Molecular Basis of Cancer 2 Flashcards
What is meant by cells having limitless replicative potential?
Feature of cancer cells
Has unrestricted proliferative capacity
Able to divide indefinitely without undergoing cellular senescence and mitotic catastrophe.
What are the six hallmarks of cancer?
Sustain proliferative signalling
Evade growth suppressors
Activate invasion and metastasis
Enable replicative immortality
Induced angiogenesis
Resist cell death
What are the two barriers in non cancerous cell for replicative immortality?
Senescnes - cells exisintg long term in a non growing but viable state.
Crisis - apoptopic death of cells
What is a telomere?
Consists of short nucleotide sequences, guanine rich, that are repeated multiple times, act as a cap over the chromosome
Are maintained by telomerase enzymes
Tends to decrease repeat length from gamete to older individuals, suggesting reduced during each division, progressive shortening of telomeres over lifespan.
Loss of telomeres results in cell senescence.
What is the normal process by which cell senescence occurs in non-cancerous cells with a functional p53 gene?
Replication - telomerase expression maintains telomere length
Replication - telomerase is not active - telomeres are progressively shortened - continues for 50-70 divisions
Expression of functional p53 protein
Then checkpoint activation and cellular senescence oocurs as telomeres too short.
Senescent cell.
What happens in a cell with shortened telomeres and non functional p53?
Shortened telomeres
No expression of functional p53
Activation of salvage and non-homolough end joining pathways
Results in dicentric chromosomes.
Undergoes metaphase and anaphase pulling apart dicentric choromsome.
This create new double stranded breaks. (this is known as the brdige-fusion breakage cycle)
Is telomerase is expressed cancer develops
If telomerase is not expressed mitotic catastrophe occurs.
What is the bridge-fusion-breakage cycle?
Occurs in cells with shortened telomeres still undergoing replication - sign of replicative disfunction
Inactive p53 gene expression
Non-homologous end joining and salvage pathway results in dicentric chromosomes (joining of parts of choromsomes so two centromeres per chromosome)
Then undergoes metaphase and anaphase resulting in dsDNA breakage.
Process repeats, resulting in high genomic instability.
What is mitotic catastrophe?
A mode of cell death due to abnormal initiation or progression of the cell cycle.
Helps prevent the formation of cancerous cells.
What is the function of hTERT telomerase?
Elongates telomeric DNA by extending it in hexanucleotide sequences.
May be activated during bridge-fusion-breakdage cycle
Leads to replicative immortality and avoidance of mitotic catastrophe.
What signalling helps regulate cancer metastasis?
Intrinsic cell singalling and mutations
Signals from the tissue environment.
What is the multi-step hypothesis model of carcinogenesis?
Carcinogenesis requires the accumulation of multiple mutations.
Mutations arise independently in different clonal cells resulting in subclones with varying abilities to grow, invade, metastases and respond to therapy.
Over time as tumours grow in size more mutations are acquired, tumours become more aggressive and acquire greater malignant potential - this is known as tumour progression.
What is meant by tumour progression?
Over time as the tumour grows it acquire new mutations, becomes more aggressive and has higher malignant potential.
What is the clonal selection process in cancer cells?
First mutation - gives slight growth advantage
Second mutation - progeny cell, more uncontrollable growth and form benign tumour
Third mutation - in progeny cells, overcome TME constrainsa nd outgrowth other masses with same genetic changes
Fourth mutation - progency metastasis via blood stream and stable daughter colonies at other sites.
Some cells in a given tumour will share genetic mutations, acquire early in their evolutionary history.
Can take decades for required mutation to occur, hence cancer risk increases with age.
How does the multip-step hypothesis of cancer development apply to colorectal cancer?
APC (TSG) mutation in single epithelial cells - cell divided to form a localised polyp - benign tumour
Genetic instability increases over daughter generations, progressive mutation of Ras (becomes oncogene as constitutively active) and mutation of p53 (loss of function), generates a malignant cell - this gain of malignant potential is known as cancer progression.
Cell porgency invade the basement membrane that surrounds tissues, eventually some tumour cells invade blood vessels which will distribute them to other sites in the body.
Additional mutations enable the tumour cells to exit from the blood vessels and proliferate at distant sites.
What are the stages of progression in the developer of cancer in the uterine cervix epithelium?
Normal epitheliul - stratified sqaoumous division only in basal layer
Low grade intra-epithelial neoplasia - dividing cells in lower 1/3, superficial cells are still flattened and show sign of differentiation but this is incomplete.
High grade IEN - all epithelial layers of prolferating cells and have defective differentiations
invasive carcinoma - cells destroy and move through basal lamina, invade underlying connective tissue.
What are some key bank terms to use when describing benign tumours gross features?
Localised
Organised
Slow and expansive growth
Non-metastatic
Non-invaisve
Encaspulated
Clear, smooth borders.
