6 Hallmarks of Cancer Flashcards
Autonomy from Growth Signals
Normal cells growth in response to extracellular growth factors
e.g EGFR (epidermal growth factor R) uses Tyrosine Kinase
Evasion from Growth Inhibitiory Signals
Growth inhibitory signals aim to restrict growth - inhibiting promalignant pathways
Pro-growth signal overcome inhibitory signals
Upregulate growth R
Activating signaling cascade
Evasion of Apoptosis
Activated extrinsically in response to TNF-Alpha
Activated instrinsically due to oxidative stress or DNA damage
Cells deficient in pro-apoptotic signals are at risk of carcinogenesis
e. BCL-2 = antiapoptotic
BAX = pro-apoptotic
p53 = pro-apoptotic
Most tumour cells have a mutation in P53 (decrease apoptosis, increase likelyhood of future mutations + resistent to cancer treatment)
Unlimited Replication
Telomerase is inactive
Telomerase is upregulated in most tumour cells, therefore, keeping telomerase long
Proteins that activate tolermerase contribute to maligannt transformation
Angiogenesis
Angiogenesis is stimulated by hypoxia
Major stimulant is the Vascular Endothelial Growth Factor (VEGR), which is upregulated in tumour cells
Inhibitors of angiogenesis are down regulated
Invasion and Local Metastisis
Most normal cells require interactions from the extracellular matrix and adjacent cells for survival
*Cancer cells don’t need to interact with adjacent cells or the extracellular matrix *
Tumour cells are free from inter and extra cellular connections via abnormal expression of Integrins
Hereditory cancer is usually associated with?
Tumour suppressor genes
Mutations that occur in germline cells
Multiple oncogenes and tumour suppressor genes are invovled in cancer development
Single gene mutation can have a dramatic effect on the risk of developing cancer
Are retinoblastoma normally Familial or Sporadic? What’s the difference between the two?
Sporadic - 60% - Unilateral
Familial - 40% Bilateral
What gene is mutated in a retinoblasoma?
A mutated Rb gene
Gene regulates cell cycle progression
Increases replication rates
Predisposed to further mutations
What hereditory genes are associated with Breast Cancer? What are these genes role?
BRCA 1 - cell cycle checkpoint regulator, inolved in repairing double strand DNA breaks. 80% risk of breast cancer. 95% risk of ovarian cancer
BRCA 2 - invovled in repair of double strand DNA breaks. 80% risk of breast cancer, 50% ovarian cancer
What do you calculate risk? What happens according to low, moderate and high risk individuals?
Risk = Age, Personal risk factors, FHx
Low risk - mammogram screening from age 50, breast awareness
Moderate Risk - Annual mammography, counselling and information
High Risk - specilist clinic, genetic counselling
How can you exploit inhereted genes in treatment? Name one treatment
Specifically BRCA1 and BRCA2
Many cancer treatments aim to damage DNA e.g chemotherapy. Therefore, BRCA1 and BRCA2 deficent tumours should be more sensitive to these agents.
e.g Cisplatin
Inhibitors of DNA repair protein PARP generate DNA damage that is repaired by **BRACA1/2 **
What is Synthetic Lethergy? How can we use this in treatment?
Combination of mutations in 2+ genes leads to cell death
Sythetic lethergy in tumours from BRCA1 and BRCA2 can be treated with PARP inhbitors.
If a PARP inhibitor is breast in a cancer cell BUT BRCA is active, then the cell is repaired but becomes a resistant tumour cell.
However, if a PARP inhibitor is used in a tumour cell where BRCA is inactive, then synthetic lethality occurs and the sensitive tumour cell dies!
What is Chronic Myeloid Leukaemia? What mutation? What treatment?
High WCC + spenomegally
Mutation in the Philadelphia Chromosome (translocation in the BCR-ABL oncogene)
Treatment = Imatinib, preventing tumor cell proliforation
(survival rate >95% at 5 years)
Viral infections and Cancer
HPV 16&18 - Cervical Carcinoma
HTLV1 - Adult T Cell Lymphoma
EBV - Burkitts Lymphoma
Hepatitis B&C - Hepatocellular Carcinoma
What’re Oncogenes? Give an example?
Mutated versions of normal human genes
Oncogenes are Dominant
Increased expression of the gene. Alter the protein product so it is more active, not degraded.
Increase activity of promalignant pathways
Inhibit activity of anti-malignant pathways.
erbB1 - encodes the EGFR - this receptor is activated even in the absence of EGF. Overactivity of the RAS-MAPK pathway
erbB2 - amplified in over 25% of breast cancers. Causes overexpression of HER2 (more aggressive and less responsive to treatment)
What are Tumor Suppressor Genes? Name some Tumour Suppressor Genes
Normal genes that supress pro-malignant pathways (including apoptosis, cell cycle checkpoints, growth inhibiton, DNA repair)
Tumour suppressor genes are recessive (therefore both alleles need to be lost for a malignant process to occur)** **
Tumour supressor genes CAN be inherited (however, more commonly mutations occur sporadically)
Loss of this function of these genes are carcinogenic
BRCA1/2, Retinoblastoma
Describe what happens with the tumour suppressor gene P53? And also what happens to P53 in cancers?
Downstream effects - cell cycle arrest, apoptosis, DNA repair, inhbition of angiogenesis
Upstream effects - DNA damage, aberrant growth signals oncogne activation, cell stress (hypoxia)
P53 is mutated in 50% of all cancers - (cells undergo mitosis with damaged DNA, cells don’t undergo apoptosis, incompetant DNA repair, tumour angiogensis persists)
What is Li-Fraumeni Syndrome?
Grossly increased cancer risk
P53 mutation is spontaneous
May arise due to a background of other mutations
Predisposes to further mutaitons
Describe what happens to a mutation in the APC tumour suppressor gene and what condition this leads to?
APC leads to Familial Adenomatous Polyposis (FAP)
Inherited
One mutant allele is present and a spontaneous mutation occurs in the other
Causes development of colonic polyps (increased predisposition to cancer)
Describe the multistep carcinogenesis in colorectal cancer
- Normal colonic epithelium (APC mutation)
- Small adenoma (K-Ras mutation)
- Large adenoma (P53 mutation)
- Carcinoma
- Metastisis
Similar pathway for other cancers
What is Leukaemia? Treatment?
Uncontrolled proliferation of the primitive cells of the bone marrow
CML is due to the philadelphia chromosome
Treatment - chemotherapy, supportive (antibitoics, antifungals, transfusions), stem cell transplant
What targeted therapys are avalible? Include those for CML and Non-hodgkin’s lymphoma
CML
Target inhibition of BCR-ABL Kinase (a translocation in the Philadelphia chromosome)
Imatinib (Inhibitor of BCR-ABL)
_Non-hodgkin’s lymphoma _
Rituximab (targets CD30 on B-cells)
Breast Cancer
Herceptin tragets HER2 on breast cancer cells
