Lecture 1

Why is angiogenesis needed?

  • Angiogenesis is the formation of new blood vessels from pre-existing ones, crucial in various physiological and pathological processes, including development, wound healing, and cancer.

Consequences of angiogenesis in therapy

  • The presence of new blood vessels can affect drug delivery and treatment efficacy in cancer therapy.

Presentation Overview

  • Key topics discussed in the presentation:

    • Why is tumor angiogenesis required?

    • The role of Vascular Endothelial Growth Factor (VEGF) in tumor angiogenesis.

    • The impact of insufficient blood vessels leading to hypoxia in tumors.

    • Definition and consequences of hypoxia.

    • The regulatory role of hypoxia on VEGF expression.

    • The association of hypoxia with therapy resistance.

    • Anti-angiogenic therapy approaches.

Role of Blood in Tumors

  1. What is the role of blood?

    • Blood is essential for supplying oxygen and nutrients to tissues, and in the context of tumors, it is crucial for their growth and metastasis.

  2. How do tumors respond to reduced blood flow?

    • Tumors may adapt by increasing angiogenesis to restore blood supply, leading to enhanced growth and potential therapy resistance.

Vascular Endothelial Growth Factor (VEGF)

  • VEGF plays a significant role as an inducer of tumor angiogenesis.

  • A study by Dvorak (2003) highlighted the effect of adenovirus expressing VEGF on angiogenesis in nude mouse models.

Insufficient Blood Vessels and Hypoxia

  • Hypoxia, or low oxygen concentration, occurs when blood vessels in tumors are insufficient to meet the demands of rapidly proliferating cancer cells.

  • Definition of hypoxia:

    • Hypoxia refers to low oxygen availability in tissues, specifically conditions where partial pressure of oxygen (pO₂) falls below 9 mmHg.

Understanding Tumor Hypoxia

  • Hypoxia is exacerbated in tumors due to:

    • High metabolic rates of tumor cells.

    • Uncontrolled cell proliferation.

  • Tumor cells situated more than 180 µm from blood vessels typically experience necrosis due to insufficient oxygen supply.

Consequences of Hypoxia

  • Hypoxic regions contribute to therapy resistance observed in cancer treatments.

    • Therapy resistance types:

    • Chemotherapy resistance

    • Radiotherapy resistance

    • Resistance to targeted molecular therapies.

Hypoxia Inducible Factors (HIFs)

  • Low oxygen levels lead to the stabilization and activation of Hypoxia Inducible Factor proteins, specifically HIF1α and HIF2α.

  • In normoxic conditions, these proteins are subject to constant degradation, but hypoxic conditions lead to their accumulation and activation.

Mechanism of HIF-Dependent Gene Regulation

  • HIFs dimerize with HIF1β (ARNT) in the nucleus and regulate numerous genes involved in aspects like:

    • Proliferation and survival (e.g., cyclins, IGF-BP2, EPO).

    • Metabolism (e.g., glucose transporters, LDHA).

    • Angiogenesis (e.g., VEGF, PAI-1).

    • Invasion and metastasis (e.g., SDF-1, E-Cadherin).

Angiogenesis and Its Induction by Hypoxia

  • Hypoxia is essential not only in pathological conditions but also during normal development. Hypoxia-Inducible Factor deficiencies can result in embryonic lethality.

  • Key pro-angiogenic proteins affected by hypoxia include:

    • VEGF

    • Angiopoietin 1 and 2

    • Fibroblast growth factors

    • Matrix metallo-proteinases (MMPs)

Hypoxic Tumors and Resistance to Treatment

  • Hypoxic tumor regions lead to:

    • Poor patient outcomes and increased resistance to chemotherapy and radiotherapy, with genetic instability as a contributing factor.

  • Factors contributing to chemotherapy resistance in hypoxic tumors include:

    • Drug supply, flux, and consumption dynamics affecting drug delivery.

    • The chaotic organization of tumor blood vessels hampers drug penetration.

Influence of Hypoxia on Radiotherapy

  • In hypoxic conditions, the effectiveness of ionizing radiation is diminished due to altered DNA damage responses.

  • Ionizing radiation creates DNA damage that can be repaired in the presence of oxygen, while hypoxia reduces this damage, leading to resistance by preventing effective treatment.

Gene Regulation Alterations Due to Hypoxia

  • Tumor cells in hypoxic conditions exhibit altered DNA damage response mechanisms, leading to increased mutation rates and instability, further driving malignant progression.

Anti-Angiogenic Therapy

  • Bevacizumab, a monoclonal antibody targeting VEGF, shows efficacy in treating various types of cancers, including:

    • Colorectal cancer

    • Lung cancer

    • Kidney cancer

    • Brain cancer

Conclusions

  • Key conclusions drawn from the study include:

    • VEGF as a crucial regulator of angiogenesis.

    • Insufficient blood supply contributing to tumor hypoxia.

    • Hypoxia fosters conditions of increased therapy resistance due to metabolic demands and poor perfusion.

Recognition of Hypoxia Research

  • Research surrounding hypoxia has been awarded the Nobel Prize for Medicine in 2019, highlighting its significance in understanding cancer biology.