CELLULAR BIOLOGY - Causes and Hallmarks of Neoplasia Flashcards
What is the most prevalent cause of cancer?
Genomic DNA damage leading to genomic instability and mutation accumulations
What are the two main types of DNA damage?
Blockage of replication machinery
Alteration of DNA sequences
What endogenous factors can induce mutations within the genome?
Replication errors
Reactive oxygen species
What exogenous factors can induce mutations within the genome?
UV radiation
Other types of radiation
Mutagenic chemicals
Chemotherapy
Radiotherapy
What is the most common virus that has been proven to induce cancer in animals?
Bovine papillomavirus
What is meant by the multi-hit model of cancer development?
The multi-hit model of cancer development refers to the combination of multiple genomic mutations required for cells to become neoplastic. Cells with a mutation become genetically unstable and thus are more susceptible to acquiring more mutations, leading to a mutation accumulation and neoplasia
Why does the risk of cancer development increase with age?
The risks of neoplasia increase with age as neoplastic cell development requires mutation accumulations which occur over time, thus making older animals more susceptible to cancer
What is a tumour suppressor?
A tumour suppressor inhibits the cell cycle, blocking proliferation and preventing tumour formation
Give two examples of tumour suppressors
p53
Retinoblastoma (pRB)
Describe what happens to the cell cycle when there is a mutation in the p53 gene?
If the p53 gene has a mutation, cells are unable to trigger cell cycle arrest or apoptosis in response to DNA damage. This allows the mutated cell to continue through the cell cycle with the mutation being copied to the daughter cells leading to genomic instability and the acquisition of more mutations
Describe what happens to the cell cycle when there is a mutation in the pRB gene?
If the pRB gene has a mutation, pRB remains in the stimulatory (phosphorylated) state, signalling the mutated cell to continue into the S phase of the cell cycle leading to the mutation being copied to the daughter cells leading to genomic instability and the acquisition of more mutations
What are proto-oncogenes?
Proto-oncogenes are normal cells involved in the regulation of cell growth
What are oncogenes?
Oncogenes are mutated proto-oncogenes which promote cell proliferation and have the ability to cause cancer
What are the three mechanisms of oncogene activation?
Translocation
Gene amplifications
Point mutations
What is translocation of oncogenes?
Translocation of oncogenes is a genetic change in which a piece of one chromosome breaks off and attaches to another chromosome and is now under the control of a strong promoter
What is gene amplification in terms of oncogene activation?
Gene amplification increases the number of oncogene copies through repeated duplication of the oncogenes resulting in increased protein levels
What are point mutations in terms of oncogene activation?
Point mutations are the expression of the oncogenes with an enhanced function
What are the six hallmarks of cancer?
- Self-sufficiency in growth factors
- Insensitivity to ‘anti-growth’ signals
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
Healthy cells require a positive growth signal in order to replicate, however, neoplastic cells can replicate with or without growth factors present. List the three mechanisms neoplastic cells use to achieve this
- Neoplastic cells can synthesise their own growth factors
- Neoplastic cells can syntheses more growth receptors
- Neoplastic cells can bypass the need to growth factors or growth receptors through modifying intracellular pathways
How can neoplastic cells achieve insensitivity to ‘anti-growth’ signals?
Neoplastic cells mutate tumour suppressor genes such as p53 and pRB
Other than mutating the p53 gene, how else can neoplastic cells evade apoptosis?
Neoplastic cells can induce over-expression of the BcL-2 oncogene which encodes for anti-apoptotic BcL-2 proteins
How do neoplastic cells achieve ‘replicative immortality’?
Neoplastic cells achieve ‘replicative immortality’ through the expression of telomerase which synthesises telomeres back onto the ends of the chromosomes to prevent the cell from entering senescence
Describe the process of tumour angiogenesis
- Expression of hypoxia inducible factor (HIF-1) by the neoplastic cells is stimulated by hypoxia
- Hypoxia inducible factor (HIF-1) stimulates the expression of vascular endothelial growth factor (VEGF) which stimulates endothelial growth and proliferation forming sprouts which migrate in the direction of the VEGF being produced by the tumour
What are the three main features of tumour vasculature?
Dilated
Tortuous
Permeable
What is tumour cell invasion?
Tumour cell invasion is the ability of tumour cells to detach from the primary tumour and invade surrounding tissues
What is metastasis?
Metastasis in the spread of neoplastic cells from the point of origin to another part of the body
What are the three main routes of metastasis?
Transcoelomic
Haematogenous
Lymphatic
What are the terms used to describe the movement of neoplastic cells into and out of the blood and lymphatic vessels for metastasis?
Intravasation
Extravasation
Describe the steps of the metastasis cascade
- Metastatic neoplastic cell detaches from the primary tumour followed by migrating to and invading the basement membrane and stroma via proteolysis
- Intravasation of the metastatic neoplastic cell
- Transportation of the metastatic neoplastic cell through the blood or lymphatic vessels
- Extravasation of the metastatic neoplastic cell
- Growth and proliferation of the metastatic neoplastic cell at a secondary site
What must happen to tumour emboli within blood vessels in order to evade the immune system and continue haematogenous metastasis?
Tumour emboli must become surrounded by host platelets to evade the host immune system
Why do neoplastic cells undergo haematogenous metastasis via the veins more than the arteries?
Tumours undergo haematogenous metastasis via the veins more than the arteries because veins have a thinner wall allowing for easier intravasation
What are two common venous routes of haemotagenous metastasis?
- Metastasis from the gastrointestinal system to the liver via the hepatic portal system
- Metastasis from the heart to the lungs via the vena cava
How can adrenal tumours cause sudden death?
Adrenal tumours grow in close proximity to the caudal vena cava and can thus rupture this vein leading to internal haemorrhage and sudden death
What is the ‘seed and soil’ theory?
The ‘seed and soil’ theory states that neoplastic cells are scattered randomly throughout the body during metastasis but only those that land in a favourable environment survive and proliferate
What is the metanistic theory of metastasis?
The metanistic theory states that metastasis is determined by the pattern of blood flow from the anatomical site of the primary tumour to the rest of the body
