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

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Cyclic AMP Signaling in Biliary Proliferation: a Possible Target for Cholangiocarcinoma Treatment? cells Review Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment? Leonardo Baiocchi 1, Ilaria Lenci 1, Martina Milana 1, Lindsey Kennedy 2,3, Keisaku Sato 2 , Wenjun Zhang 4, Burcin Ekser 4 , Ludovica Ceci 2, Vik Meadows 2, Shannon Glaser 5, Gianfranco Alpini 2,3,*,† and Heather Francis 2,3,*,† 1 Hepatology Unit, University of Tor Vergata, 00133 Rome, Italy; [email protected] (L.B.); [email protected] (I.L.); [email protected] (M.M.) 2 Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN 46202, USA; [email protected] (L.K.); [email protected] (K.S.); [email protected] (L.C.); [email protected] (V.M.) 3 Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA 4 Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA; [email protected] (W.Z.); [email protected] (B.E.) 5 Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA; [email protected] * Correspondence: [email protected] (G.A.); [email protected] (H.F.) † These authors contributed equally to this work. Abstract: 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 Citation: Baiocchi, L.; Lenci, I.; cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli Milana, M.; Kennedy, L.; Sato, K.; employing the cAMP/PKA system for the translation of messages in the intracellular space. For Zhang, W.; Ekser, B.; Ceci, L.; Meadows, V.; Glaser, S.; et al. Cyclic instance, in physiological conditions, stimulation of the secretin receptor determines an increase AMP Signaling in Biliary of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in Proliferation: A Possible Target for bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ Cholangiocarcinoma Treatment? Cells injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific 2021, 10, 1692. https://doi.org/ pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes 10.3390/cells10071692 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. Academic Editor: Isabel Fabregat Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed. Received: 25 May 2021 Keywords: cholangiocarcinoma; cAMP; cholangiocytes; proliferation; PKA; secretin Accepted: 30 June 2021 Published: 4 July 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- The biliary tree is lined by epithelial cells (i.e., cholangiocytes), which appear to iations. originate from a common stem cell compartment, the hepatic progenitor cells, similar to hepatocytes [1]. These pluripotent cells are located at the interface between the hepatocyte canaliculi and bile ductules in the canals of Hering (Figure1), the latter being the smaller branches of the biliary tree [2]. The canals of Hering extend to the interlobular ducts (i.e., bile ductules, 15–100 µm Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. in diameter), then continue in the septal area, segmental and finally, in the right and left This article is an open access article hepatic ducts, joining together at the hepatic hilum. This portion of the biliary epithe- distributed under the terms and lium is regarded as the intrahepatic one, whereas the part extending outside the liver and conditions of the Creative Commons comprising the common bile duct, the gallbladder (with cystic duct) and choledochus is Attribution (CC BY) license (https:// defined as extrahepatic [1]. Via electron microscopy, two different cholangiocyte subpopu- creativecommons.org/licenses/by/ lations in rodent livers are well recognized (small and large), lining small ducts (≤15 µm in 4.0/). diameter) or large ducts (≥15 µm in diameter) according to their size [1,3]. Large cyclic Cells 2021, 10, 1692. https://doi.org/10.3390/cells10071692 https://www.mdpi.com/journal/cells Cells 2021, 10, 1692 2 of 14 adenosine monophosphate (cAMP)-dependent cholangiocytes are considered the func- tional part of the biliary tree since they respond to gastrointestinal hormones (e.g., secretin), neuro-peptides and other modulators [4–6]. On the other hand, small Ca2+-dependent cholangiocytes [7] do not respond to secretin and proliferate to replenish the biliary epithe- lium (during damage to the large, cAMP-dependent cholangiocytes) by amplification of Ca2+-dependent signaling and de novo acquisition of large cholangiocyte phenotypes [6,8,9]. While, at the beginning, just bile duct secretory