely contributing to the development of these lesions. They are recognized more frequently now. In contrast to HPS and NRH, SOS occurred in liver transplant recipients, was associated with elevated serum bilirubin, and imaging did not suggest the presence of advanced fibrosis/cirrhosis. Liver transplantation appeared to be a viable treatment for complications related to HPS and NRH. Retransplantation for SOS yielded mixed results. HPS, SOS, and NRH should be considered when evaluating liver specimens from patients with unexplained nonfibrotic portal hypertension. Key message: Intrinsic nonfibrotic causes of portal hypertension appear to be increasing in frequency. The differential diagnosis includes NRH, HPS, and SOS. These conditions are associated with complex diseases and possibly due to treatments. Pathologists need to be aware of this differential diagnosis when presented with liver biopsies performed to assess portal hypertension.
RESUMEN
Background and Aims: The aim of this study was to review a large series of cases with hepatoportal sclerosis (HPS) as a pathologically recognizable entity in liver tissue specimens and describe the associated clinical and radiographic manifestations, along with the outcomes of this entity. Methods: Data were collected through a retrospective chart review. Results: Twenty-eight patients were identified that had pathologically defined HPS. All patients had a significant past medical history and signs and symptoms of portal hypertension. The most consistent laboratory finding was an elevated alkaline phosphatase. Radiographically, 9 patients were mistakenly identified as having advanced fibrosis/cirrhosis. The initial histologic diagnosis was made on biopsy in 20 patients and after transplant in 8 patients. The severity of symptoms was variable and required transplantation in 11 patients, 3 were treated with transjugular intrahepatic portosystemic shunt, and the remaining patients were treated symptomatically. Conclusion: HPS is associated with past medical history that may be causal in nature. Signs and symptoms may be severe enough to require liver transplantation. A significant proportion of patients are radiographically misdiagnosed as cirrhosis. In this small series, overall outcomes for transplanted patients are acceptable.
RESUMEN
ABSTRACT Introduction and aim. Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. Material and methods. We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. Results. From 2003-2014,978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 -1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. Conclusions. In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.