Lecture 10 - 12 Flashcards
What are the two kinds of inflammation?
Acute or chronic
What occurs during the resolution of an inflammation?
The levels of proinflammatory mediators and infiltrated immune cells decline
What is chronic inflammation?
It is caused by infectious or autoimmune diseases. It is a prolonged abnormal immune response that is not resolved by the normal feedback mechanisms
- associated with the development of 30% of malignancies worldwide
What is chronic inflammation thought to promote in tumours?
- tumour initiation, progression and metastasis by providing a tumour-supporting microenvironment
What is an important concept about metastatic spread?
Metastatic spread is responsible for ~90% of cancer-related mortality
What is responsible for metastatic spread?
Changes in genes controlling cell-cell and cell matrix interactions (eg., E-cadherin, integrins)
What is E-cadherin?
A transmembrane protein that mediates cell-cell interactions
What is tumour progression associated with?
- the loss of E-cadherin function and the transition to a more motile and invasive phenotype
- cell pseudopod movement
- requires the coordinated regulation of both E-cadherin-mediated cell-cell adhesions and integrin-mediated adhesions that contact the surrounding ECM
How is the regulation of E-cadherin and integrin dynamic?
Cells respond to external cues from the tumour microenvironment that regulate polarity, directional migration and invasion
How would a loss of cadherin junction occur?
E-cadherins are supported by p120, alpha and beta catenin. If any of the catenins lose their function, then there is a loss of cadherin junction
How does cadherin junctions protect the cell from cancer?
- protects from growth factors effecting the cell due to contact inhibition
- stays differentiated
What are integrins?
Heterodimeric cell-surface glycoproteins that serve to mediate cell-ECM interactions
- like cues from the extracellular environment to the actin cytoskeleton
What is EMT?
- epithelial to mesenchymal transition (EMT)
- a process normally involved in embryonic morphogenesis and wound healing/repair
- cells acquire ability to invade, resist apoptosis and to disseminate
- controlled by several TF (eg., Slug)
What is Slug?
- a zinc finger transcriptional repressor which down-regulates expression of E-cadherin
What does Slug do the cell?
- Causes a loss of adheren junctions and expression of matrix degrading enzymes, increased motility and resistance to apoptosis
What occurs if Slug expression was increased?
It induces tightly bound epithelial cells to break into a loose mesenchymal phenotype and maintenance of this phenotype enables metastasis of tumour cells
How was it determined that Slug suppresses E-cadherin transcription?
On a western blot:
- cells that had been less invasive in nature had large amounts of E-cadherin and little to no expression of Slug
- in more invasive cells, there was no E-cadherin and large amounts of Slug expressed
What three changes occur during tissue invasion and metastasis?
- Changes in genes controlling cell-cell and cell matrix interactions
- Upregulation of protease genes (eg. matrix metalloproteases)
- Down-regulation of protease inhibitors
Is genomic instability a product of being cancerous or a cause?
- cancer arises from the accumulation of multiple mutations in the same cell
- tumour cells must acquire an increased mutability
- results in the loss of p53 and DNA repair genes
What is the role of MSH2 and MSH6?
- MSH2: the protein that recognizes the mismatch
- MSH6: the protein that performs the repairs
What occurs if there are mutations in MSH2 and 6 that results in down regulation?
It will result in the loss of fidelity that is identified in cancer
What occurs if there is a double stranded DNA break repair?
- the loss is lethal to a cell
- apoptosis or necrosis
- chromosomal abnormalities
What are important proteins that if mutated can contribute to cancer?
Rad 51 (& 50), ATM, BRCA1 and BRCA2
How would a mutated ATM (eg. down-regulated)cause cancer?
- lack of ATM would decrease the phosphorylation of p53
- p53 would be unable to act on p21, Gadd45 and 14-3-3 which would result in S phase and M phase occurring.
What are the roles of BRCA1 and 2?
They act as scaffolds in assembling repair machinery
What are the differences between BRCA1 &2?
- BRCA1 is a large protein that allows other proteins to attach (including BRCA2). If knocked out, it is lethal as it is needed for DNA repair
- Rad50 is bound to BRCA1 and Rad51 is bound to BRCA2
What are the roles of Rad 50 & 51?
- both involved in double stranded DNA repair
- both allow other proteins to bind to it
- Rad50 binds to BRCA1
- Rad51 binds to BRCA2
Do normal cells prefer glycolysis or the citric acid cycle? What about cancer cells?
- normal tissues tend to use the citric acid cycle in aerobic conditions (90%), if undergoing hypoxia in anaerobic conditions then they use glycolysis (10%)
- cancer cells are more prone to using glycolysis despite high oxygen levels
What is the Warburg Effect?
Even in the presence of oxygen, cancer cells reprogram their energy metabolism to preferentially use glycolysis
What is the mechanism of the Warburg Effect?
- Ras is activated oncogenically
- With PTEN, Ras activates HIF1-alpha
- HIF1-beta binds to HIF1-alpha which allows them to enter the nucleus as a TF
- Glut1 is expressed
How do HIF1-alpha levels decrease?
- HIF1-alpha can be hydroxylated
- once hydroxylated, VHL (Von Hippel-Lindau factor (E3)) can bind HIF1-alpha
- results in the ubiquination of the complex
- negative regulation
If mitochondrial activity was decreased, how would this help a tumour?
- less HIF1-alpha available
- can not induce apoptosis
What is PET Scanning?
- Positron Emission Tomography (18 Fluorodeoxyglucose tracer)
- utilizes the reliance of cancer cells on glycolysis (glucose uptake) to generate images of the cancer
Why do cancers make the switch to glycolysis? Is there an advantage?
- One possible advantage is the glycolysis leads to an increase in anabolic substrates for lipid, protein synthesis, etc.
- Decreases the reliance on the mitochondria
Cancer cell growth is limited to areas surrounding blood vessels, What is the result of this?
- decrease of oxygen consumption
- increase in growth radius
- reduced use for mitochondrial function to conserve oxygen located in cells not near the blood vessel
How does the tumour microenvironment effect (fibroblast, endothelial cell and immune cells) the acquired traits?
- fibroblasts contribute to the support that allows cancer cells to grow large
- endothelial cells, stimulated by VEGF, allows cancer cells to enter the blood stream
- immune cells with their surveying and editing has allowed the cancer cell to avoid the editing and will seed eslewhere
