The Role of Stroma in Cholangiocarcinoma: The Intriguing Interplay between Fibroblastic Component, Immune Cell Subsets and Tumor Epithelium

Abstract

Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor epithelium. This strong desmoplasia is orchestrated by various soluble factors and signals, suggesting a critical role in shaping a tumor growth-permissive microenvironment that is responsible for CCA poor clinical outcome. Indeed stroma not only provides an abundance of factors that facilitate CCA initiation, growth and progression, but also a prejudicial impact on therapeutic outcome. This review will give an overview of tumor-stroma signaling in a microenvironment critically regulating CCA development and progression. Identification of CCA secreted factors by both the fibroblast component and immune cell subsets might provide ample opportunities for pharmacological targeting of this type of cancer.

Keywords: cancer associated fibroblasts; cholangiocarcinoma; desmoplastic stroma; tumor microenvironment; tumor-associated macrophages.

Figure 1

Cross-talk among CCA cells, CAFs, and tumor-associated macrophages (TAMs). Angiotensin II (AngII) released by cancer cells acts both in an autocrine and paracrine fashion. Stromal-derived factor I (SDF-1) expressed by CAFs increases upon AngII stimulation. SDF-1, AngII, PDGF-BB, HB-EGF, CXCL7, HGF released by CAFs promote tumor growth. Tumor Necrosis Factor (TNF-α (produced by TAMs enhance CXCR4 expression (receptor of SDF-1) in CCA. M2 TAMs favour tumor progression through the release of anti-inflammatory cytokines, chemokine and metalloproteinase. Treg cells mediate CCA tolerance producing anti-inflammatory cytokines and inhibiting Natural Killer (NK) antitumor activity.