Roles and mechanisms of ESM1 in tumor angiogenesis

Roles and mechanisms of ESM1 in tumor angiogenesis. Solid lines indicate demonstrated mechanisms and dashed lines indicate possible mechanisms. ESM1 activates the NF-κB pathway in two ways: Via the upregulation of TNF-α and IL-8, and via promotion of binding between VEGF and VEGFR2. The activated NF-κB upregulates VEGF via the transcription factor HIF-1α, thereby promoting angiogenesis. ESM1 also activates the PI3K/AKT/mTOR pathway to upregulate MMPs, VEGF and HIF-1α by facilitating the binding of VEGF with VEGFR2. Regarding EGF and its receptor EGFR, ESM1 not only directly binds to EGFR but also facilitates the binding of EGF to EGFR, leading to activation of the EGFR signaling pathway. The activated EGFR, in turn, increases ESM1 expression through the JAK/STAT3 and ERK/ELK pathways, establishing a regulatory loop between ESM1 and EGFR. Increased ESM1 also upregulates angiogenesis-related factors such as VEGFR1, VEGFR2, EGFR and VWF, thereby promoting angiogenesis. In addition, activated EGFR can upregulate HIF-1α and MMPs through the PI3K/AKT/mTOR pathway. In the MAPK pathway, ESM1 increases the expression of VEGF through ERK, JNK and p38. As for the Notch pathway, the ligand DLL4 is upregulated by ESM1, thereby inhibiting VEGF expression. ESM1, endothelial cell specific molecule-1; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor-α; IL-8, interleukin-8; VEGF, vascular endothelial growth factor; VEGFR1/2, VEGF receptor 1/2; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; MMPs, matrix metalloproteinases; HIF-1α, hypoxia-inducible factor-1α; EGF, epidermal growth factor; EGFR, EGF receptor; JAK, Janus kinase; STAT3, signal transducer and activator of transcription 3; ERK, extracellular signal-regulated kinase; ELK, ETS-like kinase; JNK, c-Jun N-terminal kinase; VWF, von Willebrand factor; DLL4, d-like ligand 4; P, phosphorylated; TAB1-3, TAK1-binding protein 1–3; TAK1, transforming growth factor-b-activated kinase 1; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; MEK/MKK, mitogen-activated protein kinase kinase; NICD, Notch intracellular domain

Publication

Roles of endothelial cell specific molecule‑1 in tumor angiogenesis (Review) (2024) Jie Zhou, et al. Oncol Lett. 2024 Mar;27(3). Figure: F3. Homo sapiens

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