Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

Abstract

Intrahepatic cholangiocarcinoma (iCCA) has over the last 10‐20 years become the focus of increasing concern, largely due to its rising incidence and high mortality rates worldwide. The significant increase in mortality rates from this primary hepatobiliary cancer, particularly over the past decade, has coincided with a rapidly growing interest among clinicians, investigators, and patient advocates to seek greater mechanistic insights and more effective biomarker‐driven targeted approaches for managing and/or preventing this challenging liver cancer. In addition to discussing challenges posed by this aggressive cancer, this review will emphasize recent epidemiological, basic, and translational research findings for iCCA. In particular, we will highlight emerging demographic changes and evolving risk factors, the critical role of the tumor microenvironment, extracellular vesicle biomarkers and therapeutics, intertumoral and intratumoral heterogeneity, and current and emerging targeted therapies regarding iCCA. Specifically, recent evidence linking non–bile duct medical conditions, such as nonalcoholic fatty liver disease and nonspecific cirrhosis, to intrahepatic cholangiocarcinogenesis together with geographic and ethnic variation will be assessed. Recent developments concerning the roles played by transforming growth factor‐β and platelet‐derived growth factor D in driving the recruitment and expansion of cancer‐associated myofibroblasts within cholangiocarcinoma (CCA) stroma as well as their therapeutic implications will also be discussed. In addition, the potential significance of extracellular vesicles as bile and serum biomarkers and therapeutic delivery systems for iCCA will be described. An integrated systems approach to classifying heterogeneous iCCA subtypes will be further highlighted, and recent clinical trials and emerging targeted therapies will be reviewed, along with recommendations for future translational research opportunities. Established international CCA networks are now facilitating collaborations aimed at advancing iCCA translational and clinical research.

Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis

“…A tight interaction exists between iCCA and tumor microenvironment cells, including myofibroblasts, immune, and endothelial cells, soluble factors such as cytokines, and components of the extracellular matrix (ECM). This functional interplay among the various cell types results in the modulation of cellular communication, differentiation, invasiveness, chemoresistance, and epithelial-to-mesenchymal transition [10,11].…”

Latent Risk Intrahepatic Cholangiocarcinoma Susceptible to Adjuvant Treatment After Resection: A Clinical Deep Learning Approach

“…Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive primary epithelial malignancy arising from the liver, and it has witnessed rising interests over the years due to rapid increase in its incidence and the resulting mortality rate (5,6). Usually, ICC is diagnosed at an advanced stage, sporadically and without an explicit etiologic factor, thereby limiting curative approaches (7). Surgery with curative intent is the current standard of care, providing the opportunity for long-term survival (8).…”

Long non‑coding RNA ZEB1‑AS1 predicts a poor prognosis and promotes cancer progression through the miR‑200a/ZEB1 signaling pathway in intrahepatic cholangiocarcinoma

“…Intrahepatic cholangiocarcinoma (IHCC) is a rare and highly aggressive primary epithelial cancer arising from the bile duct within the liver (1). The incidence and mortality rates associated with IHCC have been continuously rising over the past decade (2).…”

“…Patients are often diagnosed at an advanced incurable stage with lymph node metastasis and multicentric disease already present within the liver. Curative intent surgery is available for only 30-40% of patients with IHCC (1). Moreover, the 5-year survival rate is 30% even for patients who have undergone surgical resection (3) and is <5-10% for patients with unresectable IHCC (4).…”