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Review
. 2019 Jan;23(1):59-69.
doi: 10.1111/jcmm.13953. Epub 2018 Nov 5.

The role of tumour microenvironment: a new vision for cholangiocarcinoma

Ziyan Chen  1 , Pengyi Guo  1 , Xiaozai Xie  1 , Haitao Yu  1 , Yi Wang  2 , Gang Chen  1
Affiliations
Review

The role of tumour microenvironment: a new vision for cholangiocarcinoma

Ziyan Chen et al. J Cell Mol Med. 2019 Jan.

Abstract

Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non-immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.

Keywords: cholangiocarcinoma; tumor microenvironment; tumor stromal cells.

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Figures

Figure 1
Figure 1
The pathways participate in tumourigenesis of CCA. A, Extracellular WNT glycoproteins appear and bind to Frizzled receptors and the co‐receptors LRP5 (low‐density lipoprotein receptor‐related protein 5) and LRP6, DVL inhibit the destruction complex that made of APC, GSK3β and AXIN and results in the accumulation of β‐catenin in cell cytoplasm. β‐catenin enters nucleus and combines with TCF/LEF transcription factors to regulate the expression of target genes. Then, influencing the CCA. B, NF‐kB integrates with inhibiting factor IkB in the stationary state. After IkBs are phosphorylated by IKK or ubiquitnated by SCF‐E3 and degraded by protease, NF‐kB is activated and entering nucleus to induce the transcription of target genes. C, DSL family bind to notch receptors and stimulate the notch protein shear. And the generated NICD turns into nucleus to combine with transcription factor CLS. The compound activates the expression of target genes to induce CCA (D) EGFRs combine with EGFR ligands to activate protein kinases. Thymidine kinase is phosphorylated to stimulate Ras2/Raf2/MAPK signalling pathway, PI3K/AKT pathway and JAK/STAT pathway that play important roles in CCA carcinogenesis
Figure 2
Figure 2
Work model of the impact of tumour stromal cells on CCA. Endothelial cells promote CCA angiogenesis through pathway A (release inflammatory cytokines) and B (express COX‐1 protein). Fibroblasts induce CCA invasion via pathway A (produce periostin), B (ITGα5β1/PI3K/AKT pathway) and C (express SDF‐1), stimulate CCA metastasis through pathway A (express SDF‐1) and promote proliferation of CCA by means of pathway A (express α‐SMA) and B (produce SDF‐1). Epithelial cells promote CCA invasion via pathway A (express low level of EpCAM) and B (epithelial‐mesenchymal transition), induce CCA proliferation through pathway A (secret synemin) and stimulate CCA metastasis by means of pathway A (epithelial‐mesenchymal transition). HSCs induce the angiogenesis, invasion and metastasis via pathway A (Hedgehog signalling) and B (produce TGF‐β, PDGF and nuclear factor‐Kappa B). Macrophages stimulate invasion and metastasis of CCA via pathway A (express MMP‐9), induce CCA proliferation through Wnt signalling pathway. Cancer stem cells induce CCA proliferation by means of pathway A (produce signalling mediators)
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