Molecular Hallmarks of Cancer Flashcards
What are the main 6 hallmarks of cancer?
- Evading apoptosis
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- Sustained angiogenesis
What is the most fundamental trait of cancer cells ability to sustain chronic proliferation?
Sustainting proliferative signalling
How do cancer cells dysregulate normal proliferative signalling?
- Normal tissues carefully control the production and release of growth-promoting signals, ensuring homeostasis of cell number.
- Cancer cells deregule these signals
- Growth factors that bind cell-surface receptors, typically containing intracellular tyrosine kinase domains
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Intracellular signaling pathways that regulate progression through the cell cycle as well as cell growth
- Often these signals influence yet other cell-biological properties, such as cell survival and energy metabolism
What is the Rb protein? How does it work?
- Rb protein is a key regulator of cell cycle by preventing progression from G1 to S phase
- Negative growth factors inhibit progression of cell cycle by activating Rb protein
The inactivation of Rb gene is common event in tumours. What does this result in?
Results in resistance to -ve growth regulation (lost the gatekeeper between G1 and S phase
Via what mechanisms can tumour cells avoid immune destruction?
Binding of PD-1 and PD-L1 inhibits T cell from killing tumour cell
What is the PD-1/PD-L1 pathway?
When PD-1 is bound to another protein called PD-L1, it helps keep T cells from killing other cells, including cancer cells
How can anti-cancer drugs target the PD-1/PD-L1 pathway?
Used to block PD-1 –> allows T cell to kill tumour cell
What region of a chromosome is involved in the capability for unlimited proliferation?
Telomeres
What happens as telomeres shorten?
Telomeres shorten with age –> eventually cell dies
What is telomerase?
Telomerase, the specialized DNA polymerase that adds telomere repeat segments to the ends of telomeric DNA
How does the presence of telomerase differ between normal and cancerous cells?
Is almost absent in nonimmortalised cells but expressed at functionally significant levels in the vast majority (∼90%) of spontaneously immortalized cells, including human cancer cells.
How does the presence of telomerase enable cancer cell immortality?
telomerase is able to counter the progressive telomere erosion –> cell doesn’t die
How does the tumour active invasion and metastasis?
- Cells beak through basal lamina and enter bloodstream
- Cells adhere to and penetrate capillary wall (extravasation)
- Cells divide to form tumour –> secondary tumour
Purpose of tumours inducing angiogenesis?
Tumours require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide.
Difference between angiogenesis in normal vs cancer cells
During tumor progression, an “angiogenic switch” is almost always activated and remains on, causing normally quiescent vasculature to continually sprout new vessels that help sustain expanding neoplastic growths.
Diagram of genome instability and mutation; single vs double stranded breaks
What are inhibitors of apoptosis?
Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death e.g. the Bcl-2 family, viral inhibitor crmA, and IAP’s
Describe metabolism in normal cells under aerobic conditions
Normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter to carbon dioxide in the mitochondria
Describe metabolism in normal cells under anaerobic conditions
Glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria
Describe cancer cell metabolism
Warburg effect –> even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis
What are proto-oncogenes?
Normal genes that promote cell proliferation, survival and angiogenesis
What are oncogenes?
Mutated versions/increased expression of proto-oncogenes, causing increased/uncontrolled activity of expressed proteins
What are TSGs?
Normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (apoptosis)
What 3 categories can TSGs be grouped into?
- Caretaker genes
- Gatekeeper genes
- Landscaper genes
Difference between TSGs and proto-oncogenes?
TSGs:
- (TSG) act to maintain checkpoints (arrows, p53, RB)
- Control genome stability
- Recessive
Proto-oncogenes:
- Encode for protein directly involved in control of cell proliferation
- Allow for checkpoints to be overcome (lines; Ras, myc)
- Dominant
Difference between oncogenes and TSGs; does the mutation arise in somatic or germ cells?
Oncogenes; arises in somatic cells, not inherited
TSGs; arises in germ cells (can be inherited) OR in somatic cells
Difference between oncogenes and TSGs; dominant or recessive?
Oncogenes; mutation in one of the two alleles is sufficient (dominant)
TSGs; both alleles must be affected
Difference between oncogenes and TSGs; gain or loss of function?
Oncogenes; gain of function of a protein that signals cell division
TSGs; loss of function of a protein
Difference between oncogenes and TSGs; tissue preference?
Oncogenes; some tissue preference
TSGs; often strong tissue preference (e.g. effect of RB gene
Proto-oncogene at the cellular level:
No mutant alles –> mutation –> one mutant allele –> excessive cell proliferation
TSG at the cellular level:
No mutant alleles –> mutation –> one mutant allele –> another mutation –> two mutant alleles –> excessive cell proliferation
What type of mutation is typically seen in proto-oncogenes?
Usually gain-of-function dominant
What type of mutation is typically seen in TSGs?
Usually loss-of-function
What are RAS, myc, RAF, HER2, EGFR examples of?
Oncogenes
What is the RAS family?
A family of genes that make proteins involved in cell signaling pathways that control cell growth and cell death. Mutated (changed) forms of the RAS gene may be found in some types of cancer.
What 3 genes are involved in the RAS family?
- KRAS
- NRAS
- HRAS
What are the different mechanisms of oncogene activation?
- Translocation
- Point mutation
- Amplification
- Insertion
How can translocation lead to oncogene activation?
Translocation of an oncogene from a low to an active transcriptional site - aberrant expression of the oncogene
How can a point mutation lead to oncogene activation?
substitution of a single base within the amino acid sequence produces a hyperactive oncoprotein
How can amplification lead to oncogene activation?
Amplification by insertion of multiple copies of an oncogene – increased expression
How can insertion lead to oncogene activation?
Insertion of a promoter or enhancing gene (by retroviruses) near an oncogene – increased expression
Examples of TSGs;
- APC
- P53
- RB
- BRCA1 BRCA2
- hMLH1, hMSH2
What are gatekeeper genes involved in?
Negative regulators of the cell cycle and proliferation and positive regulators of apoptosis –> anti-oncogenes
Gatekeeper genes inhibit cell growth or induce apoptosis.
What mechanisms can result in TSG loss?
Carcinogens induce molecular abnormalities in TSGs that cause reduced/lack of protein expression/function:
- Inactivating point mutations
- Deletions
- Translocations
- Epigenetic silencing
What key cellular and molecular events needed for transformation from normal to malignant?
What does carcinogenesis involve?
Involves activation of oncogenes / inactivation of TSGs
E.g. carcinogenesis –> colon cancer
What are the steps of the metastatic cascade?
- Detachment
- Invasion
- Intravasation
- Evasion of host defences
- Adherence to endothelium
- Extravasation
