WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Boulter, Luke; Guest, Rachel V.; Kendall, Timothy J.; Wilson, David H.; Wojtacha, Davina; Robson, Andrew; Ridgway, Rachel A.; Samuel, Kay; Rooijen, Nico van; Barry, Simon T.; Wigmore, Stephen J.; Sansom, Owen J.; Forbes, Stuart J.

doi:10.1172/jci76452

Cited by 233 publications

(259 citation statements)

References 70 publications

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“…The paracrine stimulation of EMT in CCA tumor cells by TAMs may be related to the production and secretion of interleukins, TNF-α and TGF-β1 by activated macrophages [72]. More recently, TAMs have been described as potent providers of Wnt ligands [137], which are known to induce EMT in other cancers [138,139].…”

Section: Tumor-associated Macrophages (Tams) and Mast Cells (Figure 3b)mentioning

confidence: 99%

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

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

125

122

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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.

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Section: Tumor-associated Macrophages (Tams) and Mast Cells (Figure 3b)mentioning

confidence: 99%

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

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

125

122

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“…Canonical Wnt signaling results in a transcriptional response in which the transcription factor β-catenin plays a central role, whereas non-canonical Wnt signaling cascades control the cytoskeletal structure or intracellular Ca 2+ content through β-catenin-independent non-genomic actions. The canonical Wnt signaling pathway is the focus of the studies of Boulter et al [8] .…”

Section: The Wnt Signaling Cascadementioning

confidence: 99%

“…By analyzing tumoral and matched unaffected liver tissue of patients with intrahepatic or perihilar CCA, Boulter et al [8] demonstrate that Wnt ligands Wnt7B and Wnt10A are highly overexpressed in tumor tissue. Wnt7B protein was present throughout the tumor stroma, often co-localizing with a subset of CD68 + macrophages.…”

Section: Wnt Signaling In Ccamentioning

confidence: 99%

“…Through an elegant set of experiments Boulter et al [8] demonstrate that Wnt7B in tumor stroma is largely derived from recruited bone marrow-derived macrophages rather than from resident Kupffer cells, and that these cells play a key role in CCA progression. The role of macrophages in CCA growth was initially assessed in mice xenografted with three different human CCA cell lines.…”

Section: Wnt Signaling In Ccamentioning

confidence: 99%

“…Molecular-targeted therapies hold potential for personalized treatment of malignancies including CCA [7] . A recent study by Boulter et al [8] implicates the Wnt signaling cascade in cholangiocarcinogenesis. Importantly, specific inhibitors of this pathway prevented tumor development in animal models of CCA.…”

Section: Introductionmentioning

confidence: 99%

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Cholangiocarcinoma, gone without the Wnt?

Noll

Cramer

Damink

et al. 2016

WJH

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Cholangiocarcinoma (CCA) is a relatively rare malignancy of the intra-or extra-hepatic bile ducts that is classified according to its anatomical localization as intrahepatic, perihilar or distal. Overall, CCA has a dismal prognosis due to typical presentation at an advanced irresectable stage, lack of effective non-surgical treatments, and a high rate of disease recurrence. CCA frequently arises on a background of chronic liver inflammation and cholestasis. Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells. A recent study by Boulter et al implicates the Wnt signaling cascade in cholangiocarcinogenesis. Wnt ligands Wnt7B and Wnt10A were found to be highly overexpressed in human CCA tissue. Wnt7B protein was present throughout the tumor stroma, and often co-localized with a subset of CD68 + macrophages. To address in a direct manner whether Wnt signaling is engaged in development of CCA, Boulter et al explored the Wnt signaling pathway in an experimental model that recapitulates the multi-stage progression of human CCA. Wnt ligands found to be elevated in human CCA were also upregulated during the course of CCA development following thioacetamide treatment. Wnt10a increased during the (pre-cancerous) regenerative phase, while Wnt7b induction paralleled tumor growth. Along with upregulation of target genes, the findings demonstrate that the canonical Wnt pathway is progressively activated during cholangio-carcinogenesis. Macrophage depletion, eliminating a major source of Wnt7b, prevented activation of the canonical Wnt cascade, and resulted in reduced number and volume of tumors in this model. Moreover, specific inhibitors of the canonical Wnt pathway (ICG-001 and C-59) caused reduction of tumor area and number, in xenograft and thioacetamide models of CCA. The aggregated findings show that experimental, and presumably human CCA, is a Wnt-driven tumor. Modulation of Wnt signaling, alone or in combination with surgical

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Aging and biliary tract cancers: Epidemiology, molecular biology, and clinical practice

et al. 2022

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Biliary tract cancer (BTC) that contains cholangiocarcinoma, gallbladder cancer, and ampullary cancer is highly malignant and mostly diagnosed in elderly patients. Over the past decades, human life has globally risen; thus, aging emerges as the primary risk factor for BTC. However, an effective treatment for this vulnerable population remains a large clinical challenge. As a result, the incidence and mortality of TBC remains high. Here, we discuss the potential link between aging and BTC from the aspects of molecular and cellular mechanisms, surgical resection, and chemotherapy. In addition, we update a number of clinical trials that are currently ongoing in elderly patients. The overview of BTC in elderly patients is expected to help develop a new therapeutic strategy tailored to this elderly population, ultimately improving their life quality.

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WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Cited by 233 publications

References 70 publications

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

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

Cholangiocarcinoma, gone without the Wnt?

Aging and biliary tract cancers: Epidemiology, molecular biology, and clinical practice

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