Metastasis Flashcards
What is metastasis?
Spread of cancer cells from place of origin in the body
What happens to the chance of metastasis as tumour size increases?
Chance of metastasis increases
Is metastasis a regular or rare event?
Rare
Describe the mechanism of invasion + metastasis
1) Primary tumour formation leads to angiogenesis
2) Localised invasion
= Tumour cells start moving towards blood vessels
3) Intravasation
= Tumour cells breaks pass endothelial cell barrier
= Interact w/ blood components (e.g. platelets, lymphocytes)
= A lot of cancer cells are lost due to these interactions
4) Transport through circulatory system
= Can get stuck in capillaries that are highly vascularised
5) Extravasation
= Cancer cells migrate out of blood vessel
6) Formation of micrometastasis
= Need environment suitable for proliferation
= Small tumour produced
7) Colonisation - Formation of macrometastasis
Is metastatic efficiency high or low?
Low
Cancer cells are lost at each stage of metastasis
Death rates in micro metastasis can overcome proliferation -> preventing formation of macrometastasis
Name the 3 types of secondary tumours
Single, dormant cancer cells
Micrometastasis
Active, angiogenic metastasis
Is tumour dormancy different or the same in different tumour types?
Different
What other system besides circulatory can metastatic cells travel through?
Lymphatic system
Describe the “seed and soil” theory
Tumours need to have the right microenvironment to grow
Micrometastasis in certain tissues
What are the problems w/ the “seed and soil” theory?
Doesn’t explain ALL tumour metastasis
Contralateral metastasis = rare (why only 1 kidney/breast but not the other?)
How can cancer cells move from epithelial tissue -> mesenchymal tissue (blood + connective)?
Epithelial-mesenchymal transition (EMT)
= Lose epithelial phenotype
= Gain mesenchymal phenotype
Describe EMT model
Epithelial state
= Contains E-cadherins -> link cells together
= E-cadherin linked with plasma membrane via cytoplasmic tail
= Cytoplasmic tail linked w/ beta-catenin which is linked w/ alpha-catenin
E-cadherin releases beta-catenin
Beta-catenin translocates into nucleus + binds to TFs
-> mesenchymal change
What evidence supports EMT?
Cellular changes
Western blots
Loss of epithelial markers = E-cadherin = beta-catenin = alpha-catenin = cytokeratin
Gain of mesenchymal markers
= Fibronectin
= Vimentin
= N-cadherin
Change also associated w/ expression of twist (transcription factor)
How do primary tumours + secondary tumours have the same histopathology?
EMT may be reversible (depending on stromal signals)
Mesenchymal-epithelial transition (MET)
Allows secondary tumours to stay static + grow
Name the 2 forms of metastasis in bone
Osteolytic = bone (Ca deposit) breakdown
Osteoblastic = bone overgrowth
What type of cancer initiates osteolytic metastasis?
Breast cancer
How does breast cancer initiate osteolytic metastasis?
Secrete PTHrP (parathyroid hormone related peptide)
- > Activates osteoclasts by inhibiting osteoperigin (OPG = inhibitor of osteoclasts)
- > Osteoclasts digests bone
- > Release growth factors from stroma which goes to tumour cells
Describe the metastasis + drug resistance model
As secondary tumour is formed from DTCs, few cells become drug resistant
Under targeted therapy, drug-sensitive cancer cells express factors (therapy-induced secretome) that fight back
- > Accelerate growth of drug-resistant cells
- > Supports survival of drug-sensitive cells
Drug-resistant cells left can cause relapse
What are heterogeneous disseminated tumour cells (DTCs)?
Cancer cells that have left the primary tumour + survived in the circulation to land in a distant organ
