LECTURE 1 Flashcards
What are the characteristics of Benign tumours?
- Cells remain clustered together
- Do not metastasise (spread)
- Non-cancerous
- Just like normal cells
What are the characteristics of Malignant tumours?
- Spread wider distances
- Go all the way to tissues and to the bloodstream
- Metastasise uncontrollably & are cancerous
- Abnormal shape and darker & larger nucleus
What are the major classes of cancer?
- CARCINOMA = arises in epithelium
- SARCOMA = starts in supporting or connective tissues of body
- LEUKEMIA = begins in blood-forming tissues
- LYMPHOMA = forms in lymph cells
What are the hallmarks of cancer?
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
- Enabling replicative immortality
- Activating invasion & metastasis
- Inducing angiogenesis
- Resisting cell death
- Deregulating cellular energetics
What is the most prominent of the signalling channels that accelerate growth?
Growth promoting signals transmitted through the RAS_RAF-MEK-MAPK pathway
[1/3 of human tumours express an active mutant form of RAS]
What are the main members of the RAS gene family?
- KRAS
- HRAS
- NRAS
What does a mutant form of RAS cause?
Uncontrolled growth, proliferation and migration
What is TP53?
It sense the need to halt cell cycle progression and can trigger apoptosis -> 50% of tumours have mutation -> LI-FRAUMENI SYNDROME (5% chance of developing cancer by 30)
What is RB?
Gatekeeper of cell cycle progression
What happens in Necrosis?
1) Chromatin clumping, swollen organelles & fluorescent mitochondria
2) Disintegration
3) Release of intracellular contents
4) Inflammation
What happens in Apoptosis?
1) Mild convolution, chromatin compaction and segregation and condensation of cytoplasm
2) Nuclear fragmentation, Blebbing and apoptotic bodies
3) Phagocytosis
What are the immune programs that cancer cells avoid?
- APOPTOSIS (maintains homeostasis)
- NECROSIS (activated by oxygen and energy deprivation)
- AUTOPHAGY (degrading cellular organelles, autophagy generates the metabolites and nutrients that cells are unable to acquire from their surroundings)
Describe ‘Enabling replicative immortality’
The cellular timekeeper “TELOMERE” is destroyed -> cells acquire the unlimited replicative potential (CELLULAR IMMORTALITY) that is required to spawn large tumour masses
Describe the loss of telomeric repeats leads to growth arrest
1) DNA POLYMERASE is unable to replicate the tips of chromosomes -> loss of DNA at the specialised ends of chromosomes with each replication cycle
2) Loss of TELOMERIC REPEATS with each cell division cycle -> gradual telomere shortening
3) GROWTH ARREST when one or more critically short telomeres trigger P53-REGULATED DNA-DAMAGE CHECKPOINT RESPONSE
How do all cancer cells maintain their telomeres?
Increase the production of TELOMERASE ENZYME (telomerase functions by adding TELOMERIC DNA to the ends of chromosomes)
What is Angiogenesis?
Turning on new blood vessel growth to feed and nurture the growing mass of cancer cells
What do tumours require?
A steady supply of oxygen, glucose and other nutrients to evacuate metabolic waste and sustain CELL VIABILITY and PROLIFERATION
What is the function of the Hypoxia-Inducible Transcription Factor (HIF) system?
Regulates hundreds of genes, including ones that directly or indirectly induce angiogenesis and other stress-adaptive capabilities
What are the three major features of tissue invasion?
- Cell adhesion to the basement membrane
- Local proteolysis of the membrane
- Movement of the cell through the ECM
What is the difference in energy pathways for cancer cells and normal cells?
CANCER CELLS = utilise anaerobic glycolysis -> increased lactic acid production
NORMAL CELLS = utilise oxidative phosphorylation
Describe the Warburg effect
Cancer cells produce energy through a less efficient process of AEROBIC GLYCOLYSIS consisting of high levels of glucose uptake and glycolysis followed by LACTIC ACID FERMENTATION taking place in the CYTOSOL, not mitochondria, despite abundant oxygen
What drugs inhibit ‘Evading growth suppressors’?
