The Tumor Microenvironment in Cholangiocarcinoma Progression - PubMed (original) (raw)

Review

. 2021 Jan;73 Suppl 1(Suppl 1):75-85.

doi: 10.1002/hep.31410. Epub 2020 Nov 6.

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Review

The Tumor Microenvironment in Cholangiocarcinoma Progression

Luca Fabris et al. Hepatology. 2021 Jan.

Abstract

Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals 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, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.

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Figures

Figure 1.

Figure 1.. Spatial relationship of stromal cells populating the tumor microenvironment in CCA.

A) Tumoral ducts are embedded in a dense stroma, populated by CAFs identified by α-SMA (green). Inflammatory cells are recognized by their expression of CD45 (red) including macrophages and neutrophils. Nuclei are stained by DAPI (blue) (dual immunofluorescence, original magnification: 100X). B) A rich lymphatic bed decorated by the antibody recognizing the lymphatic endothelial cell marker EpCAM (clone D2-40) closely aligns the periphery of the tumoral areas (immunohistochemistry, original magnification: 100X). Histological sections were obtained from a surgical sample of a patient with intrahepatic cholangiocarcinoma undergoing hepatic resection.

Figure 2.

Figure 2.. The crosstalk between CCA cells and CAFs.

CCA cells secrete mediators such as PDGF-D and TGF-β1, which induce differentiation of hepatic stellate cells, portal fibroblasts, or circulating mesenchymal cells into activated CAFs. CAFs secrete mediators including PDGF-B, HB-EGF, and SDF-1 leading to CCA tumor growth and invasion. CAFs also contribute to fibrogenesis, leading to ECM remodeling, and to lymphangiogenesis, promoting CCA invasion through the lymphatic endothelial cell (LEC) barrier. This tumor microenvironment is proficient to CCA progression and metastases.

Figure 3.

Figure 3.. The interplay between CCA cells with CAFs and TAMs.

CCA tumor cells and CAFs secrete various mediators, such as CCL2, CSF-1, and VEGF-A, which attract circulating monocytes into the tumor area. A subset of CCA cells promote differentiation of monocyte-derived TAMs by secreting IL-13, IL-34 and osteoactivin. These mediators especially CCL2 induce monocyte differentiation into TAMs. Activated TAMs educate the tumor microenvironment to become more permissive to tumor growth and invasion at different levels. TAMs stimulate angiogenesis by secreting VEGF-A and angiopoietin, which act on liver sinusoidal endothelial cell (LSEC). TAMs induce tumor growth directly by secreting Wnt proteins (Wnt3a and Wnt7b). TAMs also dampen anti-tumor functions of T cells by inducing expression of HIF-1α.

Figure 4.

Figure 4.. Immune checkpoints regulated by CCA tumors and the microenvironment.

CCA tumor cells express high levels of PD-L1, which binds to PD-1 expressed in T cells. Activation of PD-1 signaling inhibits T cell activation and anti-cancer functions. The CCA microenvironment contains high population of Tregs and these CCA-associated Tregs express high levels of CTLA-4. Antigen presenting cells detect CTLA-4 by its receptor CD80 and this CTLA-4/CD80 signaling also inhibits T cell activation as anti-cancer cells. The tumor microenvironment expressing high levels of PD-L1/PD-1 and CTLA-4/CD80 pathways promotes immune escape of CCA cells leading to tumor growth and metastases.

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