Progression and metastasis Flashcards
characteristics of malignant tumors : progression
unlimited growth (not self-limited like in benign tumors)- as long as an adequate blood supply is available to prevent hypoxia
characterstics of malignant tumors;
migration of tumor cells into surrounding stroma where they are free to disseminate via vascular or lymphatic channels to other organs
define metastasis
spread of tumor from the primary site to form secondary tumors at other sites in the body
describe the molecular basis of tumor progression
- acquistion of specific mutations by carcinogens, multiple hits
- clonal expansion by tumor promoters
- genomic instability by DNA repair defects, aneuploidy, loss of heterozygosity
- epigenetic changes by gene promoter methylation
what is cell heterogeneity?
selevtive pressures that will determine the cellular composition of tumors such as;
- antigenicity
- growth rate
- response to hormones
- response to cytotoxic drugs
- capacity for invasion and metastasis
what does analysis of heterogeneity allow for?
done by liquid biopsises and allows for potential targets for treatment
what are the mechanisms for tumor cell invasion?
- increased mechanical pressure by rapid cellular proliferation
- hypoxia and blood supply
- increased motility of the malignant cells (epith. to mesen. transition ; EMT)
- increased prod. of degradative enzymes (MMP) by both tumor and stromal cells.
what does angiogenesis allow for?
- tumors will not grow beyond 2mm without their own blood supply as cells can’t survive lack of O2 (hypoxia)
- angiogenesis is promoted by hypoxia
what does promoting mesenchymal fate cause a loss of?
- epithelial shape and cell polarity
- cytokeratin intermediate filament expression
- epithelial adherent junction protein (E-cadherin)
what does promoting mesenchymal fate cause an acquisition of?
- fibroblast-like shape and motility
- N-cadherin
- invasiveness
- vimentin intermediate filament expression
- mesenchymal gene expression (fibronectin, PDGF receptor, avb6 integrin)
- protease secretin (MMP-2, MMP-9)
what does cellular programming for malignant progression and invasion involve?
- loss of cell-cell adhesion (cadherins)
- EMT
- changes in cell- ECM adhesion (integrins)
- cell become more motile and invasive
what is the function of adherens junctions?
joins an actin bundle in one cell to a similar bundle in the neighbouring cell
what are cadherins?
Ca2+ dependent adhesion molecules
- E-cadherin
- P-cadherin
- N-cadherin
- VE-cadherin
what does EMT cause?
greater resistence to therapy
proteolysis during tumor cell invasion
- extent of proteolysis depends on relative amounts of proteinases (MMP) and inhibitors of proteinases
- most have tissues have large amounts of TMPs (tissue inhibitor of metalloproteinases)
- some tumors e.g. pancreatic, have decreased levels of TIMPs
- inhibitors of MMPs have been successful in clinical trials
what is the overall process of metasis?
primary tumor formation > localised invasion > intravasation (interaction with platelets, lymphocytes etc) > transport through circulation > arrest in microvessels of various organs > extravasation > formation of micrometastasis > clonisation , formation of macrometastasis
what is the seed and soil hypothesis?
when a plant goes to seed, its seeds are carried in all directions but can only live and grow if they fall on congenial soil
how is the seed and soil hypothesis linked to metastasis?
specific adhesions between tumor cells & endothelial cells in target organ = favourable environment in target organ for colonisation
life in transit of a metastasising tumor
- survive host defence
- survive shear forces
- arrest at a secondary site
what mechanisms do tumors use to escape immune recognition?
- low immunogenicty ; no peptide MHC ligand, no adhesion molecules
- antigenic modulation; antibodies against tumor cell surface antigens = endocytes and degradation of the antigen.
- tumor induced immune suppression; factor e.g. TGF-b secreted by tumorcells inhibit T-cells directly
what does arresting a secondary site look like?
- cell adhesion e.g. selectin ligands and receptors
- tumor cells coated in platelets
- ‘homing’
what is ‘homing’?
- tumor cell recognition of specific ‘exit sites’ from circulation
- awareness of particularly favourable environment
what is ‘homing’ facilitated by?
existing affinity between receptor proteins on the surface of cancer cells and molecules that are abundant in specific tissues
describe an example of homing
chemokines such as CXCL12 secreted by stromal cells act as attractant for cells expressing receptor CXCR4; receptor highly expressed in breast cancer cells and acute myeloid leukaemia (AML) cells
how can survival at a distant site occur?
- latency
- dormancy
what does colonisation require?
MET; mesanchymal epithelial transition factor receptor
what is a liquid biopsy?
- sampling and analysis of non-solid biological tissue, primarily blood
- minimally invasive tech for detection of molecular biomarkers
- representative of the tissues from which the spread has come from
blood as a liquid biopsy
test for;
- CEC; circulating endothelial cells
- Extracellular micro-vesicles (exosomes)
- cell free nucleotides
- TEPs; tumor educated platelets
- CTCs; circulating tumor cells
- DTCs; disseminated tumor cells
what are circulating tumor cells?
- cells that have detached from tumor and travel through bloodstream to other parts of the body; single cells or clusters
- marker for tumor growth and -ve cancer prognosis & treatment response
- extremely rare; 1-10 per 1ml of blood
- half -life time ;<2.5hours
- found in a high background of normal cells; sensitive & specific methods are needed to study them.
why liquid biopsies?
- cancer is heterogenous disease and mutations are highly specific to tumor cells
- type and number of mutations involved in development of cancer increases as cancer progresses
- molecular properties within a tumor differ and also between metastatic sites
- primary tumor information may not = current disease condition
- no need to identiy tumor site before taking biopsy + allows for repeat sampling
what can liquid biopsies be used for?
- diagnosis
- surgery
- minial residual disease
- treatment
- follow up
- resistance
what are tumors?
clonal overgrowths & molec. properties within a tumor differ also between metastatic sites
what is tumor invasion caused by?
- increased mechanical pressure
- hypoxia conditions and angiogenesis
- EMT
- increased production of degradative enzymes by both tumor and stromal cells
