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Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1435-1443. doi: 10.1016/j.bbadis.2017.07.028. Epub 2017 Jul 27.

The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma.

Author information

1
Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy.
2
Department of Surgical, Oncological, and Gastroenterological Sciences (DiSCOG), University of Padova, 35128 Padova, Italy.
3
Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy.
4
Department of Molecular Medicine, University of Padua School of Medicine, 35121 Padua, Italy.
5
International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
6
Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
7
International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Department of Molecular Medicine, University of Padua School of Medicine, 35121 Padua, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: luca.fabris@unipd.it.

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

PMID:
28757170
PMCID:
PMC6386155
DOI:
10.1016/j.bbadis.2017.07.028
[Indexed for MEDLINE]
Free PMC Article

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