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 are caretaker genes involved in?
Caretaker genes are involved in the maintenance of the genome stability and include genes implicated in DNA repair.
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 is epigenetic silencing?
Shutdown of gene expression via methylation of CpG sequences in promoter regions
What gene is involved in retinoblastoma?
Rb1 - The retinoblastoma tumor-suppressor gene. Mutational inactivation of Rb1 causes the pediatric cancer retinoblastoma.
N.B. deregulation of the pathway in which it functions is common in most types of human cancer. The Rb1-encoded protein (pRb) is well known as a general cell cycle regulator
What is Li-Fraumeni syndrome?
An inherited familial predisposition to a wide range of certain, often rare, cancers.
What gene is involved in Li-Fraumeni?
Mutation in a tumor suppressor gene known as p53.
What is familial adenomatous polyposis?
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine –> colorectal cancer
What gene is involved in familial adenomatous polyposis (FAP)?
APC (a TSG)
What gene is involved in familial breast cancer?
BRCA1 and BRCA2
What type of TSG is BRCA1/2?
BRCA1 and BRCA2 are two high‐penetrance caretaker genes responsible for hereditary breast and ovarian cancer.
What gene is involved in Hereditary nonpolyposis colorectal cancer (HNPCC) / Lynch syndrome?
hMLH1, hMSH2
What type of TSG is hMLH1/hMSH2?
Caretaker
What key cellular and molecular events needed for transformation from normal to malignant?
What does carcinogenesis involve?
Involves activation of oncogenes / inactivation of TSGs
How many alterations (drivers) are needed to transform a normal cell into a neoplastic cell (abnormally growing cell)?
Minimum of 3-6
E.g. carcinogenesis –> colon cancer
What is Her2-positive breast cancer?
a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2)
What is HER2?
This protein promotes the growth of cancer cells. In about 1 of every 5 breast cancers, the cancer cells have extra copies of the gene that makes the HER2 protein.
What mutation is seen in approx 50% of colorectal cancers?
KRAS mutation
How does Cetuximab and Panitumumab work?
Block EGFR (epidermal growth factor receptor)
What are the steps of the metastatic cascade?
- Detachment
- Invasion
- Intravasation
- Evasion of host defences
- Adherence to endothelium
- Extravasation
What processes occur that allow tumour cells to invade?
Epithelial-mesenchymal transition:
- Loss of cell-cell adhesion
- Secretion of proteolytic enzymes
- Matrix metalloproteinases: Degrade ECM proteins
- Increased cellular motility
- Changes to cell-matrix interaction allows cell to move into the stroma
What is intravasation?
Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel.
Why are blood vessels the common method of space?
Least resistance to growth
What is perineural space?
located around a nerve or a bundle of nerve fibres
Tumours require blood supply in order to receive oxygen and nutrients. How do they achieve this?
Angiogenesis - this then increases the risk of metastasis
What do tumours secrete to promote angiogenesis?
vascular endothelial growth factor (VEGF)
How do tumour cells sustain proliferative signalling?
- Signals largely enabled by growth factors that bind to cell surface receptors with intracellular tyrosine kinase domain
- This enables proliferative signalling pathways that promotes cell cycle progression and cell growth
- Autocrine stimulation: more growth factor produced
- Elevated levels of receptors e.g. Her2 amplification
- Defective negative feedback loops
What is the MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway)?
The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division.
How can a defect in the MAP/ERK pathway lead to cancer?
Uncontrolled growth is a necessary step for the development of all cancers. In many cancers (e.g. melanoma), a defect in the MAP/ERK pathway leads to that uncontrolled growth
Cancerous mutations in MAPK pathways are frequently mostly affecting Ras and B-Raf in the extracellular signal-regulated kinase pathway.
What % of melanomas contain b-raf mutations?
40%
What is the Her2 gene?
The HER2 gene encodes a transmembrane tyrosine kinase receptor that belongs to the EGF receptor (EGFR) family –> HER2 is a growth promoting protein
What are breast cancers with higher than normal levels of HER2 called?
HER2-positive
How can tumour cells evade growth suppressors?
-
Tumour-suppressor genes negatively regulate cell growth and proliferation
- E.g. p53, Rb
- Mutations of p53 remove the DNA damage response –> allows cells with damaged DNA to survive and divide
Via what tumour suppressor does DNA damage trigger apoptosis?
Via p53 tumour suppressor
What is Bcl-2?
Normal apoptosis inhibitor:
- Bcl-2 inhibits apoptosis by binding to pro-apoptotic triggering proteins Bax and Bak, located on the outer mitochondrial membrane
How is cytochrome c involved in apoptosis?
when a cell receives an apoptotic stimulus, cytochrome c is released into the cytosol and triggers programmed cell death through apoptosis.
In tumour cells, how can apoptosis be avoided?
- p53 loss (most common)
- Increased expression of antiapoptotic factors (Bcl-2, BclXL)
- Downregulating pro-apoptotic factors (Bax, Bim)
How to tumour cells promote inflammation?
Necrotic cell death releases proinflammatory signals into the surrounding tissue microenvironment.
How can inflmmation promote tumorigenesis?
necrotic cells release IL-1, which can facilitate neoplastic growth.
How do normal cells have a limited number of successive cell growth and division cycles?
Due to progressive telomere shortening
Cancer cells require unlimited replicative potential in order to generate macroscopic tumours. How can cancer cells avoid telomere shortening and become ‘immortalised’?
Immortalised cells have been shown to express functionally significant amounts of telomerase.
What is telomerase?
a DNA polymerase that adds telomere repeat segments to ends of telomeric DNA.
What does VEGF promote?
Angiogenesis
What is the inhibitor of angiogenesis?
Thrombospondin-1
What can VEGF gene expression be upregulated by?
Hypoxia
What is E-cadherin involved in? How is this involved in cancer?
An important cell-cell adhesion molecule. Carcinoma cells (e.g. lobular breast carcinoma) are known to lose expression of E-cadherin.
What is the Epitheelial-Mesenchymal Transition (EMT)?
Transformed cells can acquire the abilities to invade, resist apoptosis, and to disseminate.
How is cellular metabolism reprogrammed in tumour cells to promote neoplastic proliferation?
Neoplastic cells favour glycolysis instead of O2-consuming mitochondrial energy production. Glycolysis uses more glucose, therefore tumour cells upregulate their glucose transporters
Which glucose transporter is there an increased expression of in tumour cells?
Increased expression of HIF1/2 alpha = increased glycolysis in tumour cells.
Are tumour suppressor genes autosomal dominant or recessive?
Autosomal recessive
Cellular proliferation is a fine balance between what 2 genes?
proto-oncogenes and TSGs (amongst other mechanisms)
What is Knudson’s two hit hypothesis?
Inactivation of TSG requires 2 mutations; inherited and sporadic (familial); or sporadic and sporadic