Lecture 6 - Tumour microenvironment, invasion and metastasis Flashcards
What percentage of cancer deaths are caused by secondary tumours?
90%
What is the process of metastasis?
- Invasion into capilaries
- arrest in organs
- adherence to vessel wall
- extravasation
- metastasis
What cells are tumours made up of?
Many different ones but endothelial cells and pericytes definitely (blood vessels)
What are the features of cells in tumours?
- Biologically heterogeneous
- Contain genotypically and phenotypically diverse subpopulations as they have arisen from different places
How did Van Scott and Reinerston (1961) investigate heterotypic signalling?
- Took autologous transplantations of skin tumours
- Transplanted onto back
- Found that if transplanted with carcinoma-associated stromal cells they profliferated but with out they did not grow
What did Van Scott and Reinsterston conclude?
- Stromal cells required to support growth of tumour
- Signalling occurs between different cell types within same tumour
What is an example of crosstalk and feedback in tumours?
Mesenchymal stem cells in tumours secrete CCL5 in response to signals released by cancer cells.
CCL5 then acts on cancer cells stimulating invasive behaviour
How does malignancy arise and what is it’s implication?
Not in a cell-autonomous manner.
The invasion-metastasis cascade may be acquired without additional mutations beyond those that were needed for primary tumour formation
Why does analyses of tumour cell genomes only reveal part of the story?
Invasion metastasis cascade happens with only a few starting mutations and a lot of cross talk between cell types
How far from a vessel is hypoxic (oxygen under 2.5mmHg)
60 microns
How far from a vessel is anoxic? (no oxygen)
90 microns
What do recruited cells (responding to angiogenic factors from cancer) to promote angiogensis?
Release TNF-a and prostaglandins
What do endothelial cells recruited to the tumour do to promote angiogenesis?
Release PDGF and HB-EGF to attract pericytes and vascular smooth muscle cells to build up structure of vessels
What is the advantage of anti-angiogenic therapy?
Targetting genetically normal cells
What is an approved anti-angiogenic drug treatment?
Bevacizimab, an anti-VEGF-A antibody which reduces tumour growth
What is a possible explanation as to why anti-angiogenic drugs only moderately improve survival?
By producing a hypoxic environment you are inducing invasion
What are the 3 classes of cell adhesion molecules expressed on cancer cells?
Cadherins
Integrins
IgSF CAMs
What changes does altered adhesion result in?
- loss of attachment to other cells
- loss of attachment to ECM
- loss of anti-growth signalling
- facilitates migration
What is the epithelial to mesenchymal transition (EMT) due to?
Change in adhesion molecules
What usually happens in EMT?
During embryonic morphogenesis and wound healing signals from neighbouring cells trigger expression of TFs that promote EMT
How do cancer cells do EMT?
epithelial cell to cell adhesion molecule E-cadherin maintains quiescent state and suppresses invasion and metastasis
Cancer cells downregulate E-cadherin
How does cancer downregulate E-cadherin?
- Mutation of E-cadherin
- Transcriptional repressson
- Proteolysis of extracellular cadherin domain
What does cancer do at the same time as downregulating E-cadherin?
Upregulates adhesion molecules associated with mesenchymal cell migration such as N-cadherin
What changes with EMT?
Increased motility
Increased resistance to apoptosis
Enables invasion and metastasis
Dissolution of cell-cell junctions
