Progression and metastasis Flashcards

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1
Q

characteristics of malignant tumors : progression

A

unlimited growth (not self-limited like in benign tumors)- as long as an adequate blood supply is available to prevent hypoxia

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2
Q

characterstics of malignant tumors;

A

migration of tumor cells into surrounding stroma where they are free to disseminate via vascular or lymphatic channels to other organs

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3
Q

define metastasis

A

spread of tumor from the primary site to form secondary tumors at other sites in the body

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4
Q

describe the molecular basis of tumor progression

A
  • 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
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5
Q

what is cell heterogeneity?

A

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

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6
Q

what does analysis of heterogeneity allow for?

A

done by liquid biopsises and allows for potential targets for treatment

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7
Q

what are the mechanisms for tumor cell invasion?

A
  1. increased mechanical pressure by rapid cellular proliferation
  2. hypoxia and blood supply
  3. increased motility of the malignant cells (epith. to mesen. transition ; EMT)
  4. increased prod. of degradative enzymes (MMP) by both tumor and stromal cells.
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8
Q

what does angiogenesis allow for?

A
  • 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
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9
Q

what does promoting mesenchymal fate cause a loss of?

A
  • epithelial shape and cell polarity
  • cytokeratin intermediate filament expression
  • epithelial adherent junction protein (E-cadherin)
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10
Q

what does promoting mesenchymal fate cause an acquisition of?

A
  • 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)
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11
Q

what does cellular programming for malignant progression and invasion involve?

A
  1. loss of cell-cell adhesion (cadherins)
  2. EMT
  3. changes in cell- ECM adhesion (integrins)
  4. cell become more motile and invasive
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12
Q

what is the function of adherens junctions?

A

joins an actin bundle in one cell to a similar bundle in the neighbouring cell

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13
Q

what are cadherins?

A

Ca2+ dependent adhesion molecules
- E-cadherin
- P-cadherin
- N-cadherin
- VE-cadherin

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14
Q

what does EMT cause?

A

greater resistence to therapy

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15
Q

proteolysis during tumor cell invasion

A
  • 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
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16
Q

what is the overall process of metasis?

A

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

17
Q
A
17
Q

what is the seed and soil hypothesis?

A

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

18
Q

how is the seed and soil hypothesis linked to metastasis?

A

specific adhesions between tumor cells & endothelial cells in target organ = favourable environment in target organ for colonisation

19
Q

life in transit of a metastasising tumor

A
  1. survive host defence
  2. survive shear forces
  3. arrest at a secondary site
20
Q

what mechanisms do tumors use to escape immune recognition?

A
  • 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
21
Q

what does arresting a secondary site look like?

A
  • cell adhesion e.g. selectin ligands and receptors
  • tumor cells coated in platelets
  • ‘homing’
22
Q

what is ‘homing’?

A
  • tumor cell recognition of specific ‘exit sites’ from circulation
  • awareness of particularly favourable environment
23
Q

what is ‘homing’ facilitated by?

A

existing affinity between receptor proteins on the surface of cancer cells and molecules that are abundant in specific tissues

24
Q

describe an example of homing

A

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

25
Q

how can survival at a distant site occur?

A
  • latency
  • dormancy
26
Q

what does colonisation require?

A

MET; mesanchymal epithelial transition factor receptor

27
Q

what is a liquid biopsy?

A
  • 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
28
Q

blood as a liquid biopsy

A

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

29
Q

what are circulating tumor cells?

A
  • 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.
30
Q

why liquid biopsies?

A
  • 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
31
Q

what can liquid biopsies be used for?

A
  • diagnosis
  • surgery
  • minial residual disease
  • treatment
  • follow up
  • resistance
32
Q

what are tumors?

A

clonal overgrowths & molec. properties within a tumor differ also between metastatic sites

33
Q

what is tumor invasion caused by?

A
  • increased mechanical pressure
  • hypoxia conditions and angiogenesis
  • EMT
  • increased production of degradative enzymes by both tumor and stromal cells