OC 10 - pathogenesis of HNC 1+2 Flashcards
What types of cancer does the term ‘head and neck cancer’ cover?
cancers of the mouth, oropharynx, nasopharynx, hypopharynx, nose, paranasal sinuses, larynx, salivary glands, ear
What are the majority of head and neck cancers?
squamous cell carcinomas (SCC)
What does SCC arise from?
lining mucosa
What is rhabdomysosaecoma?
a malignant skeletal muscle cancer
What is meant by saying neoplasia is a genetic disease?
- tumour cells usually show nuclear abnormalities
- nearly all carcinogens are mutagens
- altered DNA content (aneuploidy) is common in tumour cells
- chromosomes from tumour cells show structural abnormalities, some being characteristic of specific tumour types
- some tumours are clearly inherited and tumours can run in families
- mutations exist in genes that regulate cell behaviour
What are the (simplified) steps of carcinogenesis?
- initiation - DNA damage and mutation
- promotion - clonal expansion of abnormal cells leading to cancer
What are the components of a neoplasm?
- neoplastic cells
- blood vessels
- inflammatory cells
- (macrophages, lymphocytes, polymorphs)
- fibroblasts
- stroma
What are the key elements in cancer development?
- tumour growth
- invasive growth
- angiogenesis
- metastasis
What are the key elements of tumour growth?
- replication
- escape from senescence
- evasion of apoptosis
- limitless replicative potential
If a tumour is 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.
most tumours are monoclonal
In tumour cells, what happens in further genetic change develops in the progeny cells?
tumour becomes heterogenous
What are the stages of tumour progression?
normal cell—>transformed cell—>clonal expansion—> tumour progression—>further tumour progression
What 3 things happen in invasive growth?
- reduction in cell-cell adhesion (between tumour cells)
- invasion of basement membrane and stroma
- tumour cells need to be motile
What causes reduction in cell-cell adhesion?
reduced/loss of E-cadherin
E-cadherin - a transmembrane glycoprotein important in cell-cell adhesion
What happens during invasion of basement membrane and stroma?
- tumour cell attached to BM via integrins and matrix proteins
- tumour cells produce proteolytic enzymes e.g. collagenases, matrix metalloproteases which break up the matrix
What happens for tumour cells to become motile?
Extrude pseudopodia which attach to stromal proteins. Actin cytoskeleton enables movement
Where do groups of cells that display invasive growth predominate?
in well differentiated carcinomas e.g. SCC
What do groups of cells that display invasive growth have high levels of?
high levels of autocrine pro-migratory factors and of proteolytic enzymes
What is protected when tumour cells invade in groups?
inner cells protected from immunological assault
What properties are required for a tumour cell to invade?
- adhesion molecules
- receptors for connective tissues e.g. laminin
- proteolytic enzymes e.g. collagenases, cathepsin
- altered cell division and apoptosis - produces pressure of growth
- amoeboid movement
What is angiogenesis?
formation of new blood vessels
What is the angiogenic switch?
angiogenesis is usually under tight physiological control however control is lost in tumours —> development of rich blood supply around tumours
How are new blood vessels formed during angiogenesis?
new blood vessels formed by outgrowth of endothelial cells from post capillary venules into tumour mass
What is a critical step in progression of a small localised tumour to a bigger one with metastatic potential?
angiogenesis
What stimulates angiogenesis?
increased production of factors by tumour cells e.g. VEGF and angiogenin
What does VEGF stand for?
vascular endothelial growth factor
What is often a pre-requisition for tumour progression?
angiogenesis
Do tumours require more, less or the same oxygen and metabolites as normal cells?
tumours require less oxygen and metabolites than normal cells
How does density of tumour micro vasculature correlate with prognosis?
it does not need to correlate
What are metastasis?
tumour implants that are discontinuous with the primary lesion - “secondaries”
What effects/implications can the presence of metastasis have?
affects tumour stage and has prognosis implications
What are the common sites of metastatic disease?
- regional lymph nodes
- liver
- lung
- bone
- brain
- skin
- unusual sites - think of renal cancer, thyroid cancer, melanoma
What are the routes of metastasis?
- lymphatic
- haematogenous
- across body cavities
- across serous cavities
- across meninges/ventricles/spinal canal
- direct implantation
What type of cancer is lymphatic spread frequently seen in?
carcinomas
What type of cancer is haematogenous spread frequently seen in?
sarcomas
How does metastasis occur?
- 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
What accounts for common metastatic profiles?
circulatory patterns
Why are the lung and liver common sites of metastasis?
lung and liver are very effective at arresting circulating cancer cells
- allows tumour cells to stop and grow at a site
What is the ‘seed and soil hypothesis’?
- the seed (cancer cell) is dependant on some property of the soil (the metastatic site)
- deliver of cancer cells to a potential metastatic site is primarily mechanical - but the growth of metastatic deposit is is dependent upon compatibility with the “soil”
explained by target tissues possessing appropriate extracellular matrix and cell adhesion molecules to allow tumour cells to stop and grow at a site
Some benign tumours can progress to become malignant - what does this give evidence of?
the multiple step theory of carcinogenesis
What is the most common type of salivary gland tumour?
pleomorphic adenoma
