Intrahepatic Cholangiocarcinoma Progression: Prognostic Factors and Basic Mechanisms

doi:10.1016/j.cgh.2009.08.023

Clinical Gastroenterology and Hepatology

Volume 7, Issue 11, Supplement, November 2009, Pages S68-S78

https://doi.org/10.1016/j.cgh.2009.08.023 Get rights and content

In this review, we will examine various molecular biomarkers for their potential to serve as independent prognostic factors for predicting survival outcome in postoperative patients with progressive intrahepatic cholangiocarcinoma. Specific rodent models of intrahepatic cholangiocarcinoma that mimic relevant cellular, molecular, and clinical features of the human disease are also described, not only in terms of their usefulness in identifying molecular pathways and mechanisms linked to cholangiocarcinoma development and progression, but also for their potential value as preclinical platforms for suggesting and testing novel molecular strategies for cholangiocarcinoma therapy. Last, recent studies aimed at addressing the role of desmoplastic stroma in promoting intrahepatic cholangiocarcinoma progression are highlighted in an effort to underline the potential value of targeting tumor stromal components together with that of cholangiocarcinoma cells as a novel therapeutic option for this devastating cancer.

Section snippets

Biomarkers Correlated With Poor Outcome and Progression in Human Intrahepatic Cholangiocarcinoma

Macroscopically, intrahepatic cholangiocarcinoma, also known as peripheral cholangiocarcinoma, has been subclassified into mass-forming, periductular-infiltrating, mass-forming plus periductular-infiltrating, and intraductal papillary types.5, 6, 7 Of these, mass-forming and mass-forming plus periductular infiltrating intrahepatic cholangiocarcinomas are the most common types, with the mass-forming plus periductular infiltrating type showing the poorest survival outcome.5, 7 In comparison,

Preclinical Animal Models of Intrahepatic Cholangiocarcinogenesis and Tumor Progression Recapitulating Key Features of the Human Disease

Animal models that recapitulate key cellular, molecular, and clinical features of human intrahepatic cholangiocarcinoma progression are highly desirable, because such models would not only facilitate studies aimed at elucidating mechanisms of cholangiocarcinoma cell growth, invasion, and metastasis, but also because they could serve as valuable preclinical platforms for testing new molecular strategies for cholangiocarcinoma therapy. Table 2 lists established rodent models of intrahepatic

Role of Tumor Stroma in Intrahepatic Cholangiocarcinoma Progression

It is well-recognized that unlike hepatocellular carcinoma, intrahepatic cholangiocarcinoma typically exhibits an excessive desmoplastic reaction characterized by abundant extracellular matrix (ECM) proteins and cancer- associated fibroblasts (CAFs) predominately expressing a myofibroblast-like phenotype.58, 59 As exemplified in Figure 3A and B, intrahepatic cholangiocarcinoma is most often characterized by nests of cytokeratin 19–positive malignant ductal carcinoma cells typically surrounded

Concluding Remarks

Significant progress has been made during the past several years in defining cellular interactions and molecular pathways associated with the pathogenesis of intrahepatic cholangiocarcinoma and, as highlighted in this review, leading to the identification of various select molecular markers having potential as either prognostic indicators and/or therapeutic targets for this lethal cancer. However, translation of these findings into effective clinical strategies for the treatment of advanced

