Tumour Biology Flashcards
(32 cards)
What is metastasis?
It is a tumour deposit discontinuous with the primary tumour
Metastasis is a multifactorial process
Metastasis are the major cause of death from a malignant disease because of its difficulty to treat
Key properties of a metastatic cell
Detachment from the primary mass
Invasion of the ECM e.g. Basement membrane
Adhesion to endothelium
Extravasation
Avoidance of the immune system
Colonisation of and survival in secondary organ
What happens in detachment - loss of adhesion?
Adhesion molecules are downregulated in metastatic cancer cells
E-cadherin is common, indicating that loss of cell attachment is important for invasion.
Loss of adhesion is not just about cells detaching from each other what else happens with e-cadherins
When e-cadherin is lost beta-catenin is normally adhered too so when e-cadherins detaches it goes into the cytoplasm and is degraded in normal situations by the proteosome in combination with APC, when APC is mutated beta-catenin cannot be removed thus accumulates in the cytoplasm working in combination with transcription factors to induce EMT and cell cycle genes are influenced.
Loss of e cadherins and APC 2 genes cooperating to lead to proliferation and metastasis
What is required for tissues invasion?
Require degrading enzymes - matrix metalloproteinases required to degrade the ECM. They are normal enzymes involved in tissue remodelling.
May be secreted by tumour cells, but also by the strong which is important in tumour progression
How is the stroma abnormal in cancer
Contributes to the process of tumour invasion, tumour produces soluble factors to activate the stroma
Secreting the MMPs
Cells in stroma become activated - fibroblasts to secrete MMPs
MMPs allow the break down of the basement membrane which allows the stroma and tumour cells to interact
The tumour cells make up approximately 1% of the tumour mass.
What is the epitheilal-mesenchyme transition
This regulates invasion and metastasis
EMT is a normal process usually occurring during wound injury
Epithelial cells become spindle-like like mesenchyme
Migrates to site if damage
The reverts to epithelial morphology
This process is abnormally acquired by metastatic cells. And is used to acquire a secondary tumour site.
What regulates EMT?
Transcription factors,
Slug, snail, twist zeb1/2
Induced by TGF beta and RTK
What are the different kinds of invasion?
Ameboid - moment as a single cell in epithelia form
Mesenchymal after process of EMT
How does adhesion and extravasation occur?
As tumour cells enter small slow by size restriction and adhere through receptor ligand interactions
Travel in blood and lymph
Similar to inflammation - use identical ligand receptor adhere and extravasate like neutrophils
Outcome once colonised at secondary site
The outcome is not certain. It is dependent on the availability of growth factors and the environment to support the cells.
Patterns of metastatic spread is explained by?
Non random
Seed and soil hypothesis spread is governed the nature of the cancer cell (seed) and its new environment (soil)
Anatomical and mechanical routes - determine spread
E.g. Colorectal cancer going to the liver via the portal system .
New field: CTC
Circulating tumour cells, detect what is means for the future of the patient. Detect prognosis.
Acts in support of the seed hypothesis
What is the metastasis 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
How does hypoxia drive invasions and metastasis?
Early in cancer development tumour cells are dependent on existing blood supply but as tumour gets bigger needs more nutrients
All cancers are hypoxic O2 is lower than required to sustain normal cells
Hypoxia initiates angiogenesis by HYPOXIA INDUCIBLE FACTOR -HIF
Normoxia - HIF interacts with pVHL causes degradation by ubiquitation.
In hypoxia - no interaction with pVHL. HIF alpha and HIF beta interact and induce gene expression of VEG for example.
Differences between cancerous vasculature and normal vasculature
Tumour vasculature is chaotic and leaky, not like normal vasculature, there are lots of holes to help with tumour migration facilitating survival and spread
They have partition lumen and multiple intercellular openings
Normal vessels: have a smooth cobblestone appearance.
Other mechanism tumours change to overcome the hypoxic environment
‘Glycolytic switch’
Alters the glucose metabolism from mainly by oxidative phosphorylation but to glycolysis predominantly. More anaerobic processes
Upregulate glucose intake more receptors and metabolism inc no glucose transporters and no of metabolites - super glucose user to feed cells energy requirements
This allows them to outcompete the other cells more uptakers. So they die less cells to compete with
Creates and acidic environment which other cells cannot survive so induces more cell death.
- micro natural selection
Characteristics of malignant tumours
Malignant cell growth
Metastasis
Glycolytic switch
Angiogenic switch
Malignancy is associated with loss of:
Density dependent inhibition of growth - once normal cells reach and finite density thy stop growing, cancer cells do not stop growing and divide a lot, a tumour that exhibits density dependent inhibition is benign
Contact inhibition of movement- normal cells move away from each other cancerous cells do not they cluster forming a tumour
Anchorage dependence - normal cells need contact with substratum for growth, cancer cells do not
Adhesion- normal cells are firmly adhered to each other and to their basement membrane, cancerous cells loss of adhesion to ECM and to other cells- mobile and can metastasise
Tumour development
Multi step Mutations occur leading to Apoptosis bypass Decrease in CAMs Cell cycle deregulation Increase motility and mobility
What type of tumour exhibits density dependent inhibition of growth
Benign tumour
A tumour which does not exhibit density dependent inhibition of growth is
A malignant tumour
Process of metastasis
The tumour invades beyond normal tissue boundaries - MMP to ECM
It detaches from primary tumour mass - down reg of CAMs
Tumour enters vascular or lymphatic endothelium
EMT travel
Slow down as vessels get smaller role along the vessel become attached and extravasates
Establishes itself in the new environment local tissue invasion and angiogenesis
EMT
Cancer cells abnormally acquire this process,
Normally cells involved in repair and the immune system can change from epithelial like to mesenchymal in order to travel to the area
Cancer cells acquire this process and use is migrate
It regulated by TGF and RTK acting in slug to decrease epithelial markers and increase mesenchymal ones
