Progression and metastasis

Question 1

Explain caricinogenesis

Answer 1

• multi-stage process involving multiple hits
• initiation = interaction of carcinogen with DNA
• promotion = selective growth advantage, early pre-cancer = reversible
• progression - enhanced cell division
• malignant conversion = cancer not reversible

Question 2

What are the characteristics of a malignant tumour

Answer 2

• progression = unlimited growth, as long as an adequate blood supply is available
• invasiveness = migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs
• metastasis = spread of tumour cells from the primary site to form secondary tumours at other sites

Question 3

What are the main steps of tumour progression?

Answer 3

• acquisition of specific mutations by carcinogens, multiple hits
• clonal expansion by tumour promoters
• genomic instability by DNA repair defects, aneuploidy, loss of heterozygosity
• epigenetic changes by gene promoter, methylation

Question 4

How is cellular heterogeneity established?

Answer 4

selective pressures :

• antigenicity
• growth rate
• response to hormones
• response to cytotoxic drugs
• capacity for invasion and metastasis

Question 5

What mechanisms induce tumour cell invasion?

Answer 5

1. increased mechanical pressure caused by rapid cellular proliferation
2. hypoxia and blood supply
3. inc motility of malignant cells - EMT
4. inc production of degenerative enzymes (MMP) by other tumour cells and stromal cells

Question 6

What is the result of hyperproliferation?

Answer 6

• hyper-proliferation occurs in extracellular matrix (ECM)
• components of ECM are altered
• maintenance of cell-cell ECM context is compromised and triggers a transition towards a more mesenchymal phenotype = more motile
• stromal cells are changing
• blood vessels find it more difficult to reach tumour - areas of tumour become hypoxic

Question 7

What is the role of hypoxia in tumour cell invasion?

Answer 7

• angiogenesis
• tumour induced angiogenesis follows a similar pattern to normal angiogenesis
• VEGF is important - targetable pathway to reduce growth of tumour

Question 8

How does EMT affect tumour cell invasion?

Answer 8

new transcriptional programme:
loss of:
- epithelial shape and cell polarity
- cytokeratin intermediate filament expression
- epithelial adherent junction protein (E-cadherin)
acquisition of:
- fibroblast-like shape and motility
- n-cadherin
- invasiveness
- vimentin intermediate filament expression
- mesenchymal gene expression (fibronectin)
- protease secretion MMPs)

Question 9

Describe the effect of MMPs and TIMPs in tumour cell invasion

Answer 9

• extent of proteolysis depends on the relative amounts of proteinases (MMPs) and inhibitors of proteinases
• most tissues have large amounts of a family of inhibitors called TIMPs (tissue inhibitor of metalloproteinases)
• some tumour eg. pancreatic tumour have decreased levels of TIMPs
• although actively investigated, inhibitors of MMPs have not been successful in clinical trials

Question 10

What are the steps of metastasis?

Answer 10

• primary tumour formation
• localised invasion
• intravastation = interaction with platelets, lymphocytes, other blood components
• transport through circulation
• arrest in micro vessels of various organs
• extravasation
• formation of a micrometastasis
• colonisation = formation of a macrometastasis

Question 11

What is the seed and soil hypothesis?

Answer 11

• specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation

Question 12

How do tumour escape immune recognition?

Answer 12

1. low immunogenicity = no peptide MHC ligand, no adhesion molecules, no co-stimulatory molecules
2. antigenic modulation = antibody against tumour cell surface antigens can induce endocytosis and degradation of the antigen immune selection of antigen-loss variants
3. tumour-induced immune suppression = factors (TGF-b) secreted by tumour cells inhibit t cell directly

Question 13

How do tumour survive at distant sites?

Answer 13

• latency/dormancy

- difficult to identify

Question 14

What is a liquid biopsy?

Answer 14

• sampling and analysis of non-solid biological tissue, primarily blood.
• minimally invasive technology for detection of molecular biomarkers
• representative of the tissue from which it spread

Question 15

Why is blood a good source for liquid biopsy?

Answer 15

• elements and characteristics of disease can be found in blood
• eg. tumour educated platelets (TEPs)
• disseminated tumour cells

Question 16

What are circulating tumour cells (CTCs)?

Answer 16

• cells that have detached from a tumour and travel through the bloodstream to other parts of the body
• markers for tumour growth and negative cancer prognosis and treatment response
• extremely rare - 1-10 per 1ml of blood
• found in high background of normal cells - sensitive and specific methods are needed to study them

Question 17

Why liquid biopsies?

Answer 17

• cancer is heterogenous disease and mutations are highly specific to tumour cells
• contain several secreted cells that allow understanding of level of heterogenicity of tumour
• type and number of mutations involved in the development of cancer increases as cancer progresses
• primary tumour information may not reflect the current disease condition