Key Takeaways & Executive Findings
- •• D-mannose suppresses colorectal cancer angiogenesis and tumor growth by promoting lysosomal degradation of VEGFR2. • Mechanistically, D-mannose inactivates GSK3β via Ser9 phosphorylation, leading to TFE3 nuclear translocation and enhanced lysosomal biogenesis. • D-mannose inhibits HUVEC proliferation, migration, and capillary formation in vitro, and oral administration reduces tumor angiogenesis in mice. • These findings propose D-mannose as a potential therapeutic agent for colorectal cancer by targeting VEGFR2 stability.
Abstract
Angiogenesis is an important factor influencing the development of solid tumors, and vascular endothelial growth factor receptor-2 (VEGFR2) is a central regulator of angiogenesis. Antibodies and inhibitors against VEGFR2 have been widely used in various malignancies. However, the regulatory mechanism of VEGFR2 has not been fully clarified. Here, we show that D-mannose can significantly inhibit angiogenesis and tumor growth by degrading VEGFR2. Specifically, D-mannose inactivates GSK3β by promoting the phosphorylation of GSK3β at Ser9, enhances the nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing the lysosome-mediated degradation of VEGFR2. Thus, D-mannose significantly inhibits the proliferation, migration, and capillary formation of human umbilical vein endothelial cells (HUVECs) in vitro. Oral administration of D-mannose dramatically inhibits angiogenesis and tumor growth in mice. Our findings reveal a previously unrecognized anti-tumor mechanism of D-mannose by destabilizing VEGFR2 and provide a new strategy for the clinical treatment of colorectal cancer (CRC).
1. Introduction
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract. Recent statistics have shown that the incidence of CRC is the third highest overall incidence and the second highest mortality rate [1]. Despite advances in screening procedures and adjuvant therapy, the incidence, prevalence and mortality of CRC remain high [1]. Therefore, the development of new treatments and drugs for CRC is urgently needed.
Angiogenesis plays a crucial role in the growth, recurrence and metastasis of CRC [2]. The formation of new blood vessels provides nutrients and oxygen for tumors, thus promoting the rapid proliferation of cancer cells [3]. Various growth factors, cytokines, and mechanical cues are implicated in the induction of angiogenesis within tumors [4]. The main pro-angiogenic drivers are vascular endothelial growth factor (VEGF) and its receptors VEGFR1–3 [5], among which VEGFR2 has been identified as a critical component of VEGF-mediated angiogenesis [6].
VEGFR2 is a large 151 kDa membrane protein consisting of 7 extracellular immunoglobulin (Ig)-like domains, a single transmembrane helix, and a split intracellular kinase domain [7]. VEGFR2 has been implicated in angiogenesis in many solid tumors, including breast cancer, colon cancer, hepatoma, and gastric cancer [2,8–10]. VEGF induces receptor dimerization and subsequent phosphorylation by binding to VEGFR2, thereby maintaining downstream signaling. Phosphorylation of VEGFR2 promotes downstream activation of ERK1/2, AKT, and eNOS, which are critical for human umbilical vein endothelial cell (HUVEC) proliferation, migration, and angiogenesis [11]. Therefore, VEGFR2-blocking therapies that reduce its activity or stability and downstream signaling are of great clinical importance.
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Yu Du, Xinchao Zhang, Yixin Xu, Yuefan Zhou, Yanping Xu (2026). D-mannose suppresses the angiogenesis and progression of colorectal cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025043
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that D-mannose suppresses colorectal cancer angiogenesis and tumor growth by promoting lysosomal degradation of VEGFR2, revealing a novel anti-tumor mechanism.
How does D-mannose induce VEGFR2 degradation?
D-mannose inactivates GSK3β via phosphorylation at Ser9, which enhances nuclear translocation of TFE3, leading to increased lysosomal biogenesis and subsequent lysosome-mediated degradation of VEGFR2.
What are the clinical implications of this research?
The findings suggest that D-mannose could be repurposed as a therapeutic agent for colorectal cancer, potentially offering a safe and cost-effective strategy to inhibit tumor angiogenesis.
What experimental models were used?
The study used human colon cancer HCT116 cells and human umbilical vein endothelial cells (HUVECs) in vitro, as well as a mouse model for in vivo experiments.
What is the significance of targeting VEGFR2 in cancer therapy?
VEGFR2 is a central regulator of angiogenesis in solid tumors, and its inhibition can starve tumors of nutrients and oxygen, thereby limiting tumor growth and metastasis.
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