Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE202090 | GEO | 2023/11/15
REPOSITORIES: GEO
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Project description:Mixed hepatocellular – cholangiocarcinoma (HCC-CCA) is a highly malignant primary liver cancer of increasing incidence for which the cell of origin and molecular pathogenesis have not yet been fully elucidated. Here, by linking YFP to the progenitor cell specific promoter of Foxl1 in Mdr2-KO mice, we generated a lineage tracing mouse model for liver cancer to monitor the development of mixed HCC-CCA tumors following a prolonged period of liver inflammation. In this model of chronic hepatitis, we demonstrate that liver progenitor cells are the source of mixed HCC-CCA tumors but not of hepatocellular carcinoma (HCC). Moreover, we show that IL6, originating from senescent hepatic cells, is involved in progenitor cell proliferation and development of mixed HCC-CCA tumors via IL6 trans-signaling. These findings could form the basis for the development of novel therapeutic approaches for treatment of mixed HCC-CCA liver cancer.
2023-11-15 | GSE201995 | GEO
Project description:Mixed hepatocellular – cholangiocarcinoma (HCC-CCA) is a highly malignant primary liver cancer of increasing incidence for which the cell of origin and molecular pathogenesis have not yet been fully elucidated. Here, by linking YFP to the progenitor cell specific promoter of Foxl1 in Mdr2-KO mice, we generated a lineage tracing mouse model for liver cancer to monitor the development of mixed HCC-CCA tumors following a prolonged period of liver inflammation. In this model of chronic hepatitis, we demonstrate that liver progenitor cells are the source of mixed HCC-CCA tumors but not of hepatocellular carcinoma (HCC). Moreover, we show that IL6, originating from senescent hepatic cells, is involved in progenitor cell proliferation and development of mixed HCC-CCA tumors via IL6 trans-signaling. These findings could form the basis for the development of novel therapeutic approaches for treatment of mixed HCC-CCA liver cancer.
2023-11-15 | GSE202089 | GEO
Project description:Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling.
| PRJNA834636 | ENA
Project description:Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, bulk RNA sequencing
| PRJNA833958 | ENA
Project description:Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, single-cell RNA sequencing
| PRJNA834643 | ENA
Project description:Hepatic progenitor cells (HPC) play important roles in both liver regeneration and carcinogenesis. Combined hepatocellular-cholangiocarcinoma (CHC), a malignant primary liver tumor with poor prognosis, is thought to be of HPC origin. However, the prognostic significance of this etiology is not well defined. Therefore, we retrospectively investigated the relationship of HPC-related pathological features and long-term outcome in patients with CHC in our department. In a cohort of 80 patients identified between 1997 and 2003, including 70 patients who underwent resection with curative intent, overall survival (OS) and disease-free survival (DFS) were correlated with the proliferative activity of nontumor ductular reaction (DR) and the expression levels of HPC and biliary markers including ?-fetoprotein (AFP), keratin 7 (K7), keratin 19 (K19), oval cell (OV)-6, epithelial cell adhesion molecule (EpCAM), and c-Kit in both tumor and nontumor liver. We found that nontumor ductular reactions (DRs), specifically the proliferating cell nuclear antigen (PCNA) labeling index of the ductular reaction (PI-DR), a surrogate for transit-amplifying compartments, was an independent prognostic factor for both OS and DFS. By contrast, intratumoral expression of only one marker, absence of AFP, was associated with OS. PI-DR was also independently associated with synchronous "multicentric occurrence" in hepatocellular carcinoma components, a feature of CHC that may predispose to metachronous multifocal tumorigenesis.Proliferative ductular reaction related to HPC activation is associated with recurrence of CHC. Background HPC activation is strongly associated with multifocal occurrence and related tumor recurrence, highlighting the critical role of background liver disease, a "field effect," in the recurrence of CHC.
| S-EPMC4586114 | biostudies-literature
Project description:Fetal progenitor cells enter the maternal circulation during pregnancy and can persist for decades. We aimed to determine the role of these cells in tissue inflammation during pregnancy. WT female mice were mated to males transgenic for the EGFP (ubiquitous) or the luciferase gene controlled by the VEGF receptor 2 (VEGFR2; V-Luc) promoter. A contact hypersensitivity reaction was triggered during such pregnancies. Fetal cells were tracked by using real-time quantitative amplification of the transgene (real-time PCR), Y chromosome in situ hybridization (FISH), immunofluorescence or in vivo bioluminescence imaging. Real-time PCR disclosed fetal cells in the inflamed areas in all tested mice (17/17) with higher frequency and numbers in the inflamed compared with the control areas (P = 0.01). Double labeling demonstrated CD31+ EGFP+ fetal cells organized as blood vessels. In WT pregnant mice bearing V-Luc fetuses, a specific luciferase activity signal could be detected at the hypersensitivity site only, demonstrating the elective presence of VEGFR2-expressing fetal cells. In conclusion, using various techniques, we found the presence of fetal endothelial cells lining blood vessels in maternal sites of inflammation. These results imply that fetal endothelial progenitor cells are acquired by the mother and participate in maternal angiogenesis during pregnancy.
