Angiogenesis and Cancer

Tumours and Blood Supply

  • Tumours require a blood supply to grow and survive.
  • They typically achieve this by growing new blood vessels.

Normal Blood Vessel Development

  • Microvasculature: Small blood vessels, where most interactions with tumours occur.
    • Orderly structure: Composed of endothelial cells surrounded by a basement membrane, with pericytes and smooth muscle cells present.
  • Hemangioblasts: Pluripotent mesenchymal cells that differentiate into angioblasts (endothelial progenitor cells).
    • Angioblasts aggregate to form blood vessels during a process called vasculogenesis.
  • Differentiation: Endothelial progenitors develop into mature endothelial cells, forming primitive vascular tubes.

Angiogenic Gradient and Hypoxia

  • The angiogenic gradient is created by vascular growth factor signaling molecules from embryonic tissues under hypoxia (low oxygen levels).
  • This gradient attracts precursor cells to encourage new blood vessel formation in needed areas.
  • Pericyte Role: They migrate to new blood vessels; vascular pruning shapes the vessel network into an organized structure (arborization).

Angiogenesis vs. Vasculogenesis

  • Angiogenesis: Sprouting of new vessels from existing ones (most common in tumours).
  • Vasculogenesis: Formation of blood vessels from scratch (de novo).
  • Angiogenic switch: Process that stimulates angiogenesis by increasing VEGF levels.

Key Steps in Normal Angiogenesis

  1. VEGF Signaling: Initiates angiogenesis by stimulating endothelial cells, causing them to dissolve the basement membrane.
  2. Pericyte Dropout: Localized dissociation of pericytes promotes new vessel formation.
  3. Tip and Stalk Cells Formation:
    • VEGF influences differentiation of a leading tip cell.
    • Surrounding stalk cells proliferate under the tip cell's guidance, forming new blood vessels.
  4. Vessel Fusion and Maturation: New vessel sprouts fuse, mature, and establish a vascular loop, completing the angiogenic process once blood flow resolves local hypoxia.

Hypoxia and Cellular Response

  • HIF1⍺ Protein: A cellular sensor for hypoxia that drives VEGF expression.
    • In hypoxic conditions, it remains active due to lack of hydroxylation and subsequent degradation.

Tumour Angiogenesis and Characteristics

  • Tumour cells produce VEGF and other factors leading to uncontrolled angiogenesis.
  • Tumour vasculature is often disordered with:
    • Rough endothelial surfaces
    • Endothelial hypertrophy
    • Hyperpermeability
    • Disorderly branching patterns

Mechanisms of Tumour Vascularization

  • Angiogenesis: Main method for tumour blood supply.
  • Co-option: Tumours grow along existing blood vessels.
  • Vascular Mimicry: Tumours form vessel-like structures using ECM and tumour cells, rather than typical blood vessels.

Potential Angiogenesis Inhibition Strategies

  • Targeting various pathways involved in angiogenesis can be a therapeutic approach:
    • Disrupting tumour blood vessels.
    • Inhibiting VEGF signaling and HIF1⍺ activity.
    • Utilizing vascular disrupting agents in clinical practice.

Summary

  • Importance of understanding normal vascular development and tumour angiogenesis.
  • Hypoxia is a key trigger for angiogenesis in tumours, altering the typical controlled process seen in normal development.