lecture 7 - angiogenesis and metastasis Flashcards
What are the stages of cancer development?
Stage I - tumour is 1-4cm and has not spread outside of the primary organ
Stage II - tumour is 3-7cm - disease may be in lymph nodes or nearby tissues, but not in distant parts of the body
Stage III - Tumour is 3 to >7cm - disease can be in >1 lymph nodes or nearby tissue, but not in distant parts of the body
Stage IV - cancer has spread to distant parts of the body
What are the stages of the metastatic cascade?
1) Primary tumour growth (proliferation)
2) Angiogenesis
3) Detachment and invasion into the surrounding tissue towards the vessels
4) Intravasation into lymphatics/capillaries
5) Survival in the circulation
6) Arrest in new/secondary organ (small capillaries, adhesion to vessel wall)
7) Extravasation into the secondary tissue
8) Establishment of microenvironment
What is angiogenesis and what are three things tumours need to achieve in order to grow?
Angiogenesis is the growth of new blood vessels from pre-existing vessels
They need to change their metabolism, attract new blood vessels and co-opt new existing blood vessels
What is neoangiogenesis and what drives this process?
This is the growth of new blood vessels, specifically during tumour formation
Driven by hypoxic conditions
What is the angiogenic switch and what are some activators/inhibitors of angiogenesis?
The angiogenic switch is a balance between activators and inhibitors. When the number of activators outnumber the inhibitors, angiogenesis can occur.
Increased angiogenesis correlates with worse prognosis
VEGF is the main driver of angiogenesis, whereas endostatin, IFN-a etc., are inhibitors
What are the characteristics of tumour angiogenesis?
Uncontrolled expression of pro-angiogenic factors, disorganised vascular structure, low pericyte coverage (the blood vessel is therefore not very stabilised), increased microvasculature permeability (leakiness)
Vessels have low integrity due to high fluid pressure and lack of pericytes, so they can collapse
What are some generic types of anti-angiogenic therapies that can be used?
Inhibition of production of angiogenic proteins, neutralisation of proteins, inhibition of receptors for proteins
e.g. RTKIs, mABs (decoy receptors)
How can Bevacizumab (Avastin) be used as a treatment (side effects, susceptibility, etc.)?
This is a humanised monoclonal anti-VEGF-A antibody - neutralises VEGF-A
Cancers that are highly dependent on induction of angiogenesis by VEGF were the best responders to anti-VEGF agents (colorectal and renal cell carcinoma)
Side effects - high blood pressure, bleeding and coronary artery disease, rapid resistance to Avastin)
How can some cancers become resistant to Avastin?
Metabolic adaptation
Re-vascularisation by the expression of alternative angiogenic factors (bFGF, PDGF)
Co-option of normal peritumoural blood vessels and vascular mimicry
Blood flow alterations owing to vessel pruning and normalisation can improve blood flow
Anti-angiogenic therapy induces vascular regression, which leads to intratumoural hypoxia and selection of more invasive cancer cells that are resistant to anti-angiogenic therapy
What is EMT and how is it activated?
Epithelial to mesenchymal transition - cells become more fibroblast-like and have an increased motility/invasiveness + express mesenchymal markers
The TGFb pathway is a driver of EMT
SMADs can become activated in this pathway and translocate to the nucleus, acting as TFs and driving expression of ZEB1, SNAIL and TWIST
Autocrine signalling can also stimulate EMT - secreted factors from the microenvironment act in a paracrine fashion to induce EMT, in nearby carcinoma cells, by directly activating the expression of various EMT-inducing TFs
What is intravasation and how does survival in the circulation occur?
This is where cells enter the circulation - can transmigrate paracellularly through the endothelial cell junctions - remodelling of cell-cell junctions between endothelial cells is necessary
Leaky cell junctions - can squeeze themselves through
Circulating tumour cells (CTC) can survive by overcoming anoikis (cell death due to loss of attachment) - increase in survival signalling through other pathways
If an epithelial cell is alone in the environment, it will die as it does not receive any signals
Cells can extravasate using adhesion molecules such as selectins, CD44 and integrins
What are the four ways that cancer can spread?
- Transcoelomic: body cavity, penetrating peritoneal, pleural, pericardial or subarachnoid spaces (e.g. ovarian tumours to liver surface)
- Lymphatic spread: most common route for initial spread carcinomas (e.g. breast cancer)
- Hematogenous spread: favoured route of sarcomas and certain types of carcinomas tend to follow venous flow due to thinner walls of veins (e.g. colorectal to liver via portal vein)
- Canalicular spread: favoured by carcinomas through a small passageway (e.g. bile ducts, urinary system, subarachnoid space)
What are the two main theories for site-specific metastasis?
- First pass organ - tumour cells are carried through bloodstream and recolonise in next organ they encounter
- Seed and Soil hypothesis (Stephen Paget) – more important theory
- Provision of a fertile environment which supports the growth of the tumour cells
- Preparation of the pre-metastatic niche by myeloid-derived suppressor cells (MDSCs) and tumour exosomes
What are some therapies (generic) for treating metastatic disease?
Surgery, radiotherapy, chemotherapy, targeted therapy, hormonal therapy, immunotherapy and control of further metastases
What are some novel strategies for targeting the metastatic cascade stages?
- Metastatic colonization In addition to mutational events, tumour cells alter multiple signalling pathways in order to colonize a foreign organ + cross-talk with the microenvironment
(i) targeting angiogenesis Bevacizumab
(ii) chemokines which influence immune cell infiltration,
(iii) enzymes that modulate the microenvironment (e.g. MMPs, LOX inhibitors, senolytic drugs)
(iv) site-specific factors (RANKL) Denosumab
In development - Seeding invasion, extravasation, EMT
targeting tumour-tumour, tumour-ECM adhesion molecules, proteases (MMPs),
plasticity programs such as EMT
Dormancy (i) to keep cancer cells in the harmless dormant state,
(ii) to reactivate dormant cells to increase their susceptibility to anti-proliferative drugs, and
(iii) to eradicate dormant cancer cells.