Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma: Insights into Origins, Heterogeneity, Lymphangiogenesis, and Peritoneal Metastasis

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA that differentiates the most common macroscopic subtypes (e.g., mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma, is a prominent desmoplastic reaction manifested as a dense fibro-collagenous enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. While the pro-tumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence has been described to support CAFs potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, we provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.