Week 2 Flashcards
What is metastasis?
Spread of tumour to- and growth at- ectopic sites, via blood, lymphatics, intra-epithelial route, or trans-coelomic
What is invasion?
Growth by infiltration and destruction of surrounding tissues
What is the tissue of origin of carcinoma?
Malignant tumour derived from epithelial cells
What is the tissue of origin of sarcoma?
Malignant tumours derived from mesenchymal cells
What is the tissue of origin of melanoma?
Malignant tumour derived from neural crest cells
What is the tissue of origin of leukaemia?
Malignant tumour derived from circulating WBCs
What is the tissue of origin of lymphoma?
Malignant tumour derived from lymphatic system
Describe the basement membrane (BM):
- delineates epithelial or endothelial tissues
- secreted by basal epithelial cells/endothelial cells
- a layer of extracellular matrix (ECM)
- fibronectin, type IV collagen, laminin, etc
- a barrier to spread (esp. carcinoma cells)
What events makes up the metastatic cascade?
local invasion -> neovascularisation/angiogenesis -> detachment -> intravasation (into blood or lymph) -> transport -> lodgement/arrest -> extravasation -> growth at ectopic site -> local invasion
What are the main properties of metastatic tumour cells?
- reduced cell-cell adhesion
- altered cell-substratum adhesion
- increased motility
- increased proteolytic ability
- angiogenic ability
- ability to intravasate and extravasate
- ability to proliferate (locally and in ectopic sites)
1-4 common to invasion and metastasis, 5-7 specific to metastasis
What must be disrupted for cell-cell adhesion to be broken?
E-cadherin (e-CD) in adherens junctions
How does cell-cell adhesion occur?
Homotypic adhesion (ligand and receptor are same)- e-CD binds e-CD on adjacent cells (like a zip or a tent-peg)
What does e-CD attach to inside the cell?
alpha and beta catenin, and the actin-myosin cytoskeleton
What does e-CD require for adhesion?
Calcium (2+) in the extracellular space
What indirect mechanisms can disturb e-CD adhesion between cells?
Exon-skipping, methylation of e-CD promoter, mutations in proteins that interact with e-CD (beta-catenin, APC) and mutations in transcription factors that regulate e-CD (snail, slug, twist)
What are integrins?
- Cell adhesion molecules (CAMs), integral to plasma membrane, bind to ECM molecules
- Found in basal epithelial cells and in focal adhesions of migrating cells
What are the possible mechanisms of integrins in metastasis?
- decreased adhesion to BM surrounding epithelium
- increased migration through stroma
- increased adhesion to BM or endothelial cells of BVs
- binding site for proteolytic enzymes
What is HGF?
- Hepatic growth factor or ‘scatter factor’ can induce epithelial cells to dissociate and scatter in culture
- HGF is a mitogen (GF), a motogen (motility factor) and a morphogen
What cells are associated with the tumour microenvironment (TME)?
- Cancer-associated fibroblasts (CAFs)
- Immune cells that have infiltrated the tumour
- myofibroblasts
- tumour-associated vasculature
- pericytes
Secreting; - GFs
- chemokines
- enzymes
What are the site-specific metastasis for breast tumours?
Bone, lungs, liver and brain
What are the site-specific metastasis for lung adenocarcinoma?
Brian, bones, adrenal gland, liver
What are the site-specific metastasis for skin melanoma?
Lungs, brain, skin, liver
What are the site-specific metastasis for colorectal tumours?
Liver and lungs
What are the site-specific metastasis for pancreatic tumours?
Liver and lungs
What are the site-specific metastasis for prostate tumours?
Bones
What are the site-specific metastasis for sarcoma tumours?
Lungs
What are the site-specific metastasis for uveal melanoma tumours?
Liver
What are some of the possible mechanisms for organ tropism?
- Selective adhesion to endothelium of target organs
- Selective response to GFs at ectopic site
- Selective migration to CK source
- Factors released by tumour/other cells cause changes in prospective TME at secondary sites, creating pre-metastatic niche
- Balance of local angiogenic factors versus systemic anti-angiogenic factors (angiostatin and endostatin)
