Lecture 17 - Invasion and Metastasis Flashcards
Are most primary tumors lethal? What are metastases? Does size of tumor play a role?
Most primary tumors are not lethal. Metastases are formed by cells that have left the primary tumor. There is a strong correlation between tumor size and likelihood of metastasis.
What is the invasion-metastasis cascade? Describe the different steps.
1 - primary tumor formation 2 - localized invasion 3 - Intravasation 4 - Transport through circulation 5 - Arrest in microvessels in various organs 6 - Extravasation 7 - Fromation of a micrometastasis 8 - Colonization [macrometastasis]
What classfies a tumor as benign? What does localization imply? Why do cancer cells tend to get stuck?
Tumors are considered benign as long as they remain confined to the basement membrane.
Localized invasion does not necessarily mean that the basement membrane has been breached. It depends on the location and size.
Cancer cells can get stuck in the blood/lymphatic system since they are typically very large, and arteries & capillaries tend to constrict with age.
Describe how localized invasion occurs. What are the two ways tumors can get their nutrients from the vascular system?
First, cancer cells make room to grow. In order for this to occur, proteases are either released from cancer or stromal cells. Then, the ECM is chewed up making space.
Tumors can grow either around blood vessels to co-opt the blood supply in a sheet tumor or…. they can hijack the vascular network via angiogenesis.
What is intravasation? How do triads come into play?
In intravasation, cooperating cells (cancer, macrophage, endothelial) form triads which provide proliferative signals or release proteases to digest the ECM, breaking down vascular structures to make room and simplify invasion.
Why do many circulating tumor cells (CTCs) die during transport via circulation? Give three reasons.
State 3 strategies/methods of transport
1 - Anoikis
(programmed cell death in absence of pro-life signals)
2 - Loss of stromal mitogenic and tropic factors
3 - Shearing forces
Methods of transport:
1 - individual cells
2 - Platelet coated ball of cancer
3 - Unified phalanx (small clump of cancer cells)
What is extravasation? How does this occur?
Extravasation is the invasion of new tissues by transported cancer cells. The platelet ball technique can help cancer cells attach themselves to endothelial walls and invade, while the other techniques rely on getting stuck and releasing proteases to digest and invade.
Exactly how this works is not yet fully understood.
What is a micrometastasis? Why is it in a coma?
Micrometastasis is a small clump of cells that, due to a a high rate of metastatic inefficiency (most die off), are able to remain dormant for a very long period of time.
While you can detect them using antibodies, you just don’t know when they’ll come out of their coma or if they will even develop into a macrometastatic tumor.
The body is essentially playing the odds.
What is EMT and why is it necessary in metastasis? What does the cell lose/gain?
EMT or epithelial-mesenchymal transition, is when cells transform and many genes are reactivated to alter the cell to be better suited for transport.
The cell loses:
- cytokeratins and E-cadherins (tight-tight junctions)
[taken into the cell and lost]
-Epithelial type polarity (apical/basal in lieu of uniformity)
The cell gains:
- motility
- increased resistance to apoptosis
- proteases
What is MET and why is it necessary in metastasis?
What role does TGF-beta play in extravasation?
MET or mesenchymal-epithelial transition, is when cells transform and many genes are reactivated to alter the cell to be better suited for invasion.
Once the cell leaves the stromal environment and invades new tissue, the EMT signals cease and the cell reverts naturally via MET.
TGF-beta is an important contributor to invasivenes and the main driver behind MET. It is retained during the whole course of tumor progression.
pRb mutations remove cytotoxic elements of TGF-beta and leave it to induce proliferation. TGF-beta causes the release of PDGF (autocrine signal) and activates the NF-KB pathway.
What happens to the cell when it switches to the Mesenchymal state in relation to inhibitory proteins?
When switching to the mesenchymal state, the cell loses its inhibitory proteins and is constitutively turned on by its autocrine signalling loops.
This includes TGF-beta, canonical Wnts, and non-canonical Wnt.
This isn’t good at all for the host.
How to macrophages associate with EMT?
The recruitment of tumor associated macrophages increases the rate of EMT. The reciprocal interactions between cancer cells and macrophages increase invasiveness.
Where do the MMPs come from?
While some of the proteases are secreted by the cancer cells themselves, the majority are secreted by the stromal cells.
What do the small GTPases do for the cancer cells?
What other protein family induces cytoskeletal rearrangements?
Small GTPases increase the cancer cell motility via movement through cytoskeletal extensions (lamellipodia). The cells choosing this option are literally physically moving away from the primary tumor.
The Rho family of proteins is also helpful in rearranging the cancer cell cytoskeleton for motility.
What is the lymphatic system used for? Why is it relevant here?
Why do lymph vessels generally not penetrate any tumors?
The lymphatic system is used for draining interstitial fluid. Often you can find the first cancer cells that have broken off the primary tumor at the lymph nodes (indicator).
Lymph vessels form very poorly around tumors. They only form outside of the tumor, since they’d be crushed on the inside otherwise due to high saturation density. Hanging out on the periphery of the tumor, they catch the edge cells transition to EMT on the outside borders.
