T5: Molecular Hallmarks of Cancer Flashcards
What are the biological hallmarks of cancer?
Hallmarks of cancer overview: - Self-sufficiency in growth signals - Insensitivity to anti-growth signals - Tissue invasion and metastasis - Limitless replicative potential - Sustained angiogenesis Evading apoptosis
How are tumour cells able to sustain proliferation?
This is the most functional trait of cancer cells. Signals by growth factors that bind cell-surface receptors, typically containing intracellular tyrosine kinase domains cause intracellular signalling pathways regulating progression through the cell cycle as well as cell growth. Often the signals influence other cell-biological properties such as survival and energy metabolism.
Give an example of how are tumour cells able to evade growth suppressors.
Normally there is the Rb protein regulating progression from G1 to S phase. Negative Growth actors inhibit progression of the cell cycle by activating Rb protein. If the Rb gene is changed such as through somatic mutation family inheritance, there is inactivation of the gatekeeper. The growth suppressor is changed leading to a deregulation of growth, The cell can go from G1 to S phase without being checked.
How are tumour cells able to avoid the immune system?
Normally the tumour cell mimics the normal cell. It interacts with the PD-1 receptor. The immune cell doesn’t recognise the tumour cell as something to be destroyed. If we block the PD-1 or anti-PD-L receptor, there is no-binding and so the T-cell just binds with the T-cell receptor. It then recognises this is a cell that needs destroying. We can use this to cure a range of cancers where we had no treatments before such as metastatic melanoma or malignant melanoma.
How are tumour cells able to enable replicative immortality?
At the end of a normal cells life, the telomere of the chromosome gets shorter. Cancer cells have the ability not shorten these telomeres so they can replicate as much as they want and not die.
How are tumour cells able to promote inflammation?
Tumour cells interact with a range of interleukins and other factors to promote the growth of the factor.
How are tumour cells able to activate invasion and metastasis?
The tumour epithelium grows and expands and eventually breaks through the basal lamina and then gets access to the blood vessels. It then can travel through the blood vessels. Some cancers have preferred locations such as prostate cancer and the bone, ovarian caner spreads very much to the abdominal cavity due to metabolic circumstances on the omentum and its location. It can also spread locally or through the lymphatic system. It can then go onto develop a secondary tumour. Colorectal cancer can access the blood stream and results in a metastases in the liver. Invasion and metastases is the major cause of cancer death.
How are tumour cells able to induce angiogenesis?
A small tumour can survive by diffusion. The larger it grows, it needs more energy. It releases factors into the environment causing sprouting and then a blood supply. The tumour can then also spread through the new blood vessels. The organisation of these blood vessels is not the same as that seen in normal blood vessels - it is more disorganised.
What is a Proto-onocgene?
Proto-Oncogene - normal genes that promote cell proliferation, survival and angiogenesis
What is an oncogene?
Oncogenes - mutated versions/increased expression of proto-oncogenes causing increased/uncontrolled activity of expressed proteins.
What are differences between oncogenes and tumour suppressor genes?
Oncogenes;
- Mutations in one of the two alleles is sufficient (domination affect)
- Gain of function of a protein that signals cell division
- Mutations arises in somatic cells, it is not inherited
- Shows some tissue preference
Tumour Suppressor genes:
- Both alleles must be affected (recessive)
- Loss of function leads to tumour formation
- Mutations can be present in a germ cell or a somatic cells
- Often shows strong tissue preference egg, RB gene in the retina
How does the two-hot hypothesises have an effect in cancer?
A gain in function which is dominant in proto-oncogenes leads to excess cell proliferation. This is in contrast to a tumour suppressor gene which follows a two hit hypothesis. The allele on the other chromosome can compensate for the loss, it is protective. In tumour suppressor genes, the mutation is usually a loss of function.
Give examples of oncogenes.
Examples of oncogenes include the HER2 receptor. An amplification of HER2 can lead to breast cancer. We can then give specific target treatment to these receptors. Other examples include RAS, myc, RAF and EGFR. RAS is a family of proteins including 3 genes KRAS, NRAS and HRAS.
Give mechanisms of oncogene activation.
- Translocation of an oncogene from a low to an active transcriptional site - aberrant expression of the oncogene e.g. myc moves from chromosome 8 to 14. Continuous activation of this gene occurs in Burkitt’s lymphoma. These translocations are better characterised in haematological cancers as samples can easily be accessed.
- Point mutation - substitution of a single base within the amino acid sequence produces a hyperactive oncoprotein - generally if at the end this is a silent mutation but in the first or second location the risk is higher of a missense mutation.
- Amplification by insertion of multiple copies of an oncogene – increased expression. An example includes an amplification of HER2 seen in breast cancer.
- Insertion of a promoter or enhancing gene (by retroviruses) near an oncogene – increased expression such as HPV 16 and 18 seen in vulvar, ovarian and uterine cancers. Their DNA gets embedded in DNA leading to the activation of oncogenes.
Give examples of tumour suppression genes.
Examples include BRCA1/2, p53, APC, RB, hMLH1 (commonly seen in HNPCC) and hMLH2.
