Chapter 9: Metastasis (Secondary details) Flashcards
Put the following steps of tumor metastasis in the correct order:
Metastatic colonization, angiogenesis, intravasation, extravasation, transport and invasion.
Invasion - intravasation - transport - extravasation - metastatic colonization - angiogenesis.
How do we know that E-Cadherin acts as a tumor suppressor (please think of three ways this has been/can be researched)?
- Anti-E-Cadherin antibody treatment resulted in invasive behaviour in collagen gels.
- Transfection of E-cadherin cDNA/ORF in metastatic epithelial cells rendered the cells non-invasive.
- Mutations in the extracellular domains or gene promotor methylation has been documented in gastric and prostate carcinomas.
What will Ras signaling result in (after activation of FAK and SRC by integrins)?
Invasion, proliferation and survival of tumour cells.
What is depicted in this picture (so briefly explain what process occurs here)?
In this picture tumor-associated macrophages-assisted intravasation is depicted. On the bottom right you can see that carcinoma cells can interact with macrophages (i.e. immune cells) through CSF-1 and EGF.
True or false:
Only few tumor cells that enter the blood stream (CTCs) can form a metastatic colony.
True
True or false:
Endothelial selectins are differentially expressed on vessels of different organs. (What does this explain?)
True, it explains organotropism.
With metastatic colonization tumor cells reside in a new organ microenvironment. What is an important condition for metastatic colonization to occur?
That the tumor cells have the ability to adapt to the new organ microenvironment.
If you look at this picture, you can see that most late DTCs can already show up in tumor mass within months while most early DTCs only show up in tumor mass over decades. What is a reason for this?
As mentioned in the deck about the main part of the lecture: DTCs remain dormant in new tissue because of two reasons, either:
- the tumor cell doesn’t yet have the capacity (epigenetic changes, mutations etc.) to be malignant and grow into a tumor.
- the microenvironment of the organ doesn’t have the right conditions for the DTCs to be able to grow.
We also know that late DTCs are more mature tumor cells then early DTCs. For this, it makes sense that late DTCs can be activated much earlier in the right conditions then early DTCs (because early DTCs need a lot more time to mature).
During research exosomes from highly metastatic melanoma cells are injected intravenously. What two targets do these exosomes have?
They move towards to lymph node and bone marrow.
During research exosomes dervied from highly metastatic melanoma cells are injected intravenously. What do these exosomes stimulate in the bone marrow?
In the bone marrow exosomes increase activated MET (receptor tyrosine kinase) in bone marrow-derived cells. These cells migrate to lungs or lymph nodes to stimulate angiogenesis, invasion (increased permeability and inflammation) and metastasis of tumor cells.
During research exosomes from highly metastatic melanoma cells are injected intravenously. What do these exosomes stimulate in the lymph nodes?
The exosomes stimulate the lymph node in ECM remodeling and proangiogenesis
During research exosomes from highly metastatic melanoma cells are injected intravenously. So to summarize: what will injection of these exosomes result in?
It will result in increased ECM remodeling, tissue inflammation, vascular permeability and thus promotion of pre-metastatic niche formation.
What dictates exosomes to their target (or: what determines the organotropic metastasis of exosomes?)
Integrins on the surface of exosomes.
What can be concluded when bone-tropic tumor cells (BoT) are injected via the tail vein of mice after lung-tropic exosomes (LuT) are injected in mice retro-orbitally?
That lung-tropic exosomes prime the lung for metastasis and when the bone-tropic tumor cells are injected via the tail vein, these cells are redirected to the lung to metastasize there (((while they are actually bone specific, thus this data suggests that organotropic tumour exosomes prepare pre-metastatic niches potent enough to facilitate metastasis even for tumour cells poorly capable of colonizing these sites))).
What other specific organ exosomes display the same kind of behaviour as the lung and bone-tropic exosomes? Explain this process briefly.
Pancreatic cancer exosomes, they initiate pre-metastatic niche formation in the liver. These exosomes contain MIF (macrophage inhibitory factor) that induce liver Kuppfer cells to release TGFβ. TGFβ activates fibronectin production bij hepatic stellate cells which induces the migration and arrest of tumor-supporting bone-marrow derived cells in the liver, initiating the pre-metastatic niche.
How can tumor exosomes promote lung pre-metastatic niche formation?
Tumor exosomes activate TLR3 (Toll-like receptor 3) in alveolar epithelial type II cells. Activation of TLR3 results in production of chemokines that recruit neutrophils to the lungs to promote pre-metastatic niche formation.
Several studies conducted research about extracellular vesicle-mediated phenocopying of metastatic behaviour. They used injection of purified concentrated exosomes, therefore evidence of actual functional horizontal transfer of exosomes in vivo was lacking. A recent study used something to visualize exosome transfer and its effect on metastasis in vivo. What did they use?
They used the Cre-lox system. Here, a migratory tumor cell releases a vesicle with Cre in it. Vescile uptake leads to Cre-induced red-to-green conversion and phenocopying of metastatic behaviour.
What happens when tumor cells with normal expression of PTEN get disseminated to the brain?
There’s loss of PTEN (tumor suppressor protein) caused by exosomal microRNA. It primes the brain for metastasis outgrowth. (This can be suppressed by blockade of astrocyte exosome secretion).
