Genetic Pathways in Cancer Flashcards
Describe selective advantage? Give an example of selective advantage.
- All organisms are limited by environmental growth constraints.
- All organisms are in competition with each other.
- Mutations may alter the characteristics of an organism allowing it to outcompete its rivals.
- Such mutations are said to give a selective advantage.
- e.g. peppered moth dark variant becoming predominant after the industrial revolution - trees became darker and darker moths had a survival advantage
Outline growth restraints in normal tissues. Give an example of a tissue in which these growth restraints are particularly visible and important.
- Many normal tissues undergo continuous turnover.
- New cells are produced by cell division from stem cells and old cells die by apoptosis.
- An imbalance between the rates of cell division and cell death will cause tumour development.
- Oncogenes and TSGs affect cell proliferation and apoptosis.
- Growth control ensures that cell division is equivalent to cell death
- e.g. the colonic mucosa is a well organised and dynamic stricture. Dynamic gradients of morphogens/matrix components/signalling activity have been described. Proteomic analysis in colonic mucosa would show gradient of morphogens keeping proliferation under control and maintaining cell maturation and apoptosis. Wnt signalling activity is particularly important. There is usually a high concentration of Wnt at the base of the crypt where you want the proliferation to be highest, and there is a reduction in the level of Wnt towards the surface because towards the top you don’t want proliferation to be occuring you want the cells to undergo maturation and apoptosis. The reciprocal is BMP2/4. BMP2/4 inhibit proliferation so you have a low level at the base of the crypt and a higher level towards the surface. The lower levels at bottom of crypt mean that there is little inhibition of proliferation. The higher levels at the top of the crypt cause inhibition of proliferation and facilitate maturation of cells. Other morphogens have similar gradients to try and ensure that the colonic mucosa maintains the status quo with well organised tissue architecture and cell growth is maintained.
Wnt and EphB1 are at high concs in the crypts and low concs at the surface.
EphrinB, APC, and BMP2/4 are at low concs in the crypts and high concs towards the surface.
At what level of the gut mucosa should Wnt signalling levels be highest under normal circumstances? Why?
There is usually a high concentration of Wnt at the base of the crypt where you want the proliferation to be highest, and there is a reduction in the level of Wnt towards the surface because towards the top you don’t want proliferation to be occuring you want the cells to undergo maturation and apoptosis.
At what level of the gut mucosa should BMP2/4 signalling levels be highest under normal circumstances? Why?
BMP2/4 inhibit proliferation so you have a low level at the base of the crypt and a higher level towards the surface.The lower levels at bottom of crypt mean that there is little inhibition of proliferation. The higher levels at the top of the crypt cause inhibition of proliferation and facilitate maturation of cells.
Briefly name some of the morphogens that maintain the proliferative gradient of the colonic mucosa and where in the mucosa they are found at the highest concentrations.
Wnt and EphB1 are at high concs in the crypts and low concs at the surface.
EphrinB, APC, and BMP2/4 are at low concs in the crypts and high concs towards the surface.
What mechanisms can growth control be mediated by? What is necessary for a tumour to develop.
Growth control can be mediated via a number of different mechanisms:
1) . Levels of secreted growth factors
2) . Environmental growth inhibitory factors.
3) . Levels of secreted growth inhibitors.
4) . Intrinsic program of differentiation/apoptosis.
5) . Tumour immune response.
- For a tumour to develop these growth control mechanisms need to be subverted.
- For a tumour to survive and become malignant, it needs to also acquire further features beyond escaping growth control such as:
1) . Limitless replication/immortality
2) . Angiogenesis - needs oxygen to survive
3) . Invasion and metastasis
What factors are required for tumour development?
- For a tumour to develop growth control mechanisms need to be subverted.
- For a tumour to survive and become malignant, it needs to also acquire further features beyond escaping growth control such as:
1) . Limitless replication/immortality
2) . Angiogenesis - needs oxygen to survive
3) . Invasion and metastasis
Outline the hallmarks of cancer.
