metastatis
pressure on and destruction of adjacent tissue
obstruction of flow (e.g. malignant tumour of the colon causing intestinal obstruction)
production of hormones (e.g. adrenocorticotropic hormone [ACTH] and vasopressin [ADH] from some lung tumours)
other paraneoplastic effects (eg cachexia)
metastatic cascade
- reduced cell-cell adhesion
- altered cell-substratum adhesion
- increased motility
- increased proteolytic ability
- ability to intravasate and
extravasate - angiogenic ability
- ability to proliferate
(locally & ectopic sites)
invasion, intravasation, transport, extravasation, colonisation, angiogenesis
tumour cell invasion
- reduced cell-cell adhesion
- altered cell-substratum 3. adhesion
- increased motility
increased proteolytic ability
ability to intravasate &
extravasate
ability to proliferate
angiogenisis
epithelial cells
cohesive interactions among cells, forming continuous cell layers
three membrane domains: apical, lateral and basal
presence of tight junctions between apical and lateral domains
polarised distribution of cell components
lack of mobility with respect to their local environment
mesenchymal cells
loose or no interactions between cells
no clear apical/basolateral membranes
no cell-cell junctions
no apicobasal polarised distribution of organelles/cytoskeleton
motile cells that may have invasive properties
epithelial- mesenchyme transition, EMT
process in which epithelial cells lose their characteristic polarity, disassemble cell-cell junctions and become more migratory
e- cadherin
- adherent junction
- ca ++ dependent homotypic binding
- beta and alpha catenin
- actin cytoskeleton
- aberrant e-cadherin expression in human tumours:
e-cadherin———-> n- cadherin (no cell-cell glue), no junctions keeping cell together - most carcinomas have reduced/no e-cadherin
integrins
- cell- ECM junction
-Component of focal adhesions
found in basal epithelial cells & in focal adhesions of migrating cells
-Altered integrin expression
is frequently detected in tumours
increased proteolytic activity
Proteases expressed by both tumour and stroma
Facilitate: a. invasion of ECM at primary & secondary sites
b. digestion of endothelial BM
c. angiogenesis
d. activate proteases
serine proteases
Urokinase plasminogen activator (uPA) -> plasmin
Plasmin activates MMPs & degrades ECM
matrix metalloproteinases
MMP-2 degrades type IV collagen
cysteine proteases
Cathepsin K collagenolytic activity -> matrix degradation
modes of tumour spread- lymphatic spread
- Common mode of spread of carcinomas,
e.g. breast, colon, lung
Travel to draining lymph nodes,
e.g. from breast cancer to axillary LNs
Thereby to thoracic duct and systemic blood circulation
modes of tumour spread- haematogenous spread
Common mode of spread of sarcomas
Also some carcinomas, e.g. kidney, colorectum, prostate
modes of tumour spread- transcoaelomic spread
- across the peritoneal cavity
- incidence higher with tumours that arise from the peritoneal cavity, e.g., ovarian (up to 70 % of patients at presentation) and colorectal (up to 28 % of patients at presentation)
intravasation
Intravasation:
Attachment
Degrade BM
diapedesis
New blood vessels are leaky
Assisted by tumour-associated
macrophages: chemotactic signals
transport of tumour cells
Most tumour cells do not survive
shear stress of blood flow
immune detection
extravasation
Attachment
Degrade BM
diapedesis
blood vessels structurally sound
Similar mechanism used by WBCs
angiogenesis
new vessels are generated from existing vasculature
Tumours (both benign & malignant) need oxygen and nutrients
to survive
A tumour cell >1 mm from a capillary will become hypoxic
angiogenesis process
low oxygen, HIF transcription factor binds to VEGF
signals production of new blood vessels,
migration- interns
sprout formation- proliferation
invasion- proteases
seed and soil hypothesis
Metastasis is selective for cells that are capable of invasion, survival, intra/extravasation and proliferation at distant sites.
The success of metastatic colonisation is dependent on the interaction of tumour and the tumour microenvironment
cancer- associated fibroblasts
secrete MMPs cytokines IL-8 and VEGF
pericyte
low pericyte coverage -> leaky vessel structure -> facilitating tumour cell invasion/extravasion
immune inflammatory cells
- macrophages, neutrophils, mast cells
- Tumour-associated macrophages produce growth factors and MMPs to promote angiogenesis, cell invasion
and intravasation
