MB6 - Angiogenesis

Angiogenesis

formation, maturation and differentiation of new blood vessels from pre-existing vessels

provide O₂ and nutrients to cell and carry away CO₂ and waste

an example of a natural angiogenesis process is menstruation

Tumour angiogenesis

not programmed, depends on local signals

VEGF

Vascular endothelial growth factor

secreted by blood vessel and binds to VEGFR on endothelial cells stimulating the growth of new vessels

Issues with new vessels

• Disorganised vascular structure

• Low inter-endothelial cell junctions

• Low pericyte coverage

• Increased microvasculature permeability (leakiness)

• Low integrity vessels, can collapse

• Low perfusion

How do we control angiogenesis

Through angiogenic switch via growth factors/ cytokines and inhibitors

Angiogenesis activators

VEGF

PDGF (platelet derived GF)

bFGF (basal fibroblast GF)

all downregulated by p53

Angiogenesis inhibitors

endostatin

angiostatin

thrombospondin

all upregulated by p53

p53 in cancer

p53 function lost

cant downregulate the activators

more angiogenesis

more blood supply with O₂ and nutrients

cancer grows and thrives

Anti-angiogenic therapies

Monoclonal antibodies

• “mops up” excess VEGF

• VEGFR inhibitors

Decoy receptors

• “mops up” excess VEGF

Receptor tyrosine kinase inhibitors

Example of monoclonal antibody drugs

• bevacizumab - binds to VEGF

• ramucirumab - binds to VEGFR

Example of decoy receptor drugs

aflibercept - binds to VEGF

Example of receptor tyrosine kinase inhibitor drugs

• sorefenib

• sunitinib

Thalidomide as an anti-angiogenesis drug

inhibits phosphorylation of AKT which is crucial for the downstream signalling of wide range of growth factors such as, VEGF, FGF-2 and HIF-a

Stages of Cancer

I: tumour is 1-4cm and localised

II: 3-5cm and may have spread into the lymph nodes/ nearby tissue but not further

III: tumour is 3-7cm and disease can be in > 1 lymph nodes or nearby tissue but not in the distant parts of the body

IV: spread to distant parts of the body

Metastatic cascade

• Primary tumour growth (proliferation)

• Angiogenesis

• Detachment and invasion into the surrounding tissue towards the vessels

• Intravasation into lymphatics/ capillaries

• Survival in the circulation

• Arrest in new/ secondary organ (small capillaries, adhesion to vessel wall)

• Extravasation (leave blood cells) into the secondary tissue

• Establishment of microenvironment

  • death

  • dormant if not proliferating rapidly them chemo may not be killing it properly

  • proliferating

EMT

Epithelial to Mesenchymal Transition

The great majority of life-threatening cancers occur in epithelial tissues

• In order to acquire motility and invasiveness carcinoma cells must change their phenotype from a more epithelial to mesenchymal phenotype EMT (epithelial to mesenchymal transition

Epithelial vs Mesenchymal

Epithelial cells

• cytokeratin expression,

• adherence junctions (E-cadherin)

• epithelial cell polarisation

• epithelial markers: E-cadherin, b-catenin
  

Mesenchymal

• fibroblast-like shape

• increased motility an invasiveness

• secretion of proteases (MMPs)

• mesenchymal markers: N-cadherin, vimentin

TME to choose anticancer drugs

Tumour Microenvironment - factors to consider

Macrophages

• M1 is pro-inflammatory antitumour → preferred

• M2 is less inflammatory and and protumour

Cancer associated fibroblast

• secreting factors that digest extracellular matrix to let the cancer cells escape

Cancer cells

Cancer stem cells

Secondary Cancer sites

First place it spreads to

Breast adenocarcinoma

• bone, brain, lung and liver

Prostate adenocarcinoma

• bone

Lung small cell carcinoma

• bone, brain and liver

Skin cutaneous melaoma

• bowel, brain, lung and liver

neuroblastoma

• bone, liver and skin

colorectal carcinoma

• liver, bone and lung

Theory for site-specific metastasis

First pass organ theory

• tumour cells are carried through bloodstream and recolonise in next organ they encounter

• didnt make complete sense

Seed and Soil hypothesis theory

• Provision of a fertile environment which supports the growth of the tumour cells

MDSC

Myeloid-derived suppressor cells

sent out to prepare the pre-metastatic niche

Requirements for metastatic niches

• Compatible adhesion molecules on endothelial cells

• Appropriate growth factors and ECM

• Selective chemotaxis

• Physical features

Ways to target the metastatic cascade

Matrix metaloprotinase inhibitors (MMPIs)

• most 1st gen have poor efficacy and high toxicity

• not specific

VEGFR/MET(EMT receptor) inhibitor

Targeting metastatic recolonisation (MET)

Dormant disseminated micrometastic tumour cells (DTCs)

• reactivate dormant tumour growths and kill via chemotherapy/using other therapy

Targeting bone resorption

• metastases to bone can upregulate RANKL to activate osteoclasts and cause bone resorption.   a- RANKL Denosumab

Pamrevlumab

DTC - reactivating by fibrosis

Cabozantinib

EMT receptor

Denosumab

Target bone resorption - downregulates RANKL to inhibit osteoclasts and decrease bone resorption