L13: Metastasis Flashcards
(11 cards)
the metastatic cascade
Growth at primary site.
Detachment from primary mass
Local invasion of surrounding tissue – matrix degrading and cell migration
Movement into small blood vessels or lymphatics (“intravasation”). Inside vessel release from site of entry - as single cells, or clumps (emboli).
Survival in the circulation.
Arrest at distant site inside the vessel.
Exit from the vessel and local invasion of tissue (“extravasation”).
Growth at secondary site.
NB metastasis is VERY inefficient
growth at primary site
Mutations in oncogenes and tumour suppressor genes confer growth autonomy.
BUT - Growth >2mm diameter requires the development of a blood supply. (= Angiogenesis)
Due to release of angiogenic factors by both tumour cells and infiltrating normal cells.
e.g.
fibroblast growth factor family (FGFs)
epidermal growth factor (EGF)
transforming growth factor-α (TGF-α)
interleukin-8 (IL-8)
Vascular endothelial growth factor family (VEGF)
angiogenesis: Permits increase in tumour mass, and hence increases risk of metastasis.
Tumour blood vessels tend to be leaky, facilitating dissemination.
Extent of vascularization is a good predictor of metastatic disease. (Weidner et al, 1991; 1993)
[N.B. not all highly vascularized tumours are metastatic, e.g. adrenal
adenoma.]
EMT
EMT is
orchestrated by the transcriptional regulators Twist, Snail, Slug, SIP1 and others: direct suppressors of E-Cadherin
expression
induced reversibly by stromal factors (e.g. HGF, FGF, EGF, Wnt, TGF-β, TNF-α), which upregulate Twist, Snail, SIP1
In epithelial tumours, there is a strong association between aggressiveness (metastatic activity) and reduced expression of E-cadherin.
- Upregulation of repressors
Mechanisms for reduction of E-cadherin expression
Upregulation of Twist, Snail, Slug seen in invasive human tumours
2. Targeting of E-cadherin promoter – methylation
- Action of miRNA
- mutation
Not all invasion requires loss of
E-cadherin (collective migration)
N-cadherin
Besides loss of E-cadherin, some tumours show de-novo expression of N-cadherin.
Facilitates interaction with stromal cells (fibroblasts, endothelial cells) and promotes migration.
A cadherin switch?
Similar switch occurs during embryonic development (gastrulation), associated with migration.
invadopodia
Cancer cells have invadopodia
Actin rich protrusions that produce matrix degrading enzymes
integrin expression in cancer
Integrin expression in cancer - Integrin switching
Neoplastic cells tend to lose expression of integrins that secure their adhesion to the basement
membrane and maintain or overexpress integrins that promote migration.
Not possible to assign integrins as ‘anti-neoplastic’ or the ‘pro-neoplastic‘
BUT present evidence indicates that α2β1 and α3β1, are more likely to suppress tumour
progression, whilst αvβ3 (melanoma) αvβ6 and α6β4 often promote tumour progression.
The αvβ6 integrin is an epithelial-specific integrin and usually not detectable on non-pathologic tissues.
It is significantly upregulated by many cancers and is identified as a prognostic marker
modes of migration
Mesenchymal
Actin-based : microfilaments of F-actin, characterised by strong attachment
to the substratum (focal adhesions) generally requires matrix proteolysis. Fibroblasts,
Macrophages, neuronal growth cone
Amoeboid
Amoeboid migration is a mode of rapid motility that is driven by actin
rich pseudopods, hydrostatically-generated blebs and a highly
contractile uropod, and is characterized by weak or absent adhesion to
the substratum and little or no extracellular matrix proteolysis.
Dictyostelium amoeba
How do cells
switch between
mesenchymal
and amoeboid
migration?
They switch their Rho GTPase pathway
intravasation
macrophages—> EGF—> cancer cells
macrophages aid intravsation
cancer cells—-> CSF-1—-> macro[hages
survival in circulation
Very few neoplastic cells which enter the circulation survive (prob. less than 1 in 10,000).
Most cell death is probably due simply to turbulence or trauma, or loss of anchorage (anoikis).
May also be due to exposure to natural killer (NK) cells, T-lymphocytes or monocytes.
But defence mechanisms might also, paradoxically, promote survival:
lymphocyte-induced clumping may facilitate arrest, or shield innermost cells from trauma.
monocytes and platelets may provide angiogenic cytokines.
neutrophils may provide proteolytic enzymes.
arrest in the vessel
A major factor is physical entrapment in the
first capillary bed encountered
Specific mechanisms, similar to those used by white blood cells to cross the endothelium, may also be used.
α4β1 integrin binds to V-CAM on endothelial cells. (May facilitate arrest.)
surface receptors called selectins, present on endothelial cells, which bind to sugar moieties (Sialylated Lewisx) often expressed on tumour cells.
After arrest, extravasation and invasion of new site will involve the same mechanisms as for intravasation.
NB extravasation may not always be necessary.
targeting integrins
Cilengitide
Integrins recognize a common, minimum sequence motif of Arginine-Glycine-Aspartate (R-G-D). Cilengitide is an avb3/avb5 integrin-specific RGD-mimetic cyclic peptide – 2017 trials in multiple myeloma
Etaracizumab
A humanized monoclonal IgG1 antibody directed against the
alpha v beta 3 integrin – Phase I – Phase II
Volociximab
binds to and inhibits the activity of alpha(5)beta(1) integrin –Phase II