Cyclin-dependent kinase inhibitors
What drugs inhibit ‘Avoiding immune destruction’?
Immune activating anti-CTLA4 MAb
What drugs inhibit ‘Enabling replicative immortality’?
Telomerase inhibitors
What drugs inhibit ‘Tumour-promiting inflammation’?
Selective anti-inflammatory drugs
What drugs inhibit ‘Activating invasion and metastasis’?
Inhibitors of HGF/c-Met
What drugs inhibit the inducing of angiogenesis?
Inhibitors of VEGF signalling
What drugs inhibit ‘Genome instability and mutation’?
PARP inhibitors
What drugs inhibit ‘Resisting cell death’?
Pro-apoptotic BH3 mimetics
What drugs inhibit ‘Deregulating cellular energetics’?
Aerobic glycolysis inhibitors
What drugs inhibit ‘Sustaining proliferative signalling’?
EGFR inhibitors
What is the difference between Somatic DNA changes and Germline DNA changes?
SOMATIC DNA CHANGES
- acquired over a person’s lifetime in single cells
- can lead to cancer
- can not be inherited
GERMLINE DNA CHANGES
- present in every cell of the body including egg and sperm
- can increase cancer susceptibility
- can be inherited
What are the progressive steps of cancer?
1) HYPERPLASIA = cell divides more rapidly than normal
2) DYSPLASIA = cells change form
3) CARCINOMA IN SITU = cells stay in one place
4) MALIGNANT TUMOUR = cancer cells invade normal tissue & enter blood and lymph -> tumours form at distant sites
What does the p53 gene produce?
A protein that turns “off” the cell cycle and helps to control cell growth
Describe Proto-oncogenes
NORMAL FUNCTION: promote cell survival or proliferation
EFFECT OF MUTATION: Gain-of-function mutations allow unregulated cell proliferation and survival (usually dominant)
ORIGINS: Point mutation, chromosomal translocation & amplification
Describe Tumour-suppressor genes
NORMAL FUNCTION: inhibit cell survival or proliferation
EFFECT OF MUTATION: Loss-of-function mutations allow unregulated cell proliferation and survival (usually recessive)
ORIGINS: deletion, point mutation & methylation
Describe Caretaker genes
NORMAL FUNCTION: Repair or prevent DNA damage
EFFECT OF MUTATION: Loss-of-function mutations allow mutations to accumulate
ORIGINS: deletion, point mutation & methylation
Describe the clonal origin theory of cancer
A tumour arises initially from 1 specific cell which then develops a growth advantage over other cells
Describe the multistep nature of cancer
1) Loss of normal tumour-suppressor gene APC and a POLYP (small growth forms)
2) A benign, precancerous tumour grows
3) Activation of oncogene RAD and an ADENOMA (benign tumour) grows
4) Loss of tumour-suppressor gene p53 and a CARCINOMA (malignant tumour) develops
5) Cancer metastises
What are the non-modifiable risk factors for cancer?
- Age
- Genetics/Family history
What are the modifiable risk factors for cancer?
- Diet
- Physical activity levels
- Toxic exposures
- Immune health
- Stress levels
Describe Xeroderma Pigmentosum
A condition in which thymine dimerisation from exposure to UV is not repaired; exposure to sunlight results in SKIN LESIONS.
It is an AUTOSOMAL RECESSIVE DISORDER in which there is a decreased ability to repair DNA damage. Mutations in repair genes have been known to cause cancer.
[signs appear in infancy or early childhood & affects the eyes and areas of skin exposed to the sun]
SIGNS AND SYMPTOMS:
- severe sunburn after a few minutes in the sun
- redness & blistering
- freckling
- dry skin (XERODERMA)
- skin colouring (PIGMENTATION)
- multiple skin cancers
