Angiogenesis in Tumors and Development

Angiogenesis in Tumors

• Tumors require nutrients and oxygen for growth, stimulating angiogenesis to create new blood vessels.
• This vascularization provides resources and pathways for cancer cell invasion and metastasis.
• Tiny tumors are often dormant due to natural mechanisms preventing blood vessel formation.
• For growth, cancer cells must activate angiogenesis by releasing factors like VEGF (Vascular Endothelial Growth Factor).
• Successful angiogenesis allows access to nutrients and distant spread, enhancing tumor growth and metastasis risk.
• Angiogenesis is a crucial cancer therapy target.

Angiogenesis in Embryonic Development

• Angiogenesis is essential for embryonic development, particularly for proper blood vessel growth supporting embryo development.
• VEGF (Vascular Endothelial Growth Factor) is the primary regulator, crucial for blood vessel formation and extension.
• Insufficient VEGF, even from one deleted allele, can be lethal to the developing embryo due to inadequate blood vessel formation.
• VEGF promotes blood vessel branching, delivering essential nutrients and oxygen, vital for organ development and growth.
• Studies in mice highlight the necessity of VEGF; missing one functional allele halts development.

Normal Angiogenesis in Adults

• Angiogenesis is generally suppressed in adults, except in specific circumstances.
• Female Reproductive System: Required for menstruation, ovulation, and implantation.
• Wound Healing: Essential for the body's repair mechanisms.
• Solid tumors are limited in size (approximately 1 million cells) due to nutrient/oxygen dependence and lack of blood vessels.
• Tumors without vascularization remain small, undetectable, and dormant as microtumors.
• Tumors often experience hypoxia (low oxygen) due to limited blood flow.
• Warburg Effect: To adapt to hypoxia, cancer cells utilize anaerobic glycolysis, converting glucose to lactic acid instead of oxidative phosphorylation.
• The Warburg Effect produces ATP under low-oxygen environments and provides lactic acid for biosynthetic pathways that support rapid cell growth.
• Hypoxia-responsive genes are activated by cancer cells when stressed, supporting survival in oxygen-poor environments.

Hypoxia-Inducible Factor-1 (HIF-1)

• HIF-1 (a transcription factor) is crucial for adapting to low oxygen in cancer cells.
• It's a heterodimer consisting of HIF-1α and HIF-1β subunits.
• HIF-1α stability and nuclear translocation are dependent on oxygen levels.
• Under low-oxygen conditions, HIF-1α stabilizes and moves to the nucleus, activates genes, vital for survival in low-oxygen environments, including promoting angiogenesis and Warburg Effect.
• In normoxic conditions, HIF-1α is hydroxylated and degraded.
• HIF-1 triggers the transcription of VEGF, promoting angiogenesis.
• HIF-1 also upregulates Warburg Effect genes.

Angiogenesis in Tumors (VEGF and Receptor)

• Tumors release VEGF, a growth factor targeted to blood vessels, initiating and sustaining angiogenesis.
• VEGF binds to its receptor (tyrosine kinase) on endothelial cells to initiate a signaling pathway.
• VEGF activation of endothelial cells promotes cell proliferation and migration, directing blood vessel growth toward the tumor.
• Endothelial cells increase blood vessel production and extension due to high VEGF concentrations. Effective vessel formation supports tumor growth and metastasis.

VEGFR Gene Deletion Effect

• Deletion of VEGF receptor (VEGFR) gene inhibits tumor growth and vascularization as it blocks VEGF-mediated angiogenesis.
• Tumors in mice missing VEGFR show minimal growth compared to wild-type mice.
• This demonstrates the dependence of tumors on VEGFR to promote blood vessel growth for support.
• Tumor-induced blood vessels are disorganized and leaky compared to normal vessels, with fast-proliferating endothelial cells having fewer supporting cells.
• The leakiness provides a way to target drugs to tumors more selectively.
• The fragile vasculature facilitates cancer cell entry into the bloodstream, facilitating metastasis.
• Animal models, such as chick embryos, are used to study angiogenesis and assess anti-angiogenic drugs.

Anti-Angiogenic Therapies

• Monoclonal antibodies (e.g., Bevacizumab/Avastin): Bind VEGF, preventing signaling for new blood vessel formation.
• VEGF receptor blockers: Inhibit signaling through VEGF receptors, targeting tumor angiogenesis.
• Thalidomide: Shown to inhibit angiogenesis. Significant side effects limit its widespread use, especially during pregnancy.

Explore the role of angiogenesis in both tumor growth and embryonic development. This quiz covers the mechanisms by which blood vessels are formed and their significance in cancer therapy and embryo vitality. Test your knowledge on how VEGF influences these crucial processes.