Transforming growth factor-β1-induced epithelial–mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma

Shuang, Ze Yu; Wei, Wu; Xu, Jing; Lin, Guo-He; Liu, Yong Cheng; Lao, Xiang-Ming; Zheng, Limin; Li, Shengping

doi:10.1016/j.canlet.2014.08.030

Cited by 98 publications

(94 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, TGF-β1 expression was significantly correlated with lymph node metastasis, distant metastasis, and tumor recurrence in iCCA [73] and shorter OS both in iCCA and eCCA [69,73]. Upon TGF-β1 stimulation, the expression of epithelial markers decreased concomitantly with an increased expression of mesenchymal markers in CCA cells [18,41,48,69,[74][75][76]. Abrogation of TGF-β-dependent signaling pathway by a soluble TGF-β RII reduced CCA cell invasiveness in a murine CCA xenograft model [48].…”

Section: Transforming-growth Factor-β (Tgf-β)-dependent Signaling Is mentioning

confidence: 93%

“…In fact, Shuang et al have recently found, both in iCCA and eCCA, a significant correlation between TGF-β1 and ALDH1 (aldehyde dehydrogenase 1), a functional CSC marker. In addition, TGF-β1-induced EMT in CCA cells resulted in an acquisition of mesenchymal traits, as well as ALDH expression, which were accompanied by a decreased sensitivity to 5-fluorouracil [69].…”

Section: Emt and Therapeutic Considerations Chemoresistancementioning

confidence: 99%

“…TGF-β1-3 and their receptors TGF-β RI and RII were found expressed in both CCA tumor cells and surrounding stroma cells [65][66][67][68][69][70] while no data on TGF-β RIII expression is available. Regarding TGF-β1, it is expressed not only by invading malignant cholangiocytes, but also by stroma cells (e.g.…”

Section: Transforming-growth Factor-β (Tgf-β)-dependent Signaling Is mentioning

confidence: 99%

See 2 more Smart Citations

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

113

118

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

show abstract

Section: Transforming-growth Factor-β (Tgf-β)-dependent Signaling Is mentioning

confidence: 93%

Section: Emt and Therapeutic Considerations Chemoresistancementioning

confidence: 99%

Section: Transforming-growth Factor-β (Tgf-β)-dependent Signaling Is mentioning

confidence: 99%

See 1 more Smart Citation

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

113

118

View full text Add to dashboard Cite

show abstract

“…ALDH1 serves as a marker of cancer SCs (CSC) in several types of solid tumors, including those of the liver (14), head and neck (15), pancreas (16), lung (17,18), prostate (19), bladder (20), ovary (21), breast (22), and colon (23). On the other hand, the potential of using increased ALDH activities to identify SC subpopulations in cholangiocarcinoma remains to be verified (24). Furthermore, delineating the ALDH isoform(s) responsible for elevated enzyme activity in cholangiocarcinoma cells, as well as the correlations between ALDH upregulation and chemosensitivity of these cells to various agents, may be crucial for prognostic purposes.…”

Section: Introductionmentioning

confidence: 99%

ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients

Chen

Weng

Cheng

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Intrahepatic cholangiocarcinoma is a fatal primary liver cancer resulting from diagnosis at an advanced stage. Understanding the mechanisms of drug resistance and metastasis of cholangiocarcinoma may improve the disease prognosis. Enhanced aldehyde dehydrogenase (ALDH) activity is suggested to be associated with increased drug resistance and the metastasis. This study aims to investigate the roles of the ALDH isoforms in cholangiocarcinoma. Experimental Design: Aldefluor assays, RT-PCR, and Western blot analysis were used to identify the major ALDH isoforms contributing to Aldefluor activity in human cholangiocarcinoma cell lines. We manipulated isoform expression in HuCCT1 cells to elucidate the role of ALDH1A3 in the malignant progression of these cells. Finally, we used immunohistochemical staining to evaluate the clinical significance of ALDH1A3 in 77 hepatectomized cholangiocarcinoma patients and an additional 31 patients with advanced cholangiocarcinoma who received gemcitabine-based therapy. Results: ALDHhigh cholangiocarcinoma cells not only migrated faster but were more resistant to gemcitabine. Among the 19 ALDH isoforms studied, ALDH1A3 was found to be the main contributor to Aldefluor activity. In addition, we also found that knockdown of ALDH1A3 expression in HuCCT1 cells markedly reduced not only their sensitivity to gemcitabine, which might be attributed to a decreased expression of ribonucleotide reductase M1, but also their migration. Most importantly, this enzyme was also identified as an independent poor prognostic factor for patients with intrahepatic cholangiocarcinoma, as well as a prognostic biomarker of gemcitabine-treated patients. Conclusions: ALDH1A3 plays an important role in enhancing malignant behavior of cholangiocarcinoma and serves as a new therapeutic target. Clin Cancer Res; 22(16); 4225–35. ©2016 AACR.

show abstract

“…Shuang et al [104] demonstrated that ALDH1 is a valuable marker of CSCs in CCA. Further, patients with high ALDH1 expression had a poor prognosis in the cases of both intrahepatic and extrahepatic CCA.…”

Section: Aldh1 In Ccamentioning

confidence: 99%

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

Tomita¹,

Kanayama²,

Niwa³

et al. 2017

Updates in Liver Cancer

View full text Add to dashboard Cite

The cancer stem cell (CSC) theory posits that a small population of cells with stem celllike features is responsible for tumor growth, resistance, and recurrence in many malignancies. This theory could be a useful paradigm for designing innovative targeted drug therapies. Liver cancer is the ifth most common cancer worldwide, with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) as the predominant forms. Hepatic stem/progenitor cells are believed to be the origin of HCCs and CCAs; however, this remains a controversial topic. Aldehyde dehydrogenase (ALDH) is the main enzymatic system responsible for the clearance of acetaldehyde from the hepatocytes in the liver tissue. Therefore, ALDH1 has been suggested to be a potential, biological and CSC marker in liver cancers. We here provide an overview of the current state of knowledge of CSCs in liver and the role of ALDH1 in the development and progression of liver cancers and discuss its potential value as a prognostic and diagnostic biomarker.

show abstract

Transforming growth factor-β1-induced epithelial–mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma

Cited by 98 publications

References 43 publications

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

Contact Info

Product

Resources

About