Molecular Pathogenesis: From Inflammation and Cholestasis to a Microenvironment-Driven Tumor

Abstract

Intrahepatic cholangiocarcinoma is a primary liver cancer originating from the malignant transformation of different epithelial cell sources, not only the cholangiocyte but also the progenitor stem cell or the hepatocyte. Chronic inflammation, also extending outside the portal tract, and cholestasis are the main mechanisms promoting the pathogenetic sequence ultimately leading to the appearance of the neoplastic biliary lesion. Following tumor formation, a dense fibro-inflammatory stroma, termed “tumor reactive stroma,” progressively accumulate nearby the malignant bile ducts, further boosting tumor overgrowth and invasion. A crowd of cells composes the tumor reactive stroma among cancer-associated fibroblasts, tumor-associated macrophages, tumor-infiltrating lymphocytes, and lymphatic vessels, which lay embedded in an abnormally remodeled and stiff extracellular matrix. Herein, we will outline the molecular underpinnings responsible for the oncogenic effects of inflammation and cholestasis, underlining the different pathways and genetic perturbations. The multifaceted role played by the tumor microenvironment in driving invasiveness of intrahepatic cholangiocarcinoma is discussed, focusing on the main stromal cell types and the paracrine factors molding the pro-invasive functions of the tumoral cholangiocyte.