8- Metastasis Flashcards
What is metastasis?
- process of dissemination of a tumor from its site of origin to a distant organ, where it ultimately establishes one/more colonies
What is a primary tumor?
- tumor that first formed/ from where tumor cells originally detached
What is a secondary tumor?
- tumor mass that forms in organ different from one of origin
- can be 1 or multiple, generally multiple at later stages of disease
= Metastastic colony/ Metastatic nodule/ Secondary nodule
What are the steps of the invasion-metastasis cascade?
- referring to epithelial tumors (most steps same in others)
- Localized invasion > loss of basement membrane/ stroma invasion
- Intravasation > getting into vessel
- Transport through circulation
- Extravasation > leaving vessel
- Seeding > formation of a micrometastasis/ minimal residual disease
- Colonization > formation of a macrometastasis
What happens in localized invasion?
- initial invasion involves degradation of basement membrane
- followed by degradation of the extracellular matrix within the stroma
> breaks barriers/ releases growth factors - epithelial cells can produce proteases themselves or co-opt stromal cells (macrophages/ fibroblasts) to be able to invade/ get into stoma
- epithelial localized invasion typically occurs as a group of cells
= Collective Invasion
What happens in intravasation?
- same features that allow localized invasion allows vessel invasion
> production of proteases/ help from stromal cells (macrophages)
What is the triad formed by cancer cells in intravasation?
TMEM = tumor microenvironment of metastasis
- apposed to macrophage/ endothelial cell
What are the 4 serious challenges of transport through circulation?
- Lack of substrate-dependent survival signals > Anoikis
- Lack of growth/ survival factors initially provided by stroma
- Hydrodynamic shear forces from blood flow (in small vessels)
- Immune system > NK cells
How do tumor cells adapt for transport through circulation?
CTCs = circulating tumor cells
- pinch off large amounts of cytoplasm > to become smaller
- avoid capillaries > travel via arterial-venous shunts
- form microthrombi > coat themselves with platelets
- EMT > acquire a plastic/ flexible cytoskeleton (like RBCs)
Why do CTCs coat themselves with platelets?
- when enter vessel > shear stress promotes platelet adhesion
- platelets reduce deformation by helping distribute force on CTCs membrane more homogeneously
> preserves the integrity of the CTC - enhances attachment to vessel wall/ reduces rolling motion of CTCs
> possibly favours extravasation
What happens in extravasation?
- depends on complex interaction between cancer cells/ vessel walls (2 possibilities)
1. Immediate extravasation as individual cells
2. Platelet-assisted extravasation at later times (w/w-out proliferation)
What is seeding?
- establishment of small tumor cell clumps (micrometastases) at distant sites from the primary tumor
- micrometastases referred to as “minimal residual disease” in clinic
What can determine patient prognosis?
Minimal residual disease
- micrometastases are not the cause of death, but ↑ risk of developing macrometastases > ↑ risk of death
What is metastasis dormancy?
- capacity of tumor cells to remain viable as single cells/ clumps for long periods of time
- dormant cells not dividing > not targeted by treatment
What is metastasis inefficiency?
- failure of individual dormant cells to form micrometastases
- failure of micrometastases to form macrometastases (tumor mass)
What is colonization?
- progression of micrometastases > large/ clinically detectable macrometastases
What is the rate-limiting step of the invasion-metastasis cascade?
Colonization (last/ most complex step)
Do all cells in a tumor have the same ability to metastasize?
no > metastasis heterogeneity
- # of metastases produced by tumor proportional to # of CTC, but most CTCs do NOT form metastases (less than 0.01%)
- not all cells in primary tumor have same ability to disseminate
What is the most accepted model of cancer metastasis
Progression model
- suggests cancer is biologically heterogeneous
- metastatic capacity acquired rarely in a subpopulation of cells through genetic mutations
Although the progression model is most accepted, what is other evidence suggesting about cancer metastasis?
- primary tumor gene signature predicts metastasis > Initiation model
- cell of origin dictates metastatic behaviour (environment has role)
If there are not many mutations, how do tumor cells acquire ability to metastasize?
- evolution of cancer in cooperation with TME
- tumor microenvironment has a key role in metastasis cascade
What is plasticity?
- tumor cells change phenotype highly influenced by microenvironment
- REactivate EMT via reciprocal tumor-microenvironment interactions
What is EMT?
= Epithelial to mesenchymal transition
- process of cellular plasticity where epithelial cells lose their epithelial morphology/ acquire mesenchymal characteristics
What are some general features of EMT?
- loss of microvilli
- basal membrane disassembly
During EMT, what features are lost/ gained?
Epithelial Features (lost)
- tight cell-cell adhesions/ tight junctions (E-cadherin expression)
- static (non-motile) > non-invasive
- apical-basal polarity
Mesenchymal Features (gained)
- no cell to call adhesion
- motile > invasive (gain capacity of locomotion)
- upregulation of N-cadherin expression
- front-rear polarity
- fibroblast-like shape
- stem-cell characteristics (resistance to therapy/ self-renewal)
What are 3 mechanisms of E-cadherin loss in invasive tumors? (E > N)
- transcriptional repression by EMT-promoting factors
> Twist/ Snail/ Slug - epigenetic gene silencing by gene promoter methylation
- mutations that alter the reading frame (truncated protein)
What is a possible link between obesity/ metastasis?
- adipose tissue in secondary organs may promote MET
What is required for EMT/ invasion/ metastasis?
- constant communication between tumor/ microenvironment
What induces EMT?
- paracrine action of growth factors produced by stroma (TGF B)
How do EMT-TFs act in a pleiotropic fashion?
- repress epithelial genes/ induce mesenchymal genes
- promote self-renewal/ drug resistance
What is the take-home message for tumor metastasis?
- EMT TFs have pleiotropic cellular effects
> genetic mutations are not the only driving force of metastasis
What is the seed/ soil hypothesis?
- pattern of metastasis is NOT random/ can not simply be explained by mechanics of blood flow
> preferential colonization of specific organs
What is the take-home message on metastasis tropism?
- preference of specific type of tumor to colonize specific organs is driven by a combination of factors
> pattern of blood circulation
> presence of a favourable environment in target organ (seed/soil) - specific gene expression patterns in tumor cells
- organ-specific growth is driven by mutual interaction between tumor cell/ organ microenvironment