1) . Self sufficiency in growth signals
2) . Insensitivity to anti-growth signals
3) . Evading apoptosis
4) . Limitless replicative potential
5) . Sustained angiogenesis
6) . Tissue invasion and metastasis
Outline the steps involved in tumour evolution.
- Normal tissue is converted into a tumour by gene mutation. Takes a long time to acquire mutations and see precursor lesions in between. Lesions obvious in colon - not always visible in other tissues.
- Normal tissues develop into cancers via a number of intermediate precursor lesions.
- The adenoma carcinoma sequence describes the histological evolution of colorectal cancers.
- The Fearon-Vogelstein model describes the genetic basis of tumour evolution.
Describe the adenoma-carcinoma sequence.
1) . Change from normal to early stage adenoma. Driven by APC gene mutations. Acquisition of displastic features. Occasional crypts will look abnormal. Unicryptal early stage adenoma.
2) . Need acquisition of another mutation for abnormality to progress, usually KRAS2. Crypts will divide and you will start seeing a larger adenoma. More crypts involved. May become polyploid. APC and KRAS2 mutations alone are not enough for an invasive malignancy to form.
3) . On acquiring another mutation, usually in genes on 18q such as SMAD the adenoma continues to grow.
4) . The additional acquisition of a mutation in TP53 will result in a high grade adenoma becoming an invasive cancer.
- Can see this process histologically under the microscope. This is the histological evolution of cancer.
- Clonal expansion correlates with these stages.
- It is thought that approximately 5-6 mutations are required for malignant conversion of a normal cell.
- The sequence of occurrence of the mutations tends to be maintained (e.g. it is very rare to find p53 mutations in early adenomas).
- Mutations occur randomly throughout the genome but are selected when they give maximal growth advantage. This results in waves of clonal expansion.
How many mutations are thought to be required for the malignant conversion of a normal cell?
- It is thought that approximately 5-6 mutations are required for malignant conversion of a normal cell,.
Why do we waves of clonal expansion in tumour evolution?
- It is thought that approximately 5-6 mutations are required for malignant conversion of a normal cell.
- The sequence of occurrence of the mutations tends to be maintained (e.g. it is very rare to find p53 mutations in early adenomas). It is not that TP53 mutations don’t occur at the early stages however, it is just that at this stage APC mutation will provide a better selective advantage and so the cells with the TP53 mutations will be outcompeted.
- Mutations occur randomly throughout the genome but are selected when they give maximal growth advantage. This results in waves of clonal expansion.
- A mutation giving a selective advantage allows clonal expansion to occur. Whatever mutation outgrows all the others is the one for which a clonal.
- The stages in the adenoma-carcinoma sequence essentially correlate with the clonal expansion.
Give a brief summary of tumour selection.
- Tumours arise from normal cells as a result of random gene mutation.
- Mutations will only be selected if they give a selective growth advantage.
- Sequential mutations result in Darwinian evolution of tumours.
- This will lead to a consistent sequence of accumulation of mutations i.e. the genetic pathway.
What clonal situation arises when resistance to chemotherapy occurs?
- If you give a patient chemotherapy you are introducing another growth restraint in the form of the chemotherapy.
- When you get resistance to chemotherapy what is basically happening is that mutations are occurring and resistant clones are emerging from the malignant cells that were already there. These clones are emerging as a consequence of mutations that give resistance to that particular form of chemotherapy.
- Evolution of cancer goes on not only in the early stages but also at later stages when patients may be receiving chemotherapy.
- Once a clone emerges that is resistant to chemotherapy you either have to change the chemotherapy or you will not be able to continue treating the cancer.
Why will the genetic pathways between tumours of the same origin always be similar?
- Genetic pathways of the same origin will be similar.
- This is because the growth restraints on the cells as they have developed into a tumour have been similar. Therefore, in order for the tumours to arise they will have had to develop identical or analogous mutations to give them the selective advantages required to continue developing.
- i.e. selective advantage ensures that mutation acquisition is broadly consistent.
- A mutation will be more likely to be selected firstly if it helps to deal with environmental growth restraints, but ALSO if it interacts with the previous mutations successfully. Thus oncogenes may ‘cooperate’.
