Targeting IGF2BP2 Enhances Anti-Angiogenic Therapy in Colorectal Cancer
A new study published in Engineering identifies insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a critical regulator of angiogenesis in colorectal cancer (CRC), offering a potential strategy to improve the effectiveness of existing anti-angiogenic therapies. The research, conducted by scientists from Sun Yat-sen University and The Chinese University of Hong Kong, could lead to more effective treatments for a disease that remains a significant global health challenge.
The Challenge of Colorectal Cancer and Angiogenesis
Colorectal cancer is a leading cause of cancer-related illness and death worldwide. Over 20% of patients are diagnosed at an advanced stage, facing a five-year survival rate of only 14%.1 A key factor in tumor growth, spread, and treatment resistance is angiogenesis – the formation of new blood vessels. While anti-angiogenic drugs like bevacizumab and regorafenib are currently used, tumors often develop resistance, limiting their long-term impact.
IGF2BP2: A Novel Therapeutic Target
Researchers began by analyzing gene expression data from CRC samples, consistently finding elevated levels of IGF2BP2 in tumors with high angiogenesis. Further investigation, utilizing immunohistochemistry and single-cell RNA sequencing, confirmed a strong correlation between IGF2BP2 expression and blood vessel formation within CRC tissues.3 Higher IGF2BP2 expression was also linked to a poorer prognosis for patients.
How IGF2BP2 Promotes Tumor Growth
Experiments revealed that reducing IGF2BP2 levels in CRC cells diminished their ability to promote blood vessel growth. Conversely, increasing IGF2BP2 levels enhanced angiogenesis and vascular leakiness. In animal models, mice engineered to have increased IGF2BP2 expression in the intestines developed CRC more rapidly, while mice with reduced IGF2BP2 expression showed inhibited tumor growth and improved blood vessel structure.3
The study uncovered the mechanism behind IGF2BP2’s role: it binds to m6A-modified cell migration inducing and hyaluronan binding protein (CEMIP) mRNA, stabilizing it and increasing its secretion. Secreted CEMIP then interacts with membrane glucose-regulated protein 78 (GRP78) on endothelial cells, activating pro-angiogenic signaling pathways.3
Synergistic Effects with Existing Therapies
Importantly, targeting IGF2BP2 – through genetic manipulation, small interfering RNA delivered via lipid nanoparticles, or a chemical inhibitor – worked synergistically with anti-angiogenic drugs to suppress tumor growth in multiple CRC models.3 This suggests that IGF2BP2 could be a valuable target for enhancing the effectiveness of current treatments.
Future Directions
The findings highlight the importance of IGF2BP2 in CRC angiogenesis and offer a new avenue for improving treatment outcomes. Further research will focus on exploring the therapeutic potential of targeting IGF2BP2 in clinical trials, potentially leading to more effective therapies for colorectal cancer patients.1
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