M6L3 Tumour angiogenesis

  • Types of angiogenesis

    • Sprouting

    • Vessel cooption

    • Intussusceptive angiogenesis

    • Vascular mimicry

  • Growth of new vessels from pre-existing vessels - used for growth, invasion, metastasis

  • Angiogenic factors (VEGF) can induce immunosuppression and chemo/radioresistance

  • Steps in angiogenesis: hypoxia stimulates pericytes to separate off, BM breaks down and tip cell differentiates and migrates, stalk cells produce sprouting…

    • VEGF induces DLL4 —> Notch signalling induces lateral inhibition (closes off the vessels)

  • High angiogenesis correlated with poor outcomes

  • Many isoforms of VEGF receptors

  • Fruquitinib - potent, highly selective small molecule inhibitor of VEGFR1/2/3 tyrosine kinases for cancer therapy

  • Tumour abnormal vasculature - blind ends, temporary occlusions, breaks in vessel walls, AV shunt, red blood cell accumulation…

  • Oxygen diffusion distance is 40-140um

  • Under normoxia prolyl hydroxylases hydroxylate HIF1a and vHL ubiquitinate it for degradation, but under normaxia HIF1a is stabilised, goes to the nucleus and binds HIF1b and activates HIF1 responsive genes

  • 26 gene hypoxia response profile can be measured using RNA sequencing and related to patient outcomes

  • Other cancer pathways can interact with HIF even in the absence of hypoxia

  • Multiple cell types are involved in angiogenesis - including lyphoangiogenesis (VEGFR3), stroma can also make VEGF, bone marrow cells can differentiate into endothelial cells, myeloid cells (VEGFR1)…

  • Coagulation —> cell adhesion —> proteolysis

  • Various other proangiogenic molecules other than VEGF

  • Various other angiogenic inhibitory proteins

  • Lens of the eye does not have blood vessels due to anti angiogenic factors

  • Angiogenic switch

  • Vascular normalisation occurs as tumour vasculature develops, which is the ideal window for drug delivery

  • Patterns to bevacizumab resistance - primary vascular resistance, vascular response/metabolic adaptive resistance, vascular response/cell death

    • Upregulation of genes involved in key cancer pathways (hypoxia and metabolism, immune response and cytokines, angiogenesis…) after bevacizumab suggest possible mechanism of resistance

  • In vivo CA9 inhibition synergises with bevacizumab

  • Vessel beds are tissue specific and have different functions, which may underly tumour characteristics depending on the site of occurence

  • Endothelial metabolism can also be a target of treatment

    • ECs on tip use glycolysis

    • Stalk cells use fatty acid oxidation

  • Acidosis and hypoxia can have direct effects on immune cells as well as indirect physical effects

  • Anti-angiogenic therapy + immunotherapy implications: anti-angiogenics may exacerbate hypoxia and increase immune resistance, or it could cause blood vessel normalisation which is a good window to deliver immunotherapy - hard to predict

  • PDL1 upregulated in tumours relapsing for anti-angiogenic therapy and IF-g increases PDL1 during antiangiogenic therapy

  • Anti-PDL1 sustains response to VEGF blockade and enhances vessel normalisation during anti VEGF

  • Hypoxia activated prodrugs synergise with immunotherapy