Week 7: Metastasis and Invasion Flashcards
1
Q
Epithelial-Mesenchymal Transition (EMT)
A
- The stage where the tumour cells break away from the primary tumour
- Allows epithelial cells to lose connections with neighbouring cells to then break away from the primary tumour
- The cell undergoes reprogramming
2
Q
Proteins that increase in abundance in EMT
A
- N-cadherin
- Vimentin
- Fibronectin
- Snail1 +-2
- Twist
- Goosecoid
- FOXC2
- Sox10
- MMP-2, -3, -9
- Integrin ab6
3
Q
Proteins that decrease in abundance in EMT
A
- E-cadherin
- Desmoplakin
- Cytokeratin
- Occludin
4
Q
Proteins with increased activity in EMT
A
- ILK
- GSK-3B
- Rho
5
Q
Proteins that accumulate in the nucleus
A
- B-catenin
- Smad-2 or -3
- NF-kB
- Snail
- Slug
-Twist
6
Q
Epithelial markers
A
- E-cadherin
- Claudins
- Occludins
- ZO-1
- Desmoplakin
- Cytokeratins
7
Q
Mesenchymal markers
A
- N-cadherin
- Fibronectin
- Collagen 1/3
- Snail
- aSMA
- Vimentin
8
Q
The ECM
A
- The ECM not only acts as a supporting structure/scaffolding for cells, but it also acts as a cage
- Its 3D matrices make it difficult for normal cells to move through as they only possess 2D movement, which are 2 completely different things
- Once cancer cells become motile, they can acquire adaptations to move through the ECM or to alter it for ease of motility
9
Q
Meatrix metalloproteases (MMPs) + Tissue Inhibitors of Metalloproteases (TIMPs)
A
- MMPs are not normally expressed in epithelial cells, but is expressed in fibroblasts, and MMPs function to degrade the ECM
- TIMPS are a family of MMP inhibitors
- Most MMPs can only be inhibited after they are activated but some MMPS can bind to TIMPS in their inactive forms
- There are 4 members of TIMPs that can inhibit all MMPs
- Cancer cells can exploit fibroblasts to degrade the ECM or possess these enzymes themselves
10
Q
Metastasising with the circulatory system
A
- Different cancers have different prefences for their metastatic sites
- These preferences are a result of the circulatory system
- In some cases the cancer will settle in the organ it first passes on, but some tumour cells can circulate for hours before settling
- Lymph vasculature is also a common route for metastasis
11
Q
Challenges of surviving in the bloodstream as a cancer cell
A
- Shear forces
- Velocity-associated pressure
- The presence of immune cells
12
Q
Different cancers also have very different behaviours/tendencies/propensities for metastasis
A
- Examples:
+ Lung cancers are typically aggressive + spread early
+ Colon cancers generally spread late
+ Some cancers metastasis occurs late or rarely
13
Q
Metastasis by body cavity
A
- Some cancers can spread from organ to organ within these cavities
- Example: Peritoneal cavity contains
+ Liver
+ Stomach
+ Intestines
+ Pancreas
+ Ovaries - Tumours that develop in the above organs can spread to other organs without using any vasculature
- Production of ascites by primary tumours helps to spread cancer cells to other organs
14
Q
Metastatic colonosation
A
- Metastasis can end in colonisation or cell death, most likely cell death as metastasis is a long and inefficient process for cancer cells
- <0.02% of tumour cells entering the circulation resilt in the formation of a new tumour at a distant site
-The rate-limiting step appears to be proper establishment + colonisaiton of new tumours at distant sites, not the dissemination to these sites
15
Q
The metastatic niche
A
- Once cancer cells arrive at the distant site, they are generally incapable of significant proliferation due to an absence of necessary environmental cues
- Often these metastatic niches, ECM, secreted factors + surrounding cell types are all different than the primary site, so the tumour can remodel the environment to better suit its growth
- Some primary tumours may secrete pre-metastatic niche factors prior to arrival to make metastasis more likely
16
Q
Treating + Preventing metastasis
A
- Due to its complexity, there are many potential therapeutic targets
- Many of the therapeutic targets teo date have been MMPs + components of the EMT process
- So far there is a lot of potential targets but not a lot of success, with no current approved therapies for treating/inhibiting metastasis
17
Q
Why have the treatments failed?
A
- Robustness + adaptability of the cancer cells, where inhibiting one signalling pathway can activate an alternative pathway
- More than 1 MMP/protease is usually in play, so there are blocking only a few may not significantly slow down matrix degradation
- Blocking ECM leads to a switch in movement type ie mesenchymal to ameboid movement, which doesn’t require ECM degradation
- Usually at that point its too late to treat
18
Q
The future for metastatis therpay
A
- Targeting cancer stem cell niche
- Targeting pre-metastatic niche
- Earlier diagnosis of cancer to allow the treatment before metastasis can occur
- Combination therapies
- Activating the immune system
- Continued research into the molecular + cellular mechanisms regulating metastasis to identify new therapeutic targets
