Angiogenesis and cancer treatment Flashcards
What are the functions of angiogenesis?
- blood vessels supply oxygen, nutrients, remove waste and allow immune surveillance
- angiogenesis is essential for organ growth in the embryo and repair of wounded tissue in the adult
- abnormal angiogenesis leads to disease:
- insufficient vessel growth (stroke, MI)
- excessive vessel growth (cancer, inflammatory disorders)
What are the 3 types of angiogenesis?
- developmental/ vasculogenesis = organ growth
- normal angiogenesis = wound repair placenta during pregnancy, cycling ovary
- pathological angiogenesis = tumour angiogenesis, ocular and inflammatory disorders
What are some pro and anti-angiogenic factors?
pro-angiogenic
- VEGF, PDGF, TGF-alpha, MMPs
anti-angiogenic
- thrombospondin 1 and 2, TIMPs, angiostatin
What is the angiogenic switch?
an imbalance between stimulus and inhibitors
- balance is shifted so stimulus is excessive resulting in malignant, ocular and inflammatory disorders
What is tumour hypoxia?
- hypoxia is a strong stimulus for tumour angiogenesis
- hypoxia - low oxygen tension < 1% O2
- increases with increasing distance from capillaries
- activates genes (VEGF, GLUT-1) involved in angiogenesis, tumour cell migration and metastasis
What are the characteristics of abnormal vessels in tumours?
- leaky
- heterogenous
- tortuous serpentine
- irregular branching
- abnormal shunts
- poor drug delivery - less sensitive to chemoradiation
Describe transcriptional regulation of tumour angiogenesis
- HIF - hypoxia inducible factor
- transcription factor regulates hypoxia induced gene transcription
- heterodimer, HIF-1a and HIF-1beta subunits =
- HIF-2a
- HIF-1/2a levels are tightly regulated by O2 and are degraded in normoxia, but stabilised in hypoxia
Describe VEGF siganlling
- VEGF is the main component binds VEGFR-1 and VEGFR-2 with VEGFR-2 having the predominant role
- neuropilins (NRP1, NRP2) are VEGF co-receptors but can also signal independently
- VEGF-B has restricted angiogenic activity eg in heart
- VEGF-C and VEGF-D involved in vasculogenesis and lymphangiogenesis
VEGF signalling pathways
- VEGF regulates several endothelial cell functions -eg, proliferation, differentiation, permeability, vascular tone, and production of vasoactive molecules
- upon ligand binding, the receptor tyrosine are phosphorylated, allowing the receptor to associate with and activate a range of signalling molecules:
- PIK3 = leading to PKB activation and cell survival
- PLC- g leading to cell proliferation, vasopermeability and angiogenesis
- MAPK cascade via Raf stimulation leading to gene expression and cell proliferation
What are the types of blood vessel recruitment?
a) sprouting angiogenesis - most widely described and accepted
b) vasculogenesis - vessel formation by endothelial progenitor cells
c) intussusception - splitting of pre-exisiting vessels into two daughter vessels
d) vessel co-option - cancer cells grow around and co-opt existing vasculature
e) vascular mimicry - cancer cells become incorporated into the vessel wall
f) tumour SC to EC differentiation
molecular basis of sprouting angiogenesis I
- angiogenic stimulus
- quiescent vessel dilates
- tip cell selected
- pericyte detachment (ANG-2)
- loosening of EC junctions (VE-cadherins)
- increased vascular permeability
- degradation of basement membrane
- cell migration
molecular basis of sprouting angiogenesis II
- tip cell navigates in response to guidance signals
- adheres to ECM via integrins
- stalk cells behind tip proliferate, elongate and form a lumen
- sprouts fuse to establish perfused neovessel
- stabilisation of vessel of by pericyte recruitment
- myeloid cells (tumour cells associated macrophages secrete angiogenic factors)
molecular basis of sprouting angiogenesis III
- fusion of branches and re-establishment of quiescence, lumen formation and vessel perfusion
- cell junctions tighten
- deposition of basement membrane
- maturation of pericytes
Describe metastatic renal cell carcinoma therapy
- prior to 2005 IL-2 was the only FDA approved drug for advanced RCC
- since 2005, 8 new targeted therapies
- 2 classes of inhibitors:
- inhibitor of angiogenesis (anti-VEGF)
- mTOR pathway
What are the targeted anti-angiogenic therapies?
- Anti-VEGF = avastin
- receptor tyrosine kinase inhibitors = sunitinib, sorafenib
- mTOR - everolimus, temsirolimus
