Flashcards in L32. Dysplasia carinoma sequence: General Principles Deck (41)
disorderly but NON-NEOPLASTIC proliferation characterised by loss uniformity of cells and architectural organisation
Pleomorphic, hyperchromatic and large nuclei
With mitotic figures clearer
These all seen at all levels (not just as basal stem cells)
What are the molecular/genetic basis of malignancy?
Either inherited or acquired (usually a combination of both)
What are some genes that can have cancer causing mutations?
Tumour suppressor genes
DNA repair genes (a subset of TSG)
What is generally the occurance (in terms of cell cycle) that is happening in cancer? [2 things]
Cells are being forced out of the G0 stage and forced through the cell cycle. (oncogenes)
Cells are being pushed through different checkpoints in the cell cycle without being corrected or repaired (when they should be put into G0 or killed)
Cancers have a complex genome with chromosomal instability (Gross disorder of the chromosomes). Describe this disorder 
Multiple copies of chromosomes
Deletions of chromosomes
Translocatons (material from one chromosome moving to another)
Describe the mutation in oncogenes
Proto-oncogenes only require ONE HIT = activating mutations (Gain of function)
These drive cells into the cell cycle
Describe the mutation in tumour suppressor genes
These are regulatory genes and thus require TWO HITS in order to have a LOSS OF FUNCTION
- requires both copies
- requires an accumulation of mutations
What are some classes of proto-oncogenes that could have mutations?
Growth factor receptors = increased growth
Kinases (signal transductions)
Transcription factors in nucleus driving transcription
There are three major ways to test abnormalities in these genes. What are the three things that can be looked for?
Translocations: fluorescence can see fusion of different genes
Gene amplification: clusters of nuclear staining in single cells
Sequence mutations (sequencing techniques)
What are the various roles of tumour suppressor genes?
Cell cycle regulation
Describe the loss of heterozygosity effect
Some people are born (inherit) single copies of mutations in TSGs and can live for decades with no ill effect. But one mutation in their only remaining copy then complete loss of function and cancer results.
They have a higher risk of developing loss of function TSG
Where do the mutations in oncogenes occur vs. tumour suppressor genes?
Oncogenes tend to occur in the active portion of the gene whereas TSG mutations tend to occur in all areas of the gene as they are loss of function
What kind of mutations can occur in tumour suppressor genes
Missense, nonsense, frameshift mutations
Loss of heterozygosity
What are the 6 hallmark features of cancer development?
Evasion of apoptosis
Sustaining proliferative signalling
Evading growth suppressors
Activation of invasion and metastasis
Enabling replicative immunity
What is a pre-malignant lesion?
Not yet invasive
But carries high risk of developing malignancy
What is intraepithelial neoplasia?
Dysplasia that occurs in the epithelium: confined to the epithelium.
Want is carinoma in situ?
A very advanced dysplastic lesion that is not yet malignant. The cancer cells are still within the tissue of origin (inclusive of local lymph nodes)
What is transformation?
The movement from a low grade into high grade malignancy via an accumulation of hits into a more aggressive lesion
Describe the differences between low grade, moderate dysplasia and high grade dysplasia
Low grade: atypia seen in the basal half with abnormalities in nuclear size, shape and hyperchromasia
Moderate: atypia extends to involve middle third of epithelium
Severe dysplasia shows full thickness atypia and in severe cases is called carcinoma in situ
What happens that causes invasive nature of the tumour cells?
Breach of the basement membrane through the underlying stroma and then into vasculature (lymphatics and veins)
What four major components of the tumour microenvironment are essential to tumour existence and growth?
1. Some cancer cells may have stem cell like properties
2. Associated stromal cells (especially in the course of invasion)
3. Tumour vascular cells (angiogenesis)
4. Immune infiltrations (can be attacking tumours or attacking normal cells)
What is another important microenvironment in terms of cancer?
The metastatic site is important
Some tumours have the propensities to migrate to different sites likely due to microenvironment
Colon cancer to lung and liver
Prostate cancer tends to bone
Give three examples of areas that undergo metaplasia in response to chronic injury
1. Chronic reflux oesophagus - Barret's oesophagus
2. Chronic atrophic gastritis - intestinal metaplasia
3. Chronic inflammation/smoking - squamous metaplasia of lung bronchial epithelium
Give an example of physiological metaplasia
The cervical transformation zone: the point where the normal squamous protective epithelium of the ectocervis meets the mucous producing glandular epithelium.
This point varies with the menstrual cycle
It is an unstable immature metaplastic squamous lie mucosa and a site very susceptible to infection with HPV
Describe the HPV in terms of dysplasia and cervical cancer
A sexually transmitted infection with many serotypes with high-grade dysplasia and invasive tumour driven by E6 and E7 viral oncogenes
HPV has tropism for certain sites in the body, where is this?
Tropism for basal keratinocytes such as basal cells of transformation zone
What are the low risk vs. high risk types
types 6 and 11 - major cause of genital warts and mild squamous dysplasia (CIN1)
types 16 and 18 - high risk types causing moderate to severe squamous dysplasia (CIN2-3) and causes squamous cell carcinomas
What happens in high risk types HPVs in terms of the genome?
Low risk tend to cause transient infections with viral clearance while High risk tend to integrate with the cellular genome leading to potential tumour production.
Often E6 and E7 oncoproteins are directly interfered with by HPV integration leading to loss of p53 and Rb TSGs and lost p53 apoptosis
What is a HPV infected cell called? Describe its features
Raisenoid hyperchromatic nuclei and perinuclear clearing