A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition
Abstract
1. Introduction
- Heterogeneous response: Tumors can vary greatly in their response to anti-angiogenic therapy, not only between different cancers but also between patients with the same cancer. This variability makes it difficult to establish universal criteria for efficacy and treatment [18].
- The dynamic nature of tumor angiogenesis: Tumors can adapt to anti-angiogenic therapy over time, either by activating alternative angiogenic pathways or by adopting less angiogenesis-dependent mechanisms. This ability to adapt means that the efficacy of therapy may decrease with time or that initial responses may not be sustained, complicating the assessment of long-term efficacy [19].
- Lack of direct biomarkers: There is a lack of direct, reliable biomarkers that can accurately reflect changes in angiogenesis due to therapy. Most current methods assess tumor size or growth rates using imaging techniques such as MRI (magnetic resonance imaging) or CT (computed tomography). However, these indicators may not sensitively or specifically reflect changes in angiogenesis, especially in the early stages of treatment [20].
- Difficulty in measuring microenvironment changes: Anti-angiogenic therapies not only affect tumor cells, but also have a significant impact on the tumor microenvironment, including altering vascular permeability, interstitial pressure, and hypoxia. These changes are difficult to measure directly and quantitatively in patients [21].
2. Understanding the Splice Forms of VEGF
2.1. The Biology of VEGF Splicing
2.2. Molecular Perspective
3. Experimental Evidence of VEGF Splice Variants in Angiogenesis Inhibition
3.1. Preclinical Studies
3.2. Clinical Perspectives on VEGF165 as a Treatment for HNSCC
3.3. Potential Limitations and Future Directions
4. Pro-Angiogenic vs. Anti-Angiogenic VEGF Variants in HNSCC: Clinical Impact
5. Resistance Mechanisms and Overcoming Therapeutic Challenges
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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VEGF Splice | Variant | Receptor Binding | Biological Activity | Role in Angiogenesis |
---|---|---|---|---|
VEGF121 | Binds | VEGFR1 and VEGFR2 | Initiates cellular events leading to new vessel formation | Pro-angiogenic |
VEGF165 | Binds | VEGFR1 and VEGFR2 | Promotes proliferation and migration of endothelial cells | Pro-angiogenic |
VEGF189 | Binds | VEGFR1 and VEGFR2 | Influences extracellular matrix affecting vascular growth | Pro-angiogenic |
VEGF165b | Binds | VEGF receptors without activating angiogenic signaling | Inhibits angiogenic pathways, acts as a competitive inhibitor | Anti-angiogenic |
VEGF Variant | Type (Pro-Angiogenic/Anti-Angiogenic) | Characteristics | Clinical Implications |
---|---|---|---|
VEGF-A165 [67] | Pro-angiogenic | Promotes endothelial cell proliferation, migration, and new blood vessel formation by binding to VEGFR1 and VEGFR2. | Associated with tumor progression and metastasis in various cancers, including HNSCC. |
VEGF-A121 [68] | Pro-angiogenic | Similar to VEGF-A165 but more diffusible due to the lack of heparin-binding domains. | Plays a role in angiogenesis and tumor growth. |
VEGF-A189 [69] | Pro-angiogenic | Strongly binds to heparin and extracellular matrix components, affecting local angiogenesis. | Influences the angiogenic profile in specific tissue environments. |
VEGF-A165b [70] | Anti-angiogenic | A splice variant of VEGF-A165 that binds to VEGFR1 and VEGFR2 without activating pro-angiogenic signaling pathways. | Inhibits angiogenesis, offering a potential therapeutic target for reducing tumor growth and angiogenesis in cancers. |
VEGF-A121b [9] | Anti-angiogenic | A splice variant of VEGF-A121 that also inhibits angiogenesis by preventing VEGFR-mediated signaling. | Potentially reduces angiogenesis and tumor progression, similar to VEGF-A165b. |
VEGF-B [35] | Pro-angiogenic | Binds primarily to VEGFR1, involved in heart development and fatty acid uptake. | Role in cancer is less clear but may be involved in metabolic regulation and survival of cancer cells. |
VEGF-C [71] | Pro-angiogenic | Induces lymphangiogenesis and angiogenesis through binding to VEGFR2 and VEGFR3. | Implicated in lymphatic metastasis of solid tumors, including HNSCC, by promoting lymphangiogenesis. |
VEGF-D [72] | Pro-angiogenic | Similar to VEGF-C, promotes lymphangiogenesis and angiogenesis by binding to VEGFR2 and VEGFR3. | Potential role in lymphatic spread and metastasis of cancer, including implications for HNSCC. |
PIGF [73] | Pro-angiogenic | Binds to VEGFR1 and NRP1; involved in pathological angiogenesis, inflammation, and recruitment of myeloid cells. | Studied for its potential in cancer therapy and cardiovascular diseases, though with varying implications in different types of cancer. |
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Dumitru, C.S.; Raica, M. A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition. Int. J. Mol. Sci. 2024, 25, 8855. https://doi.org/10.3390/ijms25168855
Dumitru CS, Raica M. A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition. International Journal of Molecular Sciences. 2024; 25(16):8855. https://doi.org/10.3390/ijms25168855
Chicago/Turabian StyleDumitru, Cristina Stefania, and Marius Raica. 2024. "A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition" International Journal of Molecular Sciences 25, no. 16: 8855. https://doi.org/10.3390/ijms25168855
APA StyleDumitru, C. S., & Raica, M. (2024). A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition. International Journal of Molecular Sciences, 25(16), 8855. https://doi.org/10.3390/ijms25168855