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Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance
2022, Advances in Cancer Research
Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell type in the tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA), where they are actively involved in cancer progression through a complex network of interactions with other stromal cells. The majority of the studies investigating CAFs in iCCA have focused their attention on CAF tumor-promoting roles, remarking their potential as therapeutic targets. However, indiscriminate targeting of CAFs in other desmoplastic tumors has ended in failure with no effects or even accelerated cancer progression and reduced survival, indicating the urgent need to better understand the nuances and functions of CAFs to avoid deleterious effects. Indeed, recent single cell RNA sequencing studies have shown that heterogeneous CAF subpopulations coexist in the same tumor, some promoting- and other restricting- tumor growth. Moreover, recent studies have shown that in iCCA, diverse CAF subtypes interact differently with the cells of the TME, suggesting that CAFs may dynamically change their phenotypes during tumor progression, a field that remains uninvestigated. The characterization of heterogenous CAF subpopulations and their functionality, will provide a feasible and safer approach to facilitate the development of new therapeutic approaches aimed at targeting CAFs and their interactions with other stromal cells in the TME rather than solely tumor cells in iCCA. Here, we discuss the origin of CAFs, as well as their heterogeneity, plasticity, mechanisms and targeting strategies to provide a brief snapshot of the current knowledge in iCCA.
Matricellular proteins in intrahepatic cholangiocarcinoma
2022, Advances in Cancer Research
Citation Excerpt :
Low to no Postn expression had also been reported for select benign liver diseases and hepatocellular carcinoma (Utispan et al., 2010). Furthermore, Postn was not detected by Western blotting at 21 days after bile duct ligation in cholestatic rat liver with a periportal bile ductular reaction (Sirica et al., 2009). Sugiyama et al. (2016), however, demonstrated positive α-SMA expression together with Postn enhancement in the fine fibrotic septa around proliferating bile ducts/ductules emanating from the hepatic portal areas of wild-type mice induced by cholestatic injury produced by dietary administered 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).
Intrahepatic cholangiocarcinoma (iCCA) is typically characterized by a prominent desmoplastic stroma that is often the most dominant feature of the tumor. This tumor reactive stroma is comprised of a dense fibro-collagenous-enriched extracellular matrix (ECM) surrounding the cancer cells, together with other ECM proteins/peptides, specifically secreted matricellular glycoproteins and proteolytic enzymes, growth factors, and cytokines. Moreover, as enjoined by cholangiocarcinoma cells, this enriched tumor microenvironment is populated by various stromal cell types, most prominently, cancer-associated myofibroblasts (CAFs), along with variable numbers of tumor-associated macrophages (TAMs), inflammatory and vascular cell types. While it is now well appreciated that the interplay between cholangiocarcinoma cells, CAFs, and TAMs in particular play a critical role in promoting cholangiocarcinoma progression, therapeutic resistance, and immune evasion, it is also becoming increasingly evident that over-expression and secretion into the tumor microenvironment of functionally overlapping matricellular glycoproteins, including periostin, osteopontin, tenascin-C, thrombospondin-1, mesothelin and others have an important role to play in regulating or modulating a variety of pro-oncogenic cellular functions, including cholangiocarcinoma cell proliferation, invasion, and metastasis, epithelial-mesenchymal transition, ECM remodeling, and immune evasion. Matricellular proteins have also shown promise as potential prognostic factors for iCCA and may provide unique therapeutic opportunities particularly in relation to targeting iCCA pre-metastatic and metastatic niches, tumor cell dormancy, and immune evasion. This review will highlight timely research and its translational implications for salient matricellular proteins in terms of their structure-function relationships, as modulators of intrahepatic cholangiocarcinoma microenvironment and progression, and potential clinical value for iCCA prognosis and therapy.
Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center
2021, Revista de Gastroenterologia de Mexico
El cáncer primario de hígado es un problema de salud pública en México y en el mundo. El trasplante hepático (TH) es el tratamiento ideal para el carcinoma hepatocelular (CHC) temprano. El objetivo fue evaluar las características de los pacientes con CHC y colangiocarcinoma (CC) en dos centros e identificar a los candidatos a trasplante.
Estudio retrospectivo, observacional del 2012 al 2018 en el Centro de Hepatología (CH) y el Centro Universitario contra el Cáncer (CUCC). Se confirmó CHC o colangiocarcinoma intrahepático (CCi) en 109 pacientes, a los CHC se les aplicaron clasificaciones de estadiaje, modelos de selección para trasplante y modelo pronóstico de recidiva post-TH.
De la población total, 93% (n = 102) eran cirróticos. El 86% (n = 94) tuvo CHC (58% CH y 42% CUCC) y 14% (n = 15) CCi (40% CH y 60% CUCC). En los pacientes con CHC del CH predominó Okuda I-II, clasificación de Barcelona Clinic Liver Cancer (BCLC) A-B y niveles < 100 ng/mL de alfafetoproteína (AFP), mientras que en el CUCC predominó Okuda II-III, BCLC C-D y niveles > 1,000 ng/mL de AFP. La mitad de la población del CH con CHC cumplía con los criterios para TH, en cambio, en el CUCC solo lo hizo el 23%. Se valoraron 15 pacientes para TH y, a la fecha, se trasplantaron seis.
La neoplasia primaria de hígado más frecuente fue CHC. Los pacientes del CH presentaron la enfermedad más temprana y una proporción más alta cumplía con los criterios para TH. Solo quienes pertenecían a este centro recibieron un trasplante.
Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates.
A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients.
Of the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation.
The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.
Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression
2021, Advances in Cancer Research
Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare, but highly lethal and biologically complex primary biliary epithelial cancer arising within liver. After hepatocellular carcinoma, iCCA is the second most common primary liver cancer, accounting for approximately 10–20% of all primary hepatic malignancies. Over the last 10–20 years, iCCA has become the focus of increasing concern largely due to its rising incidence and high mortality rates in various parts of the world, including the United States. The challenges posed by iCCA are daunting and despite recent progress in the standard of care and management options for iCCA, the prognosis for this cancer continues to be dismal. In an effort to provide a framework for advancing our understanding of iCCA malignant aggressiveness and therapy resistance, this review will highlight key etiological, biological, molecular, and microenvironmental factors hindering more effective management of this hepatobiliary cancer. Particular focus will be on critically reviewing the cell origins and morpho-molecular heterogeneity of iCCAs, providing mechanistic insights into high risk fibroinflammatory cholangiopathies associated with iCCA development, and notably discussing the deleterious role played by the tumor reactive desmoplastic stroma in regulating iCCA malignant progression, lymphangiogenesis, and tumor immunobiology.
Glutamine deprivation counteracts hypoxia-induced chemoresistance
2020, Neoplasia (United States)
The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for CCA. Glutamine levels were strongly decreased in CCA samples and the growth of established human CCA cell lines was highly dependent on glutamine. Using gradual reduction of external glutamine, we generated derivatives of CCA cell lines which were able to grow without external glutamine (termed glutamine-depleted (GD)). To analyze the effects of coincident oxygen and glutamine deprivation, GD cells were treated with cisplatin or gemcitabine under normoxia and hypoxia. Strikingly, the well-established phenomenon of hypoxia-induced chemoresistance was completely reversed in GD cells. In order to better understand the underlying mechanisms, we focused on the oncogene c-Myc. The combination of cisplatin and hypoxia led to sustained c-Myc protein expression in wildtype cells. In contrast, c-Myc expression was reduced in response to the combinatorial treatment in GD cells, suggesting a functional importance of c-Myc in the process of hypoxia-induced chemoresistance. In summary, these findings indicate that the mechanisms driving adaption to tumor microenvironmental changes and their relevance for the response to therapy are more complex than expected.
Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway
2017, American Journal of Pathology
Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice. We identified three key components of the Notch pathway, Notch1, Notch2, and Jagged 1, as direct targets of miR-34a. Our further studies show that down-regulation of miR-34a is caused by Enhancer of zeste homolog 2 (EZH2)-mediated H3 lysine 27 trimethylation as well as DNA methylation. Accordingly, treatment with the EZH2 inhibitor, selective S-adenosyl-methionine-competitive small-molecule (GSK126), or the DNA methylation inhibitor, 5-Aza-2′-deoxycytidine, partially restored miR-34a levels in human CCA cells. Immunohistochemical staining and Western blot analyses showed increased EZH2 expression in human CCA tissues and cell lines. We observed that GSK126 significantly reduced CCA cell growth in vitro and intrahepatic metastasis in vivo. Our findings provide novel evidence that miR-34a expression is silenced epigenetically by EZH2 and DNA methylation, which promotes CCA cell growth through activation of the Notch pathway. Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by National Institutes of Health Grants R01 CA 83650 and R01 CA 39225 (A.E.S).

