Pathogenesis of Head and Neck cancer 1+2 Flashcards
What is the general term for Head and Neck Cancer?
Cancers of the mouth, oropharynx, nasopharynx, hypopharynx, nose, paranasal sinuses, larynx, salivary glands (thyroid, upper oesophagus)
Development of a cancer –a multistep, progressive, cumulative process.
What is the multistep theory of carcinogenesis evolved from
animal studies of carcinogens?
- Initiation- DNA damage and mutation
- Promotion-clonal expansion of abnormal cells leading to cancer
* Very simplified!!*
* Different pathways, repair mechanisms, causes of damage in humans*
What are the Key Elements in Cancer Development?
Tumour growth
- Replication*
- Escape from senescence*
- Evasion of apoptosis*
- Limitless replicative potential*
Invasive growth
Angiogenesis
Metastasis
What are the Components of a Neoplasm?
Neoplastic cells:
Blood Vessels
Inflammatory cells
- →Macrophages*
- →Lymphocytes*
- →Polymorphs*
Fibroblasts
Stroma
Most tumours are monoclonal, what does this mean?
All the cells in a tumour appear to arise from one parent cell which has undergone a genetic change.
This is then passed on to all the progeny.
Tumour cells lack the normal control mechanisms thus the clone expands due to uncontrolled proliferation
What do Transformed cells show?
- Altered nuclear/cytoplasmic ratio
- Altered and variable nuclear morphology (pleomorphism)
- Altered nuclear staining (hyperchromasia)
- Altered DNA content (aneuploidy)
- Molecular alterations in key regulatory genes
- Reduced requirements for growth factors (or serum) when grown in vitro
- Altered antigen expression
- Growth at very low cell densities in vitro
- Loss of contact inhibition (ie. still proliferate at high densities)
- Growth in an anchorage independent manner
- Immortality: ie. do not show senescence after 70 rounds of division (ie. they exceed Hayflick limit)
- Tumourigenesis in animal models
- Cancer cells have invasive properties and the potential to metastasise
- Altered surface charge
- Altered surface carbohydrate expression
What does Head and Neck SCC show?
Head and Neck SCC show marked genetic heterogeneity-loss of-function in tumour suppressor genes, eg p53, and activation of oncogenes eg EGFR
What happens in Invasive growth?
Reduction in cell-cell adhesion, eg reduced/loss of E-cadherin
Invasion of Basement Membrane and Stroma
Tumour cell attaches to BM via integrins and matrix proteins. Tumour cells produce proteolytic enzymes eg collagenase, matrix metalloproteases which break up the matrix
Tumour cells need to be motile –extrude pseudopodia which attach to stromal proteins. Actin cytoskeleton enables movement
What do groups of cells require for invasive growth?
- Requires cell-cell adhesion and communication
- Predominates in well differentiated carcinomas
- Inner cells protected from immunological assault
- High levels of autocrine pro-migratory factors and of proteolytic enzymes.
- Heterogeneous sets of cells invade together
What happens in the Angiogenesis step?
- Formation of new blood vessels
- Usually under tight physiological control however control is lost in tumours – the angiogenic switch- development of rich blood supply around tumour
- Vessels formed are abnormal
- New blood vessels formed by outgrowth of endothelial cells from post capillary venules into tumour mass
- Critical step in progression of small localised tumour to a bigger one with metastatic potential
- Stimlulus is increased production of factors by tumour cells including:
- →VEGF, angiogenin*
→Inhibition of angiogenesis anticancer therapy area (anti-angiogenic drugs)
What is the next step ‘Metastasis’?
- Tumour implants that are discontinuous with the primary lesion “Secondaries”
- Sinister event
- Non-random
- Affects tumour stage and has Prognostic implications
What happens in metastasis in the vessel?
- Tumour cells breach the basement membrane of vessel and enter vessel lumen
- Tumour cells carried to site of metastasis
- Bind to endothelial cells, penetrate BM, move out of vessel
- Establishment of metastasis, cell proliferation, angiogenesis
- Complex molecular interactions involved in these stages
