Metastasis Flashcards
Invasion
growth by infiltration and destruction of surrounding tissues.
Metastasis
spread of tumour to (and growth at) ectopic sites, via blood, lymphatics, intra-epithelial route, or trans-coelomic.
Carcinoma
Malignant tumour derived from epithelial cells
Sarcoma
Malignant tumour derived from mesenchymal cells
Melanoma
Malignant tumour derived from neural crest cells
Leukaemia
Malignant tumour derived from circulating white blood cells
Lymphoma
Malignant tumour derived from the lymphatic system
7 properties of metastatic tumours
- 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)
what is the basement membrane
- secreted by basal epithelial cells/ endothelial cells
- a layer of extracellular matrix (ECM) fibronectin,
- type IV collagen, laminin, etc. a barrier to spread
where do breast tumour commonly migrate to
bone, lungs, liver, brain
where do lung adenocarcinomacommonly migrate to
bone, brain, adrenal glands, liver
where do skin melanoma commonly migrate to
Lungs, brain, skin, liver
where do colorectal tumour commonly migrate to
liver and lungs
where do pancreatic tumour commonly migrate to
Liver and lungs
where do prostate tumour commonly migrate to
Bones
where do sarcoma commonly migrate to
Lungs
where do uveal melanoma commonly migrate to
Liver
Serine proteases
urokinase plasminogen activator (uPA), plasmin bind to receptors on tumour cell surface (uPAR)
Matrix metalloproteinases (MMPs)
- collagenases, gelatinases, stromelysins , membrane-type (MT)-MMPs - soluble forms with ECM homology can bind to integrins e.g., MMP-2 binds to avb3 - produced by WBCs, associated with tissue / wound repair
2 types of proteases
Serine proteases
Matrix metalloproteinases (MMPs)
C-met is a tumour component. what is its stromal component?
HGF
Chemokine receptor is a tumour component. what is its stromal component?
Chemokine
Protease receptor is a tumour component. what is its stromal component?
Protease
Intergrin alpha v beta 3 is a tumour component. what is its stromal component?
MMP-2
TGF is a tumour component. what is its stromal component?
Stromelysin
VEGF is a tumour component. what is its stromal component?
VEGFR
what is secreted by cells in the tumour microenvironment
growth factors, chemokines, enzymes
what acilitates tumour-stomal interactions
The tumour microenvironment
4 cells in the tumour microenvironment
cancer-associated fibroblasts (CAFs)
immune cells that have infiltrated the tumour
myofibroblasts
tumour-associated vasculature pericytes
3 possible mechanisms of Cell-substratum : integrins
↓ adhesion to BM surrounding epithelium
↑ migration through stroma
↑ adhesion to BM or endothelial cells of BVs
who do tumours bind selectively to endothelium of target organs
selectins
CD44 variants
how do cells grow at metastatic site
Selective response to GFs at ectopic site
PTHRP and IL-11
factor inducing cells to dissociate
HGF/scatter
what is HGF
- a mitogen (growth factor and a mitogen (Mobility factor)
- morphogen with a developmental role (eg in migration of limb buds)
- produced by stroll cells in a tumour (tumour microenvironment)
what does HGF bind to
c-met, a RTK on tumour epithelial cells
what does HGF/c-met activate
- increase of tyrosine
- phosphorylation of beta-catenin in tumour epithelial cells = disrupted ECD-mediated adhesion
4 stages of white blood cell extravasation
- rolling
- activation
- adhesion
- diapedesis
local angiogenic factors versus systemic anti-angiogenic factors
angiostatin & endostatin
specific interns promoting invasion and metastasis
vitronectin receptor (integrin avb3)
integrins bind CAMs in other cell types
heterotypic adhesion
what are ingrains
- cell adhesion molecules (CAMs)
- integral to plasma membrane
- bind to ECM molecules found in basal epithelial cells & in focal adhesions of migrating cells
what to integrins typically bind to
ECM
2 mutations which indirectly perturb ECD
- proteins that interact with ECD (b-catenin, APC)
- transcription factors that regulate E-cadherin (snail, slug, twist)
Possible mechanisms for organ tropism
- Selective migration to CK source (differential CKR expression)
- Factors released by tumour / other cells cause changes in prospective TME at secondary sites, creating pre-metastatic niche
• ‘exon-skipping’ in diffuse-type gastric tumours
lacking exons that encode Ca2+-binding domain
Aberrant ECD expression in human tumours
inverse correlation between ECD expression and tumour grade
