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Review
, 20 (17)

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

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Review

Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

Hsing-Ju Wu et al. Int J Mol Sci.

Abstract

Cholangiocarcinoma (CCA) is the second most common type of liver cancer, and is highly aggressive with very poor prognosis. CCA is classified into intrahepatic cholangiocarcinoma (iCCA) and extra-hepatic cholangiocarcinoma (eCCA), which is further stratified into perihilar (pCCA) and distal (dCCA). Cancer stem cells (CSCs) are a subpopulation of cancer cells capable of tumor initiation and malignant growth, and are also responsible for chemoresistance. Thus, CSCs play an important role in CCA carcinogenesis. Surface markers such as CD133, CD24, CD44, EpCAM, Sox2, CD49f, and CD117 are important for identifying and isolating CCA CSCs. CSCs are present in the tumor microenvironment (TME), termed 'CSC niche', where cellular components and soluble factors interact to promote tumor initiation. Epithelial-to-mesenchymal transition (EMT) is another important mechanism underlying carcinogenesis, involved in the invasiveness, metastasis and chemoresistance of cancer. It has been demonstrated that EMT plays a critical role in generating CSCs. Therapies targeting the surface markers and signaling pathways of CCA CSCs, proteins involved in TME, and immune checkpoint proteins are currently under investigation. Therefore, this review focuses on recent studies on the roles of CSCs in CCA; the possible therapeutic strategies targeting CSCs of CCA are also discussed.

Keywords: cancer stem cells; cholangiocarcinoma; epithelial-to-mesenchymal transition; surface markers; targeted therapy; tumor microenvironment.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The tumor microenvironment (TME), ‘Cancer stem cell (CSC) niche’ of cholangiocarcinoma (CCA). The TME contains cancer-associated fibroblasts (CAFs), cancer cells/CSCs, tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and the extracellular matrix (ECM). TAMs are recruited into the TME by chemokines, MCP-1/CCL2, C-X-C motif chemokine ligand (CXCL)1, CXCL10 and SDF-1/CXCL12, secreted by tumor cells or other stromal cells. When infiltrating into TME, monocytes differentiate into M2 macrophages upon stimulation with soluble factors, prostaglandin E2 (PGE2), and cytokines, interleukin (IL)-2, IL-10 and transforming growth factor-β1 (TGF-β1) released by CAF and other inflammatory cells. In the crosstalk between TAMs and CCA cells, matrix metalloproteinases (MMPs), IL-4, IL-6, IL-10, vascular endothelial growth factor-A (VEGF-A), tumor necrosis factor-α (TNF-α) and TGF-β were secreted by lipopolysaccharide-activated TAMs. CAFs are recruited into the tumoral area and are activated by a variety of soluble mediators produced by both tumor cells, and the multiple inflammatory cells, such as platelet-derived growth factor (PDGF-D), TGF-β, reactive oxygen species (ROS) and FGF-2. CAF further recruit inflammatory cells, monocytes, macrophages, and endothelial cells to the tumor reactive stroma (TRS), through the secretion of VEGF, FGF, MCP-1/CCL2, SDF-1 and CXCL-14. TILs include CD8+ cytotoxic T lymphocytes, cytokine-secreting CD4+ T helper lymphocytes (Th), Forkhead box P3 (FoxP3)+ T leukocyte immunosuppressive regulators/regulatory T cells (Tregs), and B lymphocytes. TILs target cancer cells, and thus serve as a primary defence against cancer. T cell activation is tightly regulated by immune checkpoint pathways. TNF-α and IL-6 promote the generation of free radicals causing damage to DNA, resulting in genetic mutations and finally lead to tumor initiation. Wnt/β-catenin, Notch, Hedgehog, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and TGFβ pathways associated with cell growth dysregulation, invasion, and metastasis were activated surrounding CSCs. Extracellular vesicles (EVs) play as carriers for the intercellular transfer of genetic information and modulation of cell signaling of cancer cells.

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