English: FIGURE 1. Schematic illustrating interaction of key elements in the tumor stroma in CCA progression. Several components of the CCA tumor microenvironment activate mechanisms that promote tumor growth, migration and activation of tumor associated angiogenesis and lymphangiogenesis. Interaction between VEC and CCA cell via VEGFR2-VEGFA assisted by neuropilin leads to tumor angiogenesis via upregulation of PI3K/Akt pathway. HIF1α activated by an inflamed tumor microenvironment stimulates CCA progression. VEGFC secreted by CCA as well by CAF (via PDGFD stimulation of tumor cells) aids in the process of lymphangiogenesis by stimulating LECs to divide via VEGFR3 engagement and upregulation of ERK/JNK pathway. Further contributing to the surrounding milieu, exosomal vesicles secreted by CCA triggers production of IL6, CCL2, CXCL1, CXC3CL1, and PDGF-AA which in turn when secreted in the tumor stroma induces CCA proliferation and growth pathways. CCA, Cholangiocarcinoma; MSC, Mesenchymal Stem Cell; LEC, Lymphatic Endothelial Cell; CAF, Cancer Associated Fibroblast; VEC, Vascular Endothelial Cell; PDGF-AA, Platelet Derived Growth Factor-AA; CXC3CL1, Chemokine Ligand 1 (Fractalkine); CCL2, C-C Motif Chemokine Ligand 2; CXCL1, C-X-C Motif Chemokine Ligand 1; IL6, Interleukin 6; VEGFR3, Vascular Endothelial Growth Factor Receptor 3; VEGFC, Vascular Endothelial Growth Factor C; VEGFA, Vascular Endothelial Growth Factor A; VEGFR2, Vascular Endothelial Growth Factor 2; PI3K, Phosphoinositide 3-kinase; Akt, Protein Kinase B; HIF1α, Hypoxia Inducible Factor 1 α; PDGFD, Platelet Derived Growth Factor D; PDGFRB, Platelet Derived Growth Factor Receptor B; ERK, Extracellular Receptor Kinase; JNK, c-Jun N-terminal Kinase.