Abstract
Simple SummaryAngiogenesis belongs to the most clinical characteristics of colorectal cancer (CRC) and is strongly linked to the activation of Wnt/β-catenin signaling. The most prominent factors stimulating constitutive activation of this pathway, and in consequence angiogenesis, are genetic alterations (mainly mutations) concerning APC and the β-catenin encoding gene (CTNNB1), detected in a large majority of CRC patients. Wnt/β-catenin signaling is involved in the basic types of vascularization (sprouting and nonsprouting angiogenesis), vasculogenic mimicry as well as the formation of mosaic vessels. The number of known Wnt/β-catenin signaling components and other pathways interacting with Wnt signaling, regulating angiogenesis, and enabling CRC progression continuously increases. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.
Highlights
The Wnt/Frizzled (Fzd)/β-catenin signaling pathway plays a significant role in physiology and pathology [1,2,3,4]
A correlation between CXCR4 expression and low E-cadherin, high N-cadherin, and high vimentin was noted, suggesting links between the stromal cell-derived factor 1 (SDF-1)/CXCR4 pathway and Wnt/β-catenin signaling [84]. When it comes to the role of serum concentration of Wnt signaling components, as markers of colorectal cancer (CRC) angiogenesis, it was proven that serum vascular endothelial (VE)-cadherin was about fourfold higher in CRC patients compared with the controls, but it was not correlated with the vascular endothelial growth factor (VEGF) level and any clinicopathological data
As the reviewed literature shows, the role of aberrant Wnt/β-catenin signaling in CRC-related angiogenesis is undisputed. These activities mostly occur due to canonical APC/β-catenin pathway activation in tumor colorectal cells, CRC stem cells, cancer-associated fibroblasts and tumor endothelial cell (EC), intensification of β-catenin expression, and translocation to the nucleus as well as positive correlations with other typical pro-angiogenic factors (e.g., VEGF, VEGRs)
Summary
The Wnt/Frizzled (Fzd)/β-catenin signaling pathway plays a significant role in physiology and pathology (including carcinogenesis) [1,2,3,4]. Two new targets of emodin action, the p300 Wnt co-activator (downregulated), and the HMG-box transcription factor 1 (HBP1) repressor (upregulated) were indicated in CRC cell lines [99] Recent research confirmed these observations through the demonstration of EMT and tumor growth inhibition. Aloin inhibited HUVEC proliferation, migration, and tube formation in vitro as well as activation of VEGFR-2 and STAT3 phosphorylation in ECs. After aloin administration in SW620 CRC cells, a downregulation of antiapoptotic (Bcl-xL), pro-proliferative (C-Myc), and angiogenic factors (e.g., VEGF) was observed. Lipoprotein-related Protein 6; ROR α—RAR-related orphan receptor α; SALL4—Zink Finger Transcription Factor Spalt (Sall)-like Protein 4; SDF-1—Stromal Cell-derived Factor 1; SER—Serine; SMAR1—Scaffold/Matrix Attachment Region Binding protein 1; STAT3—Signal Transducer and Activator of Transcription Protein 3; Tan IIA/TSA—Tanshinone IIA; TCF—T cell Factor; TCF7L2—Transcription Factor 7-like 2; TGF-β—Tumor Growth Factor beta; TGM2—Tissue Transglutaminase 2; TIPE2 (TNFAIP8L2)—Tumor Necrosis Factor α (TNFα)-induced protein 8 like 2; VEGF (R)—Vascular Endothelial Growth Factor (Receptor)
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