Identification of a candidate stem cell in human gallbladder

Manohar, Rohan; Li, Yaming; Fohrer, Hélène; Guzik, Lynda; Stolz, Donna B.; Chandran, Uma; LaFramboise, William A.; Lagasse, Eric

doi:10.1016/j.scr.2014.12.003

Cited by 16 publications

(12 citation statements)

References 46 publications

(58 reference statements)

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“…The cell surface markers, CD26, CD29, CD44, CD54, CD49b, CD49f CD133, CD90 and CD326 (EpCam) have been reported to be present on human SC and CSC in various solid tumors [44-51]. CD24 and CD66 have been shown to identify mature/differentiated cells in normal and cancer tissues, including breast cancer [52, 53]. CD49c, CD81, CD104 and EGFR have been considered to be cancer or epithelial cancer cell markers [54-57].…”

Section: Resultsmentioning

confidence: 99%

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

Kaseb

Fohrer-Ting

Lewis

et al. 2016

Experimental Cell Research

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Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens. We show that spheroid enrichment of CSC from early and short-term HNSCC cell cultures was associated with increased expression of CD44, CD133, SOX2 and BMI1 compared with normal oral epithelial cells. On immunophenotyping, five of 12 SC/CSC markers were homogenously expressed in all tumor cultures, while one of 12 was negative, four of 12 showed variable expression, and two of the 12 were expressed heterogeneously. We showed that irradiated CSCs survived and retained their self-renewal capacity across different ionizing radiation (IR) regimens. Fluorescence in situ hybridization (FISH) analyses of parental and clonally-derived tumor cells revealed different chromosome copy numbers from cell to cell, suggesting the presence of chromosomal instability in HNSCC CSC. Further, our in vitro and in vivo mouse engraftment studies suggest that CD44+/CD66− is a promising, consistent biomarker combination for HNSCC CSC. Overall, our findings add further evidence to the proposed role of HNSCC CSCs in therapeutic resistance.

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Section: Resultsmentioning

confidence: 99%

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

Kaseb

Fohrer-Ting

Lewis

et al. 2016

Experimental Cell Research

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“…The cells tend to moderately produce mucins ( 35 ) and transport bile and organic ions ( 36 – 38 ). They share many similarities with the cholangiocytes of the intrahepatic bile duct ( 39 ), and therefore the stem cells of the adult gallbladder might express similar markers, such as CD44, CD13, and LGR5 ( 40 , 41 ) and also depend on activation of the Wnt/β-catenin pathway for their maintenance ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic Effect of Salmonella Paratyphi A Infection on Human Primary Gallbladder Cells

Hartl

Iftekhar

et al. 2020

mBio

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Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC. IMPORTANCE Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the role of bacterial genotoxins has become more relevant. Salmonella enterica serovars Typhi and Paratyphi A have been clinically associated with gallbladder cancer. By harnessing the stem cell potential of cells from healthy human gallbladder explant, we regenerated and propagated the epithelium of this organ in vitro and used these cultures to model S. Paratyphi A infection. This study demonstrates the importance of the typhoid toxin, encoded only by these specific serovars, in causing genomic instability in healthy gallbladder cells, posing intoxicated cells at risk of malignant transformation.

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“…The results from KEGG analysis demonstrated that the 10 hub genes were enriched in the following pathways: ‘TGF-β signaling pathway’, ‘signaling pathways regulating pluripotency of stem cells’ and ‘complement and coagulation cascades’. These pathways have been associated with the development and progression of gallbladder cancer ( 42 – 44 ). For example, the crosstalk between the TGF-β signaling pathway and lncRNAs plays a key role in cancer.…”

Section: Discussionmentioning

confidence: 99%

Identification of UBE2T as an independent prognostic biomarker for gallbladder cancer

Zhu

Li²,

Niu

et al. 2020

Oncol Lett

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Gallbladder cancer is the most common biliary tract malignant tumor, with unfavorable patient outcomes. The present study aimed to identify potential diagnostic or prognostic biomarkers for gallbladder cancer. To do so, differentially expressed genes in the gallbladder walls and tumor tissues of patients with gallbladder cancer were analyzed via microarray. Furthermore, a protein-protein interaction network was constructed and genes with a degree score >10 were selected as hub genes. As ubiquitin conjugating enzyme E2T (UBE2T) was considered to be a hub gene, its expression was assessed via reverse transcription-quantitative (RT-q)PCR and immunohistochemistry (IHC). In addition, the association between UBE2T expression and the clinicopathological characteristics of patients with gallbladder cancer was analyzed using the χ 2 test. Furthermore, all patients were divided into high-and low groups based on UBE2T expression level and overall survival analysis was performed. Univariate and multivariate Cox regression analyses were performed to determine whether UBE2T may serve as an independent risk factor for gallbladder cancer. The results demonstrated that UBE2T expression was upregulated in the gallbladder walls and tumor tissues of patients with gallbladder cancer. Furthermore, UBE2T expression level was confirmed to be upregulated following RT-qPCR, and results from IHC demonstrated that UBE2T was predominantly expressed in the cytoplasm of gallbladder cancer cells. In addition, high UBE2T expression level was associated with clinical stage, T classification, N classification and M classification. The results from Univariate and multivariate analyses indicated that UBE2T expression level may be considered as an independent risk factor for gallbladder cancer. Taken together, the findings from this study suggested that high UBE2T expression level may contribute to the poor prognosis of patients with gallbladder cancer, and that UBE2T may act as an independent prognostic biomarker for these patients.

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Identification of a candidate stem cell in human gallbladder

Cited by 16 publications

References 46 publications

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

Genotoxic Effect of Salmonella Paratyphi A Infection on Human Primary Gallbladder Cells

Identification of UBE2T as an independent prognostic biomarker for gallbladder cancer

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