CARCINOGENESIS Flashcards
List the 8 cancer hallmarks
- Sustaining proliferative signalling.
- Evading growth suppressors - insensitivity to growth inhibitory signals.
- Resistance to cell death (by evasion of apoptosis).
- Replicative immortality (limitless replicative potential).
- Angiogenesis (new blood vessel formation).
- Reprogramming of energy metabolism.
- Evasion of immune surveillance.
- Activation of invasion/metastasis.
List a known bacterial carcinogen and list 2 tumours associated with this infection.
Helicobacter pylori infection of the stomach is associated with gastric adenocarcinoma and marginal zone B-cell lymphoma.
List 7 viruses which are known carcinogens and one tumour type associated with each virus.
- Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma).
- Hepatitis B virus (Hepatocellular carcinoma).
- Hepatitis C virus (Hepatocellular carcinoma and some lymphomas).
- Human T-lymphotropic virus (Adult T-cell leukaemia).
- Human papilloma virus 16 + 18. (Squamous cell carcinoma of cervix, penis, anus, head and neck).
- Human herpesvirus 8. (Kaposi’s sarcoma. Primary effusion lymphoma).
- Merkel cell polyomavirus. (Merkel cell carcinoma of the skin).
List 3 trematodes (flukes) which are known carcinogens and their associated tumours.
- Clonorchis sinensis (Biliary cancer. Pancreatic cancer. Gallbladder cancer).
- Opistorchis viverrini (Biliary cancer. Pancreatic cancer. Gallbladder cancer).
- Shistosoma haematobium (Squamous cell carcinoma of the bladder).
Which two tumour types are associated with exposure to ionising radiation?
Myeloid leukaemia (acute and chronic).
Papillary carcinoma of the thyroid.
List 3 skin tumours which are associated with non-ionising radiation (UVB from sunlight).
- Squamous cell carcinoma.
- Basal cell carcinoma.
- Malignant melanoma.
What is an oncogene?
Proto-oncogenes are essential for cell growth and differentiation. Mutations of proto-oncogenes form oncogenes that lead to unregulated cell growth.
List 5 oncogene types.
- Growth factors eg. platelet-derived growth factor which is mutated in some astrocytomas (brain tumours).
- Growth factor receptors eg. Her 2 which is amplified in some breast cancers.
- Signal transducers eg. RAS which is the most commonly mutated human oncogene.
- Nuclear regulators.
- Cell cycle regulators eg cyclins and cyclin-dependent kinases.
Which component of the mitogen activated protein pathway activates BRAF?
RAS
Which component of the mitogen activated protein pathway activates BRAF?
What is Knudsons two-hit hypothesis?
Knudsons two hit hypothesis applies to tumour suppressor genes and states that both copies of the gene must be affected to cause disease.
Two important tumour suppressor genes are p53 and Retinoblastoma. Describe the normal function of p53.
DNA damage triggers expression of the p53 gene which prevents the cell from entering the S-phase of the cell cycle. This means that there is arrest of the cell cycle at the G1 phase which allows DNA repair to take place by up-regulation of DNA repair enzymes. p53 stops the cell cycle by causing transcription of a cyclin dependent kinase inhibitor (p21) which blocks the CDK4/Cyclin D complex. If the DNA damage is so severe that it cannot be repaired, p53 can cause permanent cycle arrest/senescence or it can trigger apoptosis by up-regulating BAX which disrupts BCL2. This causes cytochrome c to leak from mitochondria triggering apoptosis. BCL2 normally stabilises the mitochondrial membrane blocking release of cytochrome c. As the p53 gene conserves stability of the genome, it is known as the guardian of the genome.
What is the function of the retinoblastoma gene in the cell cycle?
Retinoblastoma regulates the progression from the G1 to the S phase of the cell cycle. The E2F transcription factor is released when retinoblastoma is phosphorylated by the cyclin D/cyclin-dependent kinase 4 complex. Retinoblastoma mutation results in constitutively free E2F allowing progression through the cell cycle and uncontrolled growth of cells.