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Intrahepatic Cholangiocarcinoma Progression: Prognostic Factors and Basic Mechanisms

Section snippets

Biomarkers Correlated With Poor Outcome and Progression in Human Intrahepatic Cholangiocarcinoma

Preclinical Animal Models of Intrahepatic Cholangiocarcinogenesis and Tumor Progression Recapitulating Key Features of the Human Disease

Role of Tumor Stroma in Intrahepatic Cholangiocarcinoma Progression

Concluding Remarks

J Am Coll Surg

HPB

Clin Liver Dis

Eur J Cancer

Hum Pathol

J Hepatol

Mod Pathol

Mod Pathol

Mod Pathol

Hum Pathol

Dig Liver Dis

Hum Pathol

Lab Invest

Surgery

Hum Pathol

Am J Pathol

Hepatology

Gastroenterology

Lab Invest

Am J Pathol

Biochem Biophys Res Commun

Lab Invest

Am J Pathol

Gastroenterology

Cancer Cell

Hum Pathol

Hepatol Res

Neoplasia

Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes

Hepatogastroenterology

Hepatic resection of the intraductal papillary type of peripheral cholangiocarcinoma

Ann Surg Oncol

Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection

World J Surg

Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma

Cancer

MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma

World J Gastroenterol

MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type

Hepatology

Prognostic value of MUC4 for mass-forming intrahepatic cholangiocarcinoma after hepatectomy

Oncology Reports

Matrix metalloproteinase-7 expression and biologic aggressiveness of cholangiocellular carcinoma

Cancer

Nuclear survivin expression predicts poor outcome in cholangiocarcinoma

Hepatogastroenterology

Correlation of aPKC-ι and E-cadherin expression with invasion and prognosis of cholangiocarcinoma

Hepatobiliary Pancreat Dis Int