Flashcards in MCB Lecture 65 Neoplasia II Deck (37)
Describe the paradigm of cancer
Cancer stem cell
Conventional cancer therapies are effective against ...
The tumour cells, not the cancer stem cells or progenitors
What is a 'hit'?
This is genetic or epigenetic changes to the Cell
What is the effect on a cell of a 'hit'?
Increased self renewal potential
What are the four genetic events that result in cancer?
1. Activation of a proto oncogene
2. Deactivation of a tumour suppressor gene
3. Replication despite DNA damage
4. Inhibition of apoptosis or senescence
Describe proto-oncogene activation causing cancer
When a proto oncogene is activated, the cell undergoes increased proliferation
Why does mutation of KRAS result in cancer?
Constitutively active proliferation pathways such as MAPK
Describe mutation in tumour supressor genes resulting in cancer
Eg. APC or Rb
When APC is mutated, beta catenin is not marked for breakdown.
Beta catenin stabilises and switches on genes that result in proliferation
Which tumour suppressor genes mutate commonly to form cancer?
APC and Retinoblastoma
What does SNPs of APC cause?
1000s of polyps in the small intestines
One polyp then may undergo malignant transformation, resulting in cancer
What is the function of APC?
It is an integral part of the beta catenin destruction complex
Describe replication causing genomic instability
Which gene in commonly involved?
If DNA is replicated despite genomic instability, mutations in the cells are perputuated, possible resulting in cancer
Describe the function of p53 in healthy and cancerous cells
When there is DNA damage, three things will occur:
- try to repair the damage
- G1 arrest
When there is DNA damage, p53 isn't able to effect all these changes that would stop the perpetuation of the mutated DNA and mutation survives in the cell population
Homozygous loss of ... is seen in almost every type of cancer
Describe how inhibition of apoptosis or senescence results in cancer
Which genes are involved?
p53, Fas receptor, bcl-2, bcl-xL
If there is a mutation in any of these genes, apoptosis can not occur
Which epigenetic events result in cancer?
Histone tail modification
Where does DNA methylation occur?
On the cysteine of CpG islands in the promoter region
What is the outcome of DNA methylation?
That DNA is bulky and thus is not transcribed: is silenced
What patterns of methylation are seen in cancer?
What does this result in ?
Genome wide demethylation
CpG island hypermethylation (promoters of tumour suppressor genes)
Describe how histone tail modifications result in cancer
The histone tails can be acetylated or methylated on lysine residues resulting in either silencing or activation
This results in activation of proto oncogenes or silencing of tumour suppressor genes
Epigenetic modifications are ...
Thus they are a ... for the cell
Describe the selective pressures that cancer cells face
Natural barriers to tissues
How is diversity generated in cancer cell populations?
Consecutive rounds of mitosis, mutation
Natural selection of cancer cells results in ...
More aggressive cells
Describe the mechanism of invasion and dissemination of cancer cells
What are the genetic requirements for this to occur?
They must break down the tissue in which they are, then migrate in the blood stream, and then adhere to another tissue
- Lose Adherens junctions
- Proteolytic enzymes
- Evasion of immune systems
- Colonising the new site: GF etc
Describe the 'vogelgram model' of tumour progression using the example of adenoma formation
- hit -
Hyper-proliferative epithelium, Mucosa at risk
Malignant adenoma/ carcinoma
What criticism is there for the vogelgram model?
However, it is ok for colorectal cancer
What is the parallel model of tumour progression?
There is a population of heterogeneous progenitor cells
From this population, some will go on to form the bulk of the tumour in the tissue
Conventional treatments target these cells.
Further down the track, other cells from the progenitor population, with different mutations, form tumours.
There are now multiple tumours in the tissue, all with different mutations and resistances.
We can't treat all the tumour with the same treatment
What are the conventional cancer treatments?
Describe conventional treatment with the example of colorectal cancer
Early stage: surgery to remove the adenoma
Late stage (metastasis has occurred) : surgery, chemotherapy and radiotherapy - COMBINATION THERAPY
How does colorectal cancer arise?
Adenomas in the gut undergo malignant transformation and become metastatic
What happens in colorectal cancer metastasis
The cancerous cells spread to the liver
How does chemotherapy work?
It targets rapidly dividing cells will poor selectivity
How does radiotherapy work?
It kills malignant cells with radiation
What is problematic with the conventional cancer treatments?
They are coarse and kill healthy cells as well
What is required to proceed from hyper-proliferative epithelium to early, intermediate and late adenoma?
Accumulation of mutation: such as mutations in APC, beta catenin, KRAS