BCL2 regulates apoptosis. How do apoptosis regulators work?
Apoptosis regulators stop normal cells from dying but promote cell death in mutated cells whose DNA cannot be repaired. BCL2 prevents apoptosis by stabilising the mitochondrial membrane and blocking the release of cytochrome c. If BCL2 is disrupted, cytochrome c is released triggering apoptosis. BCL2 is overexpressed in a form of lymphoma called follicular lymphoma. Remember that lymphoma is a malignant tumour of lymphocytes. Follicular lymphoma shows a translocation between chromosomes 14 and 18 (t(14;18)) which moves the BCL2 gene from chromosome 18 to the Ig heavy chain locus on chromosome 14 causing increased BCL2. This causes enhanced stabilisation of the mitochondrial membrane preventing apoptosis and allowing the malignant lymphocytes to become immortal.
What is the role of telomerase in carcinogenesis?
Telomeres normally shorten with serial cell divisions eventually causing cell senescence. Cancers often show upregulation of telomerase.
How do cancers create a new blood supply to support their growth?
Cancers commonly produce fibroblast growth factor and vascular endothelial growth factor which are both angiogenic factors responsible for blood vessel creation.
List the hallmarks of cancer and drug classes which are being developed to target these.
- Sustaining proliferative signalling. EGFR inhibitors.
- Evading growth suppressors. Cyclin-dependent kinase inhibitors.
- Avoiding immune destruction. Immune-activating anti-CTLA4 mAb.
- Enabling replicative immortality. Telomerase inhibitors.
- Tumour-promoting inflammation. Anti-inflammatory drugs.
- Activation of invasion and metastasis. Inhibitors of HGF/c-Met.
- Angiogenesis. Inhibitors of VEGF signalling.
- Genome instability and mutation. PARP inhibitors.
- Resisting cell death. Pro-apoptotic BH3 mimetics.
- Reprogramming of energy metabolism. Aerobic glycolysis inhibitors.
What is dysplasia?
Dysplasia is disordered cell growth, which most often refers to a proliferation of pre-cancerous cells. It is also called intraepithelial neoplasia. Dysplasia often arises from longstanding hyperplasia (endometrium) or metaplasia (oesophagus and bronchus). Dysplasia is theoretically reversible with alleviation of the inciting stress. If the stressor persists dysplasia can progress to carcinoma which is irreversible.
What is a neoplasm?
Neoplasm means new growth. This growth is unregulated, clonal and irreversible. Neoplastic tumours can be benign or malignant.
Describe the differences between benign and malignant tumours.
Benign tumours remain localised, have a slow growth rate and closely resemble the tissue from which they arise. They are often circumscribed or encapsulated.
Malignant tumours are by definition invasive and are capable of directly invading the surrounding tissue and many have the capacity to metastasise. They are often rapidly growing with an irregular margin. Well-differentiated malignant tumours may closely resemble the tissue from which they arise whereas poorly differentiated malignant tumours may not look anything like their tissue of origin.
What is the difference between carcinoma in situ and invasive carcinoma?
The term carcinoma in-situ refers to an epithelial neoplasm showing all of the cellular features associated with malignancy but which has not yet invaded through the epithelial basement membrane, separating it from potential routes of metastasis (blood vessels and lymphatics).
How do you distinguish a benign cell from a malignant cell?
Malignant cells have increased nuclear to cytoplasmic ratios, show nuclear pleomorphism and hyperchromasia, have an irregular chromatin distribution pattern within their nuclei, with irregular nuclear membranes +/- prominent nucleoli.
Benign cells have low nuclear to cytoplasmic ratios. All benign nuclei show a similar nuclear size and are not hyperchromatic. They have vesicular, evenly distributed chromatin with smooth nuclear membranes.
