HC9- Invasion & metastasis Flashcards
primary tumors are noticed when they
influence the function of organs or tissues
percentage of deaths caused by primary tumors
10%
tumors in certain tissues have
high metastatic potential
example high metastatic potential
primary melanomas
examples low metastatic potential (2)
- basal cell carcinomas skin
- astrocytomas
invasion-metastasis cascade
primary tumor formation - local invasion - intravasation - transport through circulation - arrest in microvessels of various organs - extravasation - colonization = formation of micrometastasis
carcinomas location
thin sheets of epithelial cells sit on top of deep, complex layers of stroma
malignant cells that breach the basement membrane gain exces to
growth factors and blood supply
carcinomas charachteristic
breaching basement membrane of epithelium with proteases that cleave the ECM
intravasation
cancer cells enter blood vessels from stroma
for the invasion of the lumen of capillaries > cooperation between
carcinoma cells, macrophages and endothelial cells
intravasation stimulated by signaling
EGF from macrophages
blood
hostile environment for carcinoma cells
hostile environment because of (4)
- no contact with other cells
- hydrodynamic stress
- no stromal support
- diameter of carcinoma cells is larger > 3-8 um
circulating cancer cells are a
readout value for therapy efficacy
readout value therapy efficacy (2)
- comparison between cancers and patients is complicated
- measuring tumor DNA in blood > accumulated mutations and translocations
circulating cancer cells spend very little time in circulation because they
are immobilized in the lungs > can escape to other organs
primary mechanism metastasis
trapping in small vessels
extravasation
invasion into surrounding tissue
for extravasation help is needed from
macrophages for certain factors
forms of extravasation (2)
- through the vessel wall
- growth within the vessel
colonization
most complex step
first step colonization
formation of micrometastases
probability for the formation of a macroscopic metastase
low
micrometastases breastcancer
30% of patients have hundred-thousand micrometastases in the bone marrow
presence of micrometastases
indactive for a bad prognosis
initial micrometastases
genetically distinct > cells that were able to disseminate but not colonize > strong selective pressure
second wave of metastases
genetically similar > well adapted cells > faster growth in hostile environments
metastatic showers
responsible for most deaths > metastases of metastases
micrometastases can
remain dormant for a long time
epithelial-mesenchymal transition (EMT)
shedding of epithelial phenotype and detaching
EMT is necessary for
motility and invasiveness
EMT is essential in
embryogenesis and wound healing
EMT can occur through fundemental changes in gene expression
- downregulation of E-cadherin and cytokeratins
- upregulation of vimitin
vimitin
intermediate filament mesenchymal tissue
EMT is seen at
edges of carcinomas that invade
E-cadherin
tethered to the actin filaments via a complex of alpha and beta catenins
E-cadherin cancer
- internalized
- expression suppressed
suppressed expression of E-cadherin in carcinoma
breast, colon, prostate, stomach, liver, esophagus, skin, kidney and lung
EMT induction
stromal signals can be conveyed by many factors that act in paracrine/autocrine fashion
tumor-associated macrophages express
TNF-alpha, EGF
factors expressed in embryogenesis and wound healing
snail, slug, twist
EMT transcription factors can
induce a stem cell state > critical for metastasis
mesenchymal-epithelial transition (MET) occurs
after extravasation and invasion of other tissues > helps to colonize
extracellular proteases
excavate a passage through ECM
ECM contains
fibronectin, tenascin, laminin, collagens and proteoglycans
matrix metalloproteinases (MMPs) are secreted by
macrophages, mast cells and fibroblasts
activities of MMPs occur with
normal cell proliferation and tissue maintenance
controling MMPs
excreted as inactive pro-enzymes > must be cleaved by other proteases
proteolysis in cancer
continous process
ectotopic expression of MMPs
carcinogenesis
network of lymphatic vessels in tissue
drain interstitial fluid
lymhatic vessels in cancer and stimulated cells
generation is promoted
collapse of lymphatic vessels in cancer
insufficient pressure
cancer cell positive lymph nodes
surrogate marker of metastasis
tropism
diffent cancers display distinct tropism towarda colonizing various organs or tissues
explanation tropism
certain cancer cells are uniquely equipped
seed and soil hypothesis
metastatizing cancer cells (seeds) find a compatible home in certain hospitable tissues (soil)
sites of metastasis (5)
- seed and soil hypothesis
- determined by layout vessels
- sites of chronic inflammation
- tumor self-seeding
- vascular ZIP-code
sites of chronic inflammation
can attract certain cells
tumor self-seeding
tropism towards site of primary tumor
vascular ZIP-code
receptors on the walls of capillaries attract circulating tumor cells
dormant micrometastases can
reduce long-term survival > non-cycling > therapy resistant
immune system may suppress growth of
micrometastases
genetic determinants of metastases
only a subpopulation of the genetic diversity of the primary tumor found
