Chapter 9: Metastasis (Book, main) Flashcards
Spreading can be either monoclonal or polyclonal and the pattern of spreading can be either linear or branched. What’s the meaning of monoclonal, polyclonal, linear spreading and branched spreading?
- Monoclonal -> being seeded by one cell or subclone.
- Polyclonal -> being seeded by two or more subclones.
- Linear spreading -> from primary tumor to metastasis.
- Branched spreading -> one primary tumor seeding two or more other metastases.
(e. = cross-seeding in the picture)
What is cross-seeding?
Subclones can be seeded from other metastases. So not only can a primary tumor metastasize to another organ. But the metastase can form new metastases.
What are the steps of metastasis?
Invasion, intravasation, transport, extravasation and metastatic colonization.
Different cells ((tumor stroma ->) fibroblasts, mesenchymal stem cells or immune cells) can secrete certain factors that can induce EMT. What factors can be secreted by the tumor stroma?
HGF, EGF, PDGF and TGF-b all induce EMT in neighboring tumor cells via their specific receptors (MET kinase receptors (EGFR, PDGF-R and TGFR).
One of the transcription factors that is activated for induction of EMT is Snail. How does Snail act?
Snail binds to E-box sequences in epithelial genes (such as in the promotor region of the E-cadherin promotor) and recruits Polycomb repressor complex. This leads to histone modification and epigenetic regulation to repress gene expression (E-cadherin holds cells in place).
Another transcription factor that is highly activated for induction of EMT in cancers is Twist. What happens when Twist is inhibited?
It results in the loss of several steps of metastasis, including intravasation.
What is the function of CAMs and cadherins?
They mediate homotypic (same cell type) and heterotypic (different cell types) cell recognition. They hook cells into place extracellularly (a. in the picture)
Cadherins are calcium-dependent transmembrane glycoproteins. How do cells stay hooked to each other via cadherins?
Cadherins interact via catenins (b. in the picture)
(catenins can also bind to transcription factors and induce gene expression in the nucleus)
You should already know that integrins are responsible for cell-ECM contact. For metastasis, the cell must be freed from the contact it has with the ECM. Integrins receptors are heterodimers made up of a range of α and β subunits that mediate cell-ECM contact and intracellular signal transduction. What is the function of the α and β subunits?
The recognition of the different components of the ECM, for example collagen or fibronectin, depend on the α and β subunit composition.
Many ligands for integrin receptors contain three-amino acid sequence of Arg(R)-Gly(G)-Asp(D) that is involved in integrin binding. What happens upon ligand binding?
The integrins cluster in the membrane and affect the cytoskeleton through interaction with actin-binding proteins and specific kinases such as FAK.
What is the function of FAK and how does it fullfil its function?
FAK mediates cell motility through recruitment of Src and activation of the RAS pathway.
Integrins also have a role in anoikis (apoptosis triggered in response to lack of ECM ligand binding and loss of cell adhesion). How is anoikis achieved?
Integrins without suitable ECM ligand recruit caspase-8 to the membrane and trigger apoptosis.
(Already discussed in lecture): What proteases are important in degrading a path through the ECM and stroma?
Serine proteases and MMPs (MMPs can cleave extracellular domain of E-cadherin and contributes to the loss of cell-cell junctions).
MMPs are also important in intravasation because they can also cleave other proteins residing on the outside of cells. Because of this, there’s careful regulation of these proteins. How is this regulated?
They are synthesized as latent enzymes (zymogens) and require proteolytic cleavage to be activated. They are also regulated by inhibitors called TIMPs.
Transport through the bloodstream is “one-way”. Tumor cells travel singly or as clumps with platelets, called emboli, in the direction of blood flow. Why are these embolies present?
Because they may protect the tumor cells from sheer forces and immune cells inside the bloodstream.
