Chapter 9: Metastasis (Lecture, main) Flashcards
Name cells that are involved in metastasis.
Tumour cells, endothelial cells, macrophages, neutrophils, T cells.
Name components of the basement membrane.
Laminins, type IV collagen, proteoglycans
Why is spread of cells throughout the body lethal?
It can result in interference with organ function when metastasis causes physical obstruction or competes with normal cells for nutrients and oxygen.
What is the definition of organotropism in regard to metastasis?
Organotropism is the attraction of cancer cells to particular organs.
How can most cases of organotropism be explained? What is an exception of this explanation?
By the directionality of the blood flow. Only metastasis from kidneys to thyroid can’t be explained by the directionality of the blood flow.
What is the seed and soil hypothesis (-Paget 1889)?
That the seeds of a plant (i.e. metastatic cancer cells) are carried in all directions but they can only live and grow if they fall on congenial soil (i.e. tissue that has the right conditions for metastatic growth).
A pre-estalished niche is tissue that provides the right conditions for tumour cells to grow. What is an example of a pre-established niche and why?
The bone marrow, the cells that create bone marrow are called osteoblasts. Bone formation is done through a process called remodelling. The bone marrow contains a lot of (different) growth factors and through the process of remodelling, these growth factors can be secreted. These growth factors can be used by cancer cells in order to grow.
So in order for metastatic tumour cells to grow at a metastatic place, a niche has to be established. These can be either already present (pre-established) or still need to be formed (pre-metastatic niche formation). What happens during pre-metastatic niche formation?
The cancer cells of the primary tumour release several systemic factors that act upon the future pre-metastatic niche to make this site more suitable for cancer cells to reside.
Just have a look at this picture of pre-metastatic niche formation. She didn’t discuss it in any detail the lecture..
Ok
What is one thing to keep in mind in the process of tumor metastasis?
That tumors are highly heterogeneous. This means that tumour cells consist of multiple subclones with different mutations and epigenetic alterations. This also means that there are different patterns for tumors to metastasize.
The different steps in tumor metastasis:
- Invasion - 2. Intravasation - 3. Transport (blood, lymph) - 4. Extravasation - 5. Metastatic colonization - 6. Angiogenesis
Explain these processes.
- Invasion = cancer cells penetrate the basement membrane and expand their growth into surrounding tissue.
- Intravasation = the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel
- Transport (blood, lymph) = cancer cells get transported through the blood or lymph nodes.
- Extravasation = cancer cells exit the blood or lymph vessels and enter other tissue elsewhere
- Metastatic colonization = at the secondary cancer site, metastatic cells survive and proliferate to form metastases within this site.
- Angiogenesis = the tumor forms blood vessels to maintain itself.
What is an important step in invasion during tumor metastasis?
Epithelial-mesenchymal transition (EMT)
Describe how the process of epithelial-mesenchymal transition (EMT) can be activated.
Cells of the stroma release EMT-inducing signals such as TGFb and HGF. They mostly bind to kinase receptors (TGFbR or MET receptor) on tumor cells. Signal transduction occurs which activates transcription factors, which then induce transcription of several proteins like N-cadherin and MMPs.
During epithelial-mesenchymal transition (EMT) epithelial cells can change into quasi-epithelial cells, quasi-mesenchymal cells and at last mesenchymal cells. Describe how these phenotypes help with invasion or intravasation/extravasation.
Proteins like N-cadherin and MMPs act as an EMT signal. Epithelial cells change into quasi-epithelial and quasi-mesenchymal cells (partial EMT). These cells facilitate motility and invasion into stroma. When they change into the mesenchymal cells, they facilitate intravasation and extravasation.
What molecules are needed during invasion for:
- Cell-cell contact
- Cell-ECM contact
- ECM degradation
- Cell-cell contact –> Cell-adhesion molecules
- Cell-ECM contact –> Integrins
- ECM degradation –> Proteases
What is the difference between a αvβ3-negative tumour and a αvβ3-positive tumour?
If the αvβ3-negative tumour detaches itself from the ECM it will undergo anoikis (due to the lack of ECM ligand binding and loss of cell adhesion). If the αvβ3-positive tumour is detached from the ECM, it can survive due to its anchorage independence. Integrin αvβ3 can still activate SRC and with that Ras signaling.
Name the difference between a normal blood vessel and tumor blood vessel regarding:
- branching pattern
- pericytes
- endothelial cells
- basement membrane
- a normal blood vessel has a hierarchal branching pattern while a tumor blood vessel has a unorganized branching pattern
- the normal blood vessel is covered by pericytes while the tumor blood vessel has loss of pericytes.
- In the normal blood vessel endothelial cells are polarized and aligned while in tumor blood vessels there’s loss of endothelial cell interconnection.
- in normal blood vessels the basement membrane is alinged and normal while in the tumor blood vessel it’s dispersed and abnormal.
After intravasation of cancer cells they will be transported in lymph or blood vessels. What can be suggested based on the size of a tumor cell (relatively larger then normal cells) in regard to the capillaries?
This is called the concept of first-pass organ. Tumor cells are larger than 10 um while most capillaries have a diameter of 8 um. From here it can be suggsted that a large proportion of tumor cells get trapped in the first capillary bed they encounter.
Fill in: Breast cancer typically spreads to the … (1) because it passes the …. (2) and gets trapped in the first capillary bed here.
- Lungs
- superior vena cava (and also lymphatic vessels)
- Many tumor cells in metastasis have an epithelial phenotype, what is needed for disseminated tumor cells (DTCs) in order to metastasize and colonize to a new organ?
- Epithelial tumor cells in the primary tumor ‘undergo’ intravasation in order to circulate in the blood. What is needed for these cells to be able to circulate in the blood?
- Mesenchymal-to-epithelial transition (MET)
- Epithelial-to-mesenchymal transition (EMT)
In this picture you can see the different stages of disseminated tumor cells (DTCs). There’s a difference between early and late DTCs, what is this difference?
Early disseminated tumor cells are tumor cells that metastasize from a pre-invasive lesion at a primary organ site. Late disseminated tumor cells are tumor cells that metastasize from an established primary tumor.
How can early disseminated tumor cells (DTCs) generate an early pre-metastatic niche (EPDN)?
By crosstalking with different normal cell types (like osteoclast, fibroblast, immune cells, endothelial cells). These niches can either be dormancy-supportive or growth-supportive.
What is a systemic factor that is involved in recruitment of bone marrow cells? What is special about this factor?
Exosomes, they contain small RNAs (make sure you get the picture).
What dictates exosomes to their target (or: what determines the organotropic metastasis of exosomes?)
Integrins on the surface of exosomes.
