Neuroendocrine Changes in Cholangiocarcinoma Growth

Sato, Keisaku; Francis, Heather; Zhou, Tianhao; Meng, Fanyin; Kennedy, Lindsey; Ekser, Burçin; Baiocchi, Leonardo; Onori, Paolo; Mancinelli, Romina; Gaudio, Eugenio; Franchitto, Antonio; Glaser, Shannon; Alpini, Gianfranco

doi:10.3390/cells9020436

Cited by 7 publications

(7 citation statements)

References 108 publications

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“…In cholangiocarcinoma (CCA), cellular growth and expansion also deserve interest as possible targets for therapy. Several molecular cascades such as the Janus kinase/signal transducer and activator of transcription, p38 MAP kinase (MAPK), Akt (AKA, protein kinase B, PKB) or fibroblast growth factor/fibroblast growth factor receptor may stimulate cell growth and impact biliary proliferation [ 16 , 17 ]. Both hyperplastic and neoplastic cholangiocyte growth are frequently associated with changes in intracellular cAMP levels [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Baiocchi

Lenci

Mihalj

et al. 2021

Cells

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Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.

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Section: Introductionmentioning

confidence: 99%

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Baiocchi

Lenci

Mihalj

et al. 2021

Cells

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“…Several cholangiocyte receptors have been reported to control cholangiocyte proliferation under different physiological and pathological conditions 8 , 9 , 11 , 40 . These receptors include secretin receptor (Sctr) 41 , estrogen receptor (Esr), insulin receptor (Insra and Insrb), glucagon-like-peptide receptor 2 (Glpr2), nerve growth factor receptor (Ngfr) and sphingosine 1 phosphate receptor 2 (S1pr2) 40 , 42 – 45 , etc. Expression of these cholangiocyte receptor genes in cholangiocytes and hepatocytes of WT and kras + adult zebrafish after Dox induction were analyzed by RT-qPCR.…”

Section: Resultsmentioning

confidence: 99%

Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model

Helal

Yan

Gong

2021

Sci Rep

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It has been well known that tumor progression is dependent on secreted factors not only from tumor cells but also from other surrounding non-tumor cells. In the current study, we investigated the role of cholangiocytes during hepatocarcinogenesis following induction of oncogenic krasV12 expression in hepatocytes using an inducible transgenic zebrafish model. Upon induction of carcinogenesis in hepatocytes, a progressive cell proliferation in cholangiocytes was observed. The proliferative response in cholangiocytes was induced by enhanced lipogenesis and bile acids secretion from hepatocytes through activation of Sphingosine 1 phosphate receptor 2 (S1pr2), a known cholangiocyte receptor involving in cholangiocyte proliferation. Enhancement and inhibition of S1pr2 could accelerate or inhibit cholangiocyte proliferation and hepatocarcinogenesis respectively. Gene expression analysis of hepatocytes and cholangiocytes showed that cholangiocytes stimulated carcinogenesis in hepatocytes via an inflammatory cytokine, Il17a/f1, which activated its receptor (Il17ra1a) on hepatocytes and enhanced hepatocarcinogenesis via an ERK dependent pathway. Thus, the enhancing effect of cholangiocytes on hepatocarcinogenesis is likely via an inflammatory loop.

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“…( 7 ) Because early diagnosis of CCA is challenging and treatment options are limited, therapeutic approaches are necessary. ( 42 ) However, there are no gold‐standard experimental models of CCA, and the most common animal models are xenograft models, which do not mimic CCA development and the tumor microenvironment. ( 43 ) Organoids generated from primary cells of tumor biopsies are also referred to as “tumoroids,” which means tumor‐like organoids resembling 3D tumor complexity and the tumor microenvironment.…”

Section: Organoids As Experimental Models Of Cholangiopathiesmentioning

confidence: 99%

Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma

et al. 2021

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Cholangiopathies, such as primary sclerosing cholangitis, biliary atresia, and cholangiocarcinoma, have limited experimental models. Not only cholangiocytes but also other hepatic cells including hepatic stellate cells and macrophages are involved in the pathophysiology of cholangiopathies, and these hepatic cells orchestrate the coordinated response against diseased conditions. Classic two-dimensional monolayer cell cultures do not resemble intercellular cell-to-cell interaction and communication; however, three-dimensional cell culture systems, such as organoids and spheroids, can mimic cellular interaction and architecture between hepatic cells. Previous studies have demonstrated the generation of hepatic or biliary organoids/spheroids using various cell sources including pluripotent stem cells, hepatic progenitor cells, primary cells from liver biopsies, and immortalized cell lines. Gene manipulation, such as transfection and transduction can be performed in organoids, and established organoids have functional characteristics which can be suitable for drug screening. This review summarizes current methodologies for organoid/spheroid formation and a potential for three-dimensional hepatic cell cultures as in vitro models of cholangiopathies. (Hepatology 2021;74:491-502).I n vitro cell culture models are key in liver research to supplement the lack of human samples or in vivo animal models. (1) Importantly, the human body consists of three-dimensional (3D) cellular interactions and structures with noncellular components, and classic two-dimensional (2D) monolayer culture models do not mimic this interaction between cells and components or matrices. In the past decade, techniques of 3D cell culture systems, such as organoids and spheroids, have been developed to mimic hepatic structure and cellular interaction in vitro. (2) These 3D cell culture models have more accurate physiological environmental conditions resembling in vivo complex architecture, microenvironment, and cellular functions and may be more appropriate for biomedical studies than monolayer models. (2,3) The definitions of the terms "organoid" and "spheroid" can vary or overlap depending on previous studies. Organoids are generally recognized as an in vitro "miniorgan" or complex tissue-like structure with multiple cell types. (3) Spheroids are often referred to as "simple cell aggregates" with a single cell type. Organoids are generated from (1) tissue-derived primary cells, (2) progenitors, (3) embryonic stem cells (ESCs), or (4) induced pluripotent stem cells (iPSCs), which can selfassemble and differentiate into organ-like cell clusters

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Neuroendocrine Changes in Cholangiocarcinoma Growth

Cited by 7 publications

References 108 publications

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model

Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma

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