activities were studied with regard to biliary tract diseases, lately also, biliary proliferative phenotypes have gained interest [10–12]. Cells 2021, 10, x For instance, atypical cholangiocyte proliferation, characterized by truncated tortuous2 of bile 15 ducts, has been observed in adult cholestatic liver diseases such as primary biliary cholan- gitis (PBC) and primary sclerosing cholangitis (PSC) [13,14]. Both diseases are defined as ductopenia, since changes and evolution of proliferation determine a reduction of total bile ducts in the end [15]. BILE Bile canaliculi Canals of Hering Bile ductules Bile duct Hepatocytes Stem cells Cholangiocytes Cholangiocytes Figure 1. The main cells and ultrastructural districts encountered by the bile (black arrow) while moving from the hepatocytes to the bile ducts. FigureIn 1. cholangiocarcinoma The main cells and ultrastructu (CCA), cellularral districts growth encountered and expansion by the bile also (black deserve arrow) interest while as possiblemoving from targets the hepatocy for therapy.tes to Several the bile ducts. molecular cascades such as the Janus kinase/signal transducer and activator of transcription, p38 MAP kinase (MAPK), Akt (AKA, protein kinaseThe B, canals PKB) orof fibroblastHering extend growth to factor/fibroblastthe interlobular ducts growth (i.e., factor bile receptorductules, may15–100 stimu- μm latein diameter), cell growth then and continue impact biliaryin the septal proliferation area, segmental [16,17]. Both and hyperplastic finally, in the and right neoplastic and left cholangiocytehepatic ducts, joining growth together are frequently at the hepatic associated hilum. with This changes portion in of intracellular the biliary epithelium cAMP lev- elsis regarded [18]. In as this the review, intrahepatic after one, a general wherea descriptions the part extending of cAMP outside signaling the and liver its and role com- in parenchymalprising the common and biliary bile cell duct, functions, the gallbladder we will discuss(with cystic the most duct) recent and findingscholedochus regarding is de- thefined relationship as extrahepatic between [1]. the Via cAMP-dependent electron microscopy, pathway two anddifferent cancer cholangiocyte of the biliary tractsubpopu- (e.g., cholangiocarcinoma).lations in rodent livers are well recognized (small and large), lining small ducts (≤15 μm in diameter) or large ducts (≥15 μm in diameter) according to their size [1,3]. Large cyclic 2.adenosine cAMP Signaling monophosphate (cAMP)-dependent cholangiocytes are considered the func- tionalcAMP part of was the first biliary discovered tree since in 1958they re andspond introduced to gastrointestinal the concept hormones of a “second (e.g., messen- secre- ger”tin), neuro-peptides system [19]. In and fact, other this molecule, modulators together [4–6]. On with the cyclic other guanosinehand, small monophosphate Ca2+-dependent (cGMP),cholangiocytes has been [7] identifieddo not respond as an important to secretin intracellular and proliferate translator to replenish of membrane the biliary signal- epi- ingthelium originating (during from damage hormones, to the large, growth cAMP-d factors,ependent cytokines cholangiocytes) and other molecules by amplification [20]. In theof Ca general2+-dependent transduction signaling mechanism, and de novo the stimulated acquisition receptor of large activates cholangiocyte the corresponding phenotypes G-coupled[6,8,9]. While, protein, at the leading beginning, to increased just bile duct adenylyl secretory cyclase-mediated activities were cAMP studied synthesis. with regard The followingto biliary tract steps diseases, include cAMPlately bindingalso, biliary to protein proliferative kinase phenotypes A (PKA) or anhave exchange gained proteininterest activated[10–12]. For by instance, cAMP (EPAC) atypical and cholangiocyte also cyclic nucleotide-gated proliferation, characterized ion channels by [21 truncated]. Canonical tor- G-protein-coupledtuous bile ducts, has receptor/cAMP/PKA been observed in adul signalingt cholestatic is depicted liver indiseases Figure2 such. as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) [13,14]. Both diseases are defined as ductopenia, since changes and evolution of proliferation determine a re- duction of total bile ducts in the end [15]. In cholangiocarcinoma (CCA), cellular growth
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