Tumour Angiogenesis, Invasion, and Metastasis Flashcards
What are the characteristics of malignant tumours?
- Growth: unlimited growth; not self-limited as in benign tumours - as long as adequate blood supply is available.
- Invasiveness: Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs.
- Metastasis: Spread of tumour cells from the primary site to form secondary tumours at other sites in the body.
Describe the sequential process of metastasis
- Transformation: The cell starts to proliferate until it reaches a certain size
- Angiogenesis: New blood vessels start to form around the tumour.
- Motility and Invasion: Then, the tumour escapes through blood vessels and lymphatics. It forms multi-cell aggregates.
- Embolism: It embolises in the lungs primarily, and other organs where it then metastasis.
- Arrest and Adherence: It arrests to form micrometastases and arrests in the capillary bed.
- Extravasation into organ parenchyma
- In response to the microenvironment, the tumour will undergo further cell proliferation and angiogenesis.
- Then forms further metastases.
Summarise the key steps in cancer progression
- There are extensive mutagenic and epigenetic changes followed by clonal expansion.
- Then, the cell undergoes angiogenesis to overcome the limitations that hypoxia proposes.
- There is the transformation from epithelial to mesenchymal allowing for intravasation and extravasation.
- Then, the colonization of target organs which will allow the expansion of the micrometastases.
- Finally, the release of the metastatic cells that have required the ability to colonise.
What is angiogenesis?
Angiogenesis is the formation of new blood vessels from pre-existing vessels.
What is vasculogenesis?
Vasculogenesis is the formation of new blood vessels from progenitors.
What are the three types of angiogenesis and what sort of growth do they form/used in?
- Developmental/vasculogenesis which leads to organ growth.
- Normal angiogenesis occurs in wound repair, the placenta during pregnancy and cycling ovary, and other physiological processes.
- Pathological angiogenesis occurs in tumours, ocular and inflammatory disorders (affect macular degeneration). This is when you do not want new blood vessel growth.
Difference between breast cancer in situ and invasive human breast cancer
In situ breast cancer is not well vascularised therefore it is unable to grow beyond a certain size without its own blood supply (tumours aren’t able to grow beyond about 1-2mm(3) without their own blood supply). However, in invasive human breast cancer; there are lots of cell types so there is a loss of rigid structures. This will increase the blood vessel network.
Describe the process of tumour angiogenesis
- Tumours become hypoxia as they move away from the nearby capillary.
- When they become too big, they do not have enough oxygen or nutrients so an angiogenic switch occurs. The tumour secretes factors that promote the growth of vessels.
- Angiogenic factors such as vascular endothelial growth factor (VEGF) is secreted from the tumour. This is a cytokine that diffuses and initiates the endothelial cell near the capillary to migrate and proliferate.
- When enough proliferation occurs, a vessel network will form around the tumour = blood vessel network.
- Depending on the genomic instability, the tumour cell can be heterogenic which causes changes in the oncogene causing other cells to mutate so there are lots of offshoots.
- A cell can escape the primary tumour through the vascular network leading to metastatic spread.
How is hypoxia a stimulus for tumour angiogenesis?
As the distance between the tumour and the capillary increases, there is lower oxygen tension. Therefore areas of the tumour will have a reduction in oxygen and become hypoxic. Hypoxia activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis. Such as GF being released e.g. VGEF.
Give examples of angiogenic factors secreted by tumour cells to stimulate directional growth of endothelial cells
- Vascular Endothelial Growth Factor (VGEF)
- Fibroblast Growth Factor-2 (FGF-2)
- Transforming Growth Factor-Beta (TGF-Beta)
- Hepatocyte growth factor/scatter factor (HGF/SF)
What ways are angiogenic factors released?
- Secreted by tumour cells
- Stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases
What is the function of matrix metalloproteinases (MMPs) enzymes?
Facilitate invasion and give the enzymatic capacity to spread the tumour.
How is the VGEF signalling cascade activated?
- VGEF binds to the tyrosine kinase receptor causing dimerization.
- It activates the pathways that stimulate cell growth, gene expression, etc. Ras, MAPK, PkB, and PkC
- These are all in operation in the endothelial cell following VEGF binding. It allows for cell proliferation and vasopermeability, Angiogenesis, Cell Survival, and Gene expression.
What are the mechanisms the tumour cell adopts for motility and invasion?
- Increased mechanical pressure caused by rapid cellular proliferation
- Increased motility of the malignant cells (epithelial to mesenchymal transition) - switches to a different cell and becomes de-differentiated - fibroblast cells.
- Increased production of degradative enzymes by both tumour cells and stromal cells.
How does the epithelial-mesenchymal transition occur?
- The epithelial-like cells express cell-cell adhesion molecules and other cell apparatus so it keeps the epithelial features.
- The genes that make them epithelial cells become downregulated e.g. adhesion molecules and actins
- There is an upregulation of cell pathways to change into a mesenchymal cell such as P13K (targeted by a lot of therapies at the moment). This drives the expression of genes e.g. fibronectin.
