molecular basis of cancer

Question 1

Describe the transformation process causing a normal cell to become a malignant cell.

Answer 1

The process of transformation is a multi-step process. Malignant transformation occurs due to a number of properties of the cell becoming altered:

1. There is no density dependent inhibition of growth, e.g. normal cells stop growing due to contact inhibition. Cancer cells lose this ability.
2. They lose anchorage independence (e.g. the ability to grow in soft agar).
3. They vary in morphology. This can be seen via histology measures. For example, staining sections with Haematoxylin and Eosin allows visualisation of structures. Usually appears very disordered, unorganised, sometimes several nuclei due to rapid cell replication.
4. They acquire tumourigenicity, e.g. the ability to grow in mice (PDX models).
5. The growth factor requirements increase. Growth factors are overstimulated causing limitless potential to replicate and avoid apoptosis.

Question 2

What can cause alterations or driver mutations?

Answer 2

1. Carcinogenic chemicals
2. Radiation
3. DNA Viruses (HPV)
4. RNA Viruses (HTLV-1)
5. Chemotherapy (can cause second primary)
6. Radiotherapy
7. Replication errors
8. Some hereditary (5%)

Question 3

Explain proto-oncogenes and tumour suppressor genes and how they may cause tumourigenesis.

Answer 3

Activation of proto-oncogenes promotes tumourigenesis (e.g. oncogenes are altered forms of proto-oncogenes). Inactivation of tumour suppressor genes promotes tumourigenesis.

Question 4

Describe the role of p53 in mediating tumourigenesis

Answer 4

DNA damage results in ATM activation which catalyses phosphorylation of p53. Phosphorylated p53 activates p21 transcription factor which is a CDK inhibitor (binds CDK-cyclin complex to inhibit activity). The cell cycle is then arrested and DNA can be repaired. If irreparable, then the cell is apoptosed.

In cancer there may be alteration of TP53 (e.g. disruption or deletion) causing inactivated p53 protein. This results in uncontrolled cell proliferation and uncontrolled DNA damage as p53 is unable to activate p21, therefore unable to sequester CDK-cyclin complex.

Question 5

Why do metastases from primary cancers have certain sites that primarily migrate to?

Answer 5

This occurs due to the cancer cells being favoured in specific sites, as well as the ease of migration to nearby sites.

Question 6

Describe the process of epithelial-mesenchymal transition and how it is mediated.

Answer 6

EMT is an essential process for formation of metastases. This is mediated by integrin, selection, and MMPs, VEGFs, etc. MMPs for example cleave proteins to degrade the extracellular matrix, allowing increased motility of the tumour cells via ECM remodelling. Other factors known to play key roles include: TFF3 which regulates the expression of TWIST and SNAIL. This process can be suppressed by E-Cadherins and TIMPs, etc. To resert themselves at other sites, tumour cells must undergo the opposite transition, e.g. mesenchymal-epithelial transition.