ArticleThe Journal of clinical investigation2006
Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
Article in The Journal of clinical investigation, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
134 citing papers in PubMed, 1 synthesis or guideline pooled it, 208 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study.British journal of cancer · 2018Trial
- Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer.International journal of clinical oncology · 2008Trial
- PTEN-AKT2 regulates mixed lineage liver cancer development and sensitizes cancer cells to TGFβ treatment.Oncogene · 2026Article
- SREBP-driven lipogenesis coupled with ferroptosis resistance as a therapeutic target in PTEN-loss extrahepatic cholangiocarcinoma.JHEP reports : innovation in hepatology · 2026Article
- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
- Preclinical mouse models for studying cholangiocarcinoma.Liver research (Beijing, China) · 2026Review
- PTEN-AKT2 Regulates Mixed Lineage Liver Cancer Development and Sensitizes Cancer Cells to TGFβ Treatment.Research square · 2026Article
- [Pathology of liver tumours in animal models].Pathologie (Heidelberg, Germany) · 2025Review
- Drivers of Pancreatic Cancer: Beyond the Big 4.Cancers · 2025Review
- Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma.The American journal of pathology · 2025Review
- The Impact of Normal Hepatobiliary Cell Zonation Programs on the Phenotypes and Functions of Primary Liver Tumors.Liver cancer · 2025Review
- Targeting the tumor microenvironment in cholangiocarcinoma to improve immune checkpoint blockade: potential strategies and translational pre-clinical models.Clinical & translational immunology · 2025Review
- Liquid biopsy in gallbladder carcinoma: Current evidence and future prospective.The journal of liquid biopsy · 2024Review
- PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.Journal of hepatology · 2024Article
- Cellular Origins and Lineage Plasticity in Cancer.Cold Spring Harbor perspectives in medicine · 2024Review
- Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.Disease models & mechanisms · 2024Article
- Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver.American journal of physiology. Gastrointestinal and liver physiology · 2024Article
- The heterogeneity of signaling pathways and drug responses in intrahepatic cholangiocarcinoma with distinct genetic mutations.Cell death & disease · 2024Article
- p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis.Cancer research communications · 2023Article
74 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.