Cancer Biology Flashcards
Basic cancer terminology
- neoplasm (tumour) = a new and abnormal growth
- benign = grow slowly and remain localised
- malignant = grows quickly and invades other sites
- metastasis = when a tumour spreads to another part of the body
Morphology of neoplastic cells
- become larger with variably shaped nuclei
- disorganised arrangement due to many dividing cells
- variation in size and shape
- loss of normal features
- become more basophilic
What is tumorigenesis?
DOUBLE CHECK THIS
Tumorigenesis is the gain of malignant properties in normal cells including:
- dedifferentiation
- fast proliferation
- metastasis
- evasion of apoptosis/immunosurveillance
- dysregulated metabolism and epigenetics
What are the 6 characteristics of cancer cells?
- Self sufficiency in growth signals: autonomous drive to proliferate
- Insensitivity to growth-inhibitory signals: inactivation of tumour suppressor genes that normally inhibit growth
- Evasion of apoptosis: suppress and inactivate genes and pathways that normally allow cells to die
- Limitless replication potential: activate specific gene pathways that render them immortal even after generations of growth
- Sustained angiogenesis: acquire the capacity to draw out their own supply of blood and blood vessels
- Tissue invasion and metastasis: acquire the capacity to migrate to other organs, invade other tissues and colonise these organs
Name some growth factors and state their function
- Colony stimulating factor (CSF) - myeloid lineage in haematopoiesis
- Thrombopoietin - production of platelets
- Erythropoietin (EPO) - production of RBCs
What is an oncogene?
A gene whose product is involved in inducing cancer. Most oncogenes are mutated forms of normal genes (proto-oncogenes) involved in the control of cell growth or division
What is a proto-oncogene?
A normal cellular gene that encodes a protein usually involved in regulation of cell growth and proliferation, and when mutated, becomes a cancer promoting oncogene
What is a tumour suppressor gene?
A gene whose encoded protein directly or indirectly inhibits progression through the cell cycle and in which a loss of function mutation is oncogenic
Chronic myeloid leukaemia accounts for 15-20% of adult leukaemias. Which molecular defect is associated with CML?
A chromosomal translocation resulting in the bcr-abl fusion
How does unregulated cell proliferation occur?
- Molecules that initiate or speed up proliferation are switch on.
- Molecules that inhibit or slow down proliferation are switched off.
List some molecules that can be switched on to lead to unregulated cell proliferation.
- hormones - peptide growth factors
- cell surface receptors (EGFR, HER2, c-Met)
- cytoplasmic molecules (Ras, BRAF, Abl, Src)
- nuclear molecules (cyclin D, Myc, Fos, Jun)
How can pronto-oncogenes becomes oncogenes?
- deletion/point mutations
- regulatory mutations
- gene amplification
- chromosome rearrangement
Describe a deletion/point mutation in reference to proto-oncogenes becoming oncogenes
Hyperactive protein is made in small amounts
Describe a regulatory mutation in reference to proto-oncogenes becoming oncogenes
A normal protein is greatly overproduced
Describe a gene amplification in reference to proto-oncogenes becoming oncogenes
Normal protein greatly overproduced
Describe a chromosome rearrangement in reference to proto-oncogenes becoming oncogenes
- nearby regulatory DNA sequence causes normal protein to be overproduced
- fusion to actively transcribed gene produces hyperactive fusion proteins
How does RAS contribute to unregulated cell proliferation?
- RAS is GTPase protein that transduces signals from cell surface receptors
- a point mutation can cause hyperactive RAS that is on all the time
- this has a dominant effect
- 30% of all tumours screened carry RAS gene mutations
How does BRAF contribute to unregulated cell proliferation?
- BRAF is a kinase that transduces signals from cell surface receptors
- a point mutation can lead to a hyperactive kinase activity that is on all the time
- this has a dominant effect
- 50% of all melanomas have a mutated BRAF
How does EGFR contribute to unregulated cell proliferation?
- is a cell surface receptor that receives extra cellular signal
- deletion of the extracellular portion leads to it being active in the absence of EGF
- this has a dominant effect
- eg. Non-small cell lung cancer
How does ERB B2 (HER2) contribute to unregulated cell proliferation?
- it is a transmembrane receptor that receives signals from other cells
- can be affected by gene amplification
- it is amplified in 20% of breast cancers and indicates a poor prognosis
What is the Philadelphia translocation?
- the translocation mutation of BCR gene on chromosome 22 and ABL gene on chromosome 9
- this leads to the fusion of BCR and ABL to form a BCR-ABL hybrid gene
- this is found in chronic myeloid leukaemia
What happens when tumour suppressor genes are lost or inactivated?
Give examples.
Negative regulators of cell proliferation are removed and they contribute to the abnormal proliferation of tumour cells.
- RB ‘off’ —> retinoblastoma, sarcomas, bladder, breast and lung carcinomas
- p53 ‘off’ —> brain tumours; breast, colon/rectum, oesophageal, liver and lung carcinomas, sarcomas, leukaemias and lymphomas…this is the most frequently mutated gene in cancer >50%
- BRCA1 ‘off’ —> breast and ovarian carcinoma
What is Li-fraumeni syndrome?
An inherited familial predisposition to a wide range of certain cancers
- due to a mutation in p53
In order for a cell to metastasise it must breach their basement membrane. Which molecule would help to facilitate this invasive potential?
MMP-8 (a protease that degrades collagen as basement membrane contains collagen IV)
How can cells evade apoptosis?
- BCL-2 inhibits apoptosis
- increased expression of pro-survival BCL-2 proteins is found in many cancer types e.g. lymphomas
How can cells acquire limitless replication potential?
Telomeres!
- in most somatic cells telomeres shorten with age
- telomerase can ‘add on’ to telomeres aka make them longer
- increased expression of telomerase immortalises cells in culture
- telomerase upregulation or reactivation is found in many forms of cancer
How can a tumour organise its own blood supply?
- a tumour will initially get nutrients via diffusion
- it can’t grown beyond 1-2mm in diameter without a blood supply
- the tumour becomes hypoxic
- this stimulates the tumour to produce VEGF
- VEGF induces blood vessels to grow towards tumour
How can a tumour metastasise?
- defective adherens junction: epithelial tumours often lose E-cadherin (part of junction) partially or completely
- defective ECM junctions: integrins form part of cell-ECM junctions, altered integrin expression is often detected in tumours
- tumours can ‘chew’ through via matrix metalloproteinases (MMPs) e.g. MMP-8 or urokinase plasminogen activator (uPA)
Name 4 drugs that target oncogenic pathways
- Trastuzmab (Herceptin) targets HER2 in breast cancer
- Bevacizumab targets VEGF in colorectal and non-small cell lung cancer
- Imatinib targets ABL in chronic myeloid leukaemia
- Vemurafenib targets BRAF in melanoma