| S-EPMC1794298 | biostudies-literature
Project description:BackgroundCardiac liver cirrhosis secondary to Fontan procedure has been associated with hepatocellular carcinoma at a younger age. However, Fontan associated liver disease and combined hepatocellular-cholangiocarcinoma has not been previously reported. Combined hepatocellular-cholangiocarcinoma is a rare cancer that accounts for 2-5% of primary liver tumors and poses significant diagnostic and treatment challenges. This case highlights these needs and potential screening and treatment considerations. Herein we describe a case of combined hepatocellular-cholangiocarcinoma in a patient with autism, congenital heart disease, and Fontan procedure.Case descriptionThe patient is a 27-year-old male who presented with a liver mass detected on MRI performed in the context of a rising alpha-fetoprotein during a screening visit. Biopsy of the mass revealed a combined hepatocellular-cholangiocarcinoma which was staged as localized. Due to the COVID-19 pandemic and subsequent halt of all elective surgeries, the patient received local therapy with chemoembolization followed by pembrolizumab. The disease progressed though, and therapy was changed to gemcitabine plus cisplatin. Patient received 2 cycles of therapy, after which he and his family decided to transfer medical care to Memorial Sloan Kettering. Next generation sequencing of the tumor revealed TP53 and FGFR2 mutations. By then patient was also found to have lung metastasis. To help address the hepatocellular carcinoma, lenvatinib was added. Patient had sustainable disease control for about a year, yet eventually developed thrombocytopenia complicated by an episode of gastrointestinal bleeding. With a worsening performance status, adverse events of the treatment, and recurrent hospitalizations, a goals of care discussion with his family led to the discontinuation of active cancer therapy and patient was started on best supportive care. Patient remained in active follow-up until the time of this report and passed away less than a year from initiating best supportive care alone.ConclusionsThis challenging case raises awareness towards screening and monitoring all patients with Fontan procedure for Fontan associated liver disease and liver cancers, including combined hepatocellular-cholangiocarcinoma. To the best of our knowledge, this is the first description of combined hepatocellular-cholangiocarcinoma occurring in the context of cardiac cirrhosis. The management difficulties that led to altering the goals of care, is another reminder of the dynamic nature of the care oncologists would provide.
| S-EPMC9830364 | biostudies-literature
Project description:BackgroundPatients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) are not traditionally considered eligible for liver transplantation (LT) due to poor outcomes.AimTo compare outcomes between living donor LT (LDLT) patients with hepatocellular carcinoma (HCC) and LT patients with cHCC-CC and to identify risk factors for tumor recurrence and death after LT in cHCC-CC patients.MethodsData for pathologically diagnosed cHCC-CC patients (n = 111) who underwent LT from 2000 to 2018 were collected for a nine-center retrospective review. Patients (n = 141) who received LDLT for HCC at Samsung Medical Center from January 2013 to March 2017 were selected as the control group. Seventy patients in two groups, respectively, were selected by 1:1 matching.ResultsCumulative disease-free survival (DFS) and overall survival (OS) in the cHCC-CC group were significantly worse than in the HCC group both before and after matching. Extrahepatic recurrence incidence in the cHCC-CC group was higher than that in the HCC group (75.5% vs 33.3%, P < 0.001). Multivariate analysis demonstrated that the cHCC-CC group had significantly higher rates of tumor recurrence and death compared to the HCC group. In cHCC-CC subgroup analysis, frequency of locoregional therapies > 3, tumor size > 3 cm, and lymph node metastasis were predisposing factors for tumor recurrence in multivariate analysis. Only a maximum tumor size > 3 cm was a predisposing factor for death.ConclusionThe poor prognosis of patients diagnosed with cHCC-CC after LT can be predicted based on the explanted liver. Frequent regular surveillance for cHCC-CC patients should be required for early detection of tumor recurrence.
| S-EPMC10405106 | biostudies-literature
Project description:Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase ?1 (MAT?1) have lower PHB1 expression, and we reported that c-MYC interacts directly with both proteins. Furthermore, c-MYC and MAT?1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MAT?1, and c-MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG, and c-MAF. Both PHB1 and MAT?1 heterodimerize with MAX, bind to the E-box element, and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element and is occupied mainly by MAX, MNT, and MAT?1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF, and MAFG in cancer cells and human HCC/CCA. All 8-month-old liver-specific Phb1 knockout mice developed HCC, and one developed CCA. Five-month-old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation.We have identified that PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box and positively regulates MAT1A while suppressing c-MYC, MAFG, and c-MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA. (Hepatology 2017;65:1249-1266).
| S-EPMC5360526 | biostudies-literature