Molecular mechanisms of Cholangiocarcinoma progression: role of the tumor microenvironment.

Cholangiocarcinoma (CCA) is an aggressive tumor whose incidence is increasing. CCA is characterized by a strong desmoplastic reaction, a strong invasiveness and a very poor prognosis. Surgical treatment is the most used, but the results are poor because most CCAs, at the time of diagnosis, already have metastases to the local lymph nodes. The lack of effective therapies reflects the uncertainties regarding the molecular mechanisms that govern tumor progression in CCA. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of innate and adaptive immune cells. The ultimate role of the reactive tumor stroma is still incompletely understood; however, recent studies suggest that the tumor microenvironment may play a key role in CCA progression and its invasiveness. CCA cells exchange autocrine/paracrine signals to other cancer cells and to the infiltrating cell types and heavily influence their microenvironment. This cross-talk is under the control of signaling mechanisms, morphogenetic transcription factors, and oncogenes and is ultimately mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication in cancer biology, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communication between CCA cells and other liver cells provide a potential novel target for the treatment of CCA.