The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma

Abstract

Prognosis of cholangiocarcinoma, a devastating liver epithelial malignancy characterized by early invasiveness, remains very dismal, though its incidence has been steadily increasing. Evidence is mounting that in cholangiocarcinoma, tumor epithelial cells establish an intricate web of mutual interactions with multiple stromal components, largely determining the pervasive behavior of the tumor. The main cellular components of the tumor microenvironment (i.e. myofibroblasts, macrophages, lymphatic endothelial cells), which has been recently termed as 'tumor reactive stroma', are recruited and activated by neoplastic cells, and in turn, deleteriously mold tumor behavior by releasing a huge variety of paracrine signals, including cyto/chemokines, growth factors, morphogens and proteinases. An abnormally remodeled and stiff extracellular matrix favors and supports these cell interactions. Although the mechanisms responsible for the generation of tumor reactive stroma are largely uncertain, hypoxia presumably plays a central role. In this review, we will dissect the intimate relationship among the different cell elements cooperating within this complex 'ecosystem', with the ultimate goal to pave the way for a deeper understanding of the mechanisms underlying cholangiocarcinoma aggressiveness, and possibly, to foster the development of innovative, combinatorial therapies aimed at halting tumor progression. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Keywords: Cancer-associated fibroblasts; Extracellular matrix; Lymphatic endothelial cells; Tumor desmoplasia; Tumor-associated macrophages.

Fig. 1.

Pathological changes of the stromal compartment occurring in cholangiocarcinogenesis. Under physiological conditions, biliary epithelial cells are typically surrounded by a thin layer of extracellular matrix (ECM) proteins, whose turnover is finely regulated by a small number of lowly proliferating fibroblasts. Upon neoplastic transformation of the biliary epithelium, the surrounding stroma gradually undergoes a multifaceted pathological remodeling, which is substantially based on the persistent activation of fibroblasts, the aberrant deposition of both structural and non-structural ECM components, and the massive recruitment of inflammatory cells (mainly macrophages). In particular, the compositional changes that deeply affect the ECM ultimately result in a stiffer cell microenviroment, which may deleteriously mold the behavior of cancer cells (see text for further details).

Fig. 2.

Basement membrane crossing by neoplastic cholangiocytes. Normal bile ducts, as well as primary cancer lesions, are lined by a continuous, laminin-rich basement membrane, which both separates biliary cells from the interstitial matrix, and communicates with them through integrin receptors, thereby deeply affecting epithelial cell behavior. As cancerous lesions are emerging, malignant cells (red) start to degrade the basement membrane through the broad release of matrix metalloproteinases (MMPs), acting in concert with activated fibroblasts (purple) previously coopted within the portal area. Once the basement membrane has been dismantled, cancer cells can effectively disseminate throughout the interstitial matrix, thus getting easier access to lymphatic vessels (green) closely aligned with the activated fibroblasts.