Lesson 12 Angiogenesis Pathway and Treatment

• CRICOS Provider 00115M
• MED3ATA Cancer Module
• Christine Hawkins
• Lecture 12.1: Inducing Angiogenesis
• Hallmark – part 1: feeding tumours
• Commonwealth of Australia
• Copyright Act 1968
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• Throughout these cancer lectures: Brown text is examinable, Grey text is just for your interest: not examinable
• Raza A et al, American Journal of Hematology, 85: 593-598, 2010
• New vessels


  • Often not properly stabilised
• Low O2 leads to Hypoxia induced genes
• Hypoxic tumour cells produce Vascular Endothelial Growth Factor (VEGF)
• VEGF (and other factors) stimulate

  1. Destabilisation of nearby blood vessels

  2. Sprouting of new branches towards the tumour
• Cancer cells are genomically unstable and respond to selective pressures by rapidly evolving, making them difficult to target therapeutically as resistance often develops
• Hypoxic tumour cells promote angiogenesis via VEGF
• Tumour vasculature is formed by non-cancerous endothelial cells which are genomically stable and uniform, perhaps easier to target than cancer cells
• The permeability of tumour vasculature contributes to metastasis
• This step typically not achieved in tumour vasculature
• The relatively low blood pressure within tumour vessels hinders penetration of chemotherapy drugs and oxygen into tumours, reducing chemotherapy and radiotherapy efficacy
• Drugs that prevent neo-angiogenesis


  Could stop cancers growing and prevent metastasis
• Lee WS et al Experimental & Molecular Medicine 52: 1475–1485, 2020
• Drugs that normalise tumour vessels

  Could boost chemotherapy/ radiotherapy efficacy
• Jain RK, Science 307: 58-62, 2005
• Judah Folkman: 'Solid tumors can grow to visibility only if they can vascularize themselves. Therefore, the mechanism by which tumor implants stimulate neovascularization must be well understood before therapy based upon interference with angiogenesis can be devised.'
• Jain RK, Nature Medicine 9: 685–693, 2003
• Antibodies that block the interaction between VEGF and its receptors reduced tumour growth in mice and normalised the architecture of tumour vasculature
• Bevacizumab


  Humanised anti-VEGF monoclonal antibody developed for clinical use
• Tumour vasculature


  • Higher density of blood vessels than normal tissue
  • Blood vessels are poorly connected with lots of dead ends
  • Slower blood flow than in normal vessels
  • Tumours have poor lymphatic drainage
  • Higher interstitial pressure (more liquid within tumour tissue) so fluid seeps out of the tumour
  • Can limit penetration of chemotherapy drugs into tumours
  • Weaker walls, more leaky than regular vessels
• Bevacizumab only very slightly improves outcomes compared with chemotherapy alone
• Morikawa S et al Am J Pathol 160: 985-1000, 2002
• Bevacizumab is approved in Australia for various advanced/metastatic/recurrent solid cancers in conjunction with chemotherapy
• Pericytes


  • Tightly wrapped around normal vessels
  • Disorganised and looser association with tumour vessels
• Bevacizumab is very expensive for the marginal survival benefit it provides, but is taxpayer-subsidised in Australia
• Green = endothelial cells, Red = pericytes
• Hashizume H et al, Am J Pathol 156: 1363-1380, 2000
• Anti-angiogenic drugs


  Drugs that inhibit the enzymatic activity of the VEGF receptor kinase
• Like bevacizumab, anti-angiogenic drugs only confer marginal survival benefits
• Endothelial cell lining of tumour vessels

  • Irregular and contains gaps
• Sorafenib, an anti-angiogenic drug, significantly improved median overall survival in patients with previously untreated hepatocellular carcinoma compared to placebo