Lecture 3 - Tumour Biology - The Nature of Cancer Flashcards
What is matastasis?
What is invasion?
metastasis = the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and then colonise normal tissues elsewhere in the body invasion = the direct migration and penetration by cancer cells into neighbouring tissues
What are the 5 mechanisms responsible for metastasis?
- loss of adhesion
- production of enzymes such as metalloproteinases which degrade the ECM
- entry into blood and lympathatic vessels
- extravasation
- colonisation
Describe the processes in detachment/loss of adhesion
- adhesion molecules down regulated in metastatic cancer
- downregulation of E-cadherin is common (adherens junction)
- beta-catenin attaches E-cadherin to actin in cell, loss of E-cadherin can increase the amount of free beta-catenin
- This free beta-catenin moves into cytoplasm where it is normally degraded by the proteosome (APC gene required)
- however a mutation in APC can leave free beta-catenin
- this has oncogenic properties
Explain how detachment/loss of adhesion can be an example of gene cooperation to promote metastasis
loss of two genes together
APC and Ecadherin –> cancer
Describe 2 processes that facilitate tissue invasion x2
- enzymes
- requires degrading enzymes - metric metalloproteinases
- these are normal enzymes usually involved in wound healing
- may be secreted by tumour cells, but also by stroma e.g. fibroblasts
- tumour cells secrete factors that activate stromal cells which produce enzymes that degrade BM - epithelial-mesenchymal transition
- epithelial cells become mesenchymal (flatter, spindle shaped)
- this facilitates cell migration
- regulated by SLUG and SNAIL transcription factors
What are the two kinds invasion?
collective invasion = sheets, strands and clusters
single cell motility = ameboid and mesenchymal
Describe the process of adhesion to epithelium and extravasation
as tumour cells enter small capillaries they slow by size restriction and adhere through receptor ligand interactions
- similarities to neutrophils
Cancer spread is non-random
What are the two hypotheses as to why?
- Paget = ‘seed and soil’ hypothesis, certain cancer types only go to where the right microenvironment is
- Ewing = metastasis occurs purely by anatomic and mechanical routes
What is the importance of circulating tumour cells?
CTC mediated metastasis
Metastasis in an ongoing process so there are always cells present in the circulation
- important tool for diagnosis and assessment of treatment responses
What is meant by the metastatic niche?
tumour cells secrete factors which act systemically, modifying the local environment and recruiting host immune cells, facilitating the appropriation of these sites for later colonisation
What initiates angiogenesis?
What is this regulated by?
hypoxia
hypoxia induced factor (HIF), in normoxia interaction between HIF and pVHL causes degradation of HIF
HIF = a transcription factor that leads to transcription of pro-angiogenic factors such as VEGF
Describe structure angiogenesis of the tumour cell
chaotic, poorly strucutured, this further allows cells to enter blood vessel systems
Describe the ‘glycolytic switch’
tumours use glycolysis as major route to energy generation, they up regulate glucose uptake and metabolism
by increasing glucose transporters and activity of hexokinase enzymes
This switch is induced by hypoxia, this allows tumour cells to outcompete normal cells for scarce glucose supply, surrounding cells die, allowing tissue invasion
How does glycolysis affect the tumour microenvironment?
lactate acidifies it
- cancer cells more resistant to acidity than normal cells
- allows tissue invasion
