Classical Angiogenic Signaling Pathways and Novel Anti-Angiogenic Strategies for Colorectal Cancer

Abstract

Although productive progress has been made in colorectal cancer (CRC) researchs, CRC is the second most frequent type of malignancy and the major cause of cancer-related death among gastrointestinal cancers. As angiogenesis constitutes an important point in the control of CRC progression and metastasis, understanding the key signaling pathways that regulate CRC angiogenesis is critical in elucidating ways to inhibit CRC. Herein, we comprehensively summarized the angiogenesis-related pathways of CRC, including vascular endothelial growth factor (VEGF), nuclear factor-kappa B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Wingless and int-1 (Wnt), and Notch signaling pathways. We divided the factors influencing the specific pathway into promoters and inhibitors. Among these, some drugs or natural compounds that have antiangiogenic effects were emphasized. Furthermore, the interactions of these pathways in angiogenesis were discussed. The current review provides a comprehensive overview of the key signaling pathways that are involved in the angiogenesis of CRC and contributes to the new anti-angiogenic strategies for CRC.

Anti‐angiogenesis in colorectal cancer therapy

“…99 Their activation is positively associated with cell survival, angiogenesis, apoptosis, and metastasis in CRC. 100 Moreover, in CRC, the expression of NF-κB (p65) is directly associated with the expression level of HIF-1α, VEGF, and vascular invasion. 101 The NF-κB pathway promotes the expression of multiple angiogenic factors, including VEGF, PDGF-BB, CXCL1, CXCL8, MMP-2, MMP-9, COX-2, and IL-8, ulteriorly inducing tumor angiogenesis.…”

“…TGM2 upregulates the expression of Wnt3a and β-catenin, whereas TM4SF1 activates the Wnt/β-catenin/c-Myc/SOX2 signaling pathway, thereby promoting angiogenesis in CRC. 100 Moreover, the COX-2/PGE2/EP4 axis, 121 notch signaling pathway, 100 c-MET/hepatocyte growth factor (HGF) signaling pathway, 122 and EPH/ephrin signaling system 123 are all related to angiogenesis in CRC. These various factors and pathways are connected and cross each other like points and lines.…”

“…NF‐κB signaling has two different but interactive pathways: the canonical (activated by TNF‐α, lipopolysaccharide, and IL‐1) and non‐canonical (activated by BAFF, CD40, receptor‐activated NF‐κB ligand, and lymphotoxin β) pathways 99 . Their activation is positively associated with cell survival, angiogenesis, apoptosis, and metastasis in CRC 100 . Moreover, in CRC, the expression of NF‐κB (p65) is directly associated with the expression level of HIF‐1α, VEGF, and vascular invasion 101 .…”

“…Humans have 19 Wnts, suggesting it is a complicated signaling and biological process 117 . The Wnt signaling pathway has two branches: canonical and non‐canonical pathways 100 . β‐catenin is a crucial member of the canonical pathway as a switch, and its expression is promoted by activated Wnt signaling 118 .…”

Immune Checkpoint Inhibitor-Based Combination Therapy for Colorectal Cancer: An Overview

“…In addition to inhibiting the VEGF/VEGFR pathway, TKI drugs may also inhibit targets related to immune regulation, such as platelet-derived growth factor receptor (PDGFR), angiopoietin-2 receptor (TIE2), and colony-stimulating factor 1 receptor, and have stronger synergy with immunotherapy. [92][93][94] EGFR EGFR is a member of the epidermal growth factor receptor (HER) family, which includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3), and HER4 (erbB4). 95,96 Studies have shown that EGFR is overexpressed or abnormally expressed in many solid tumors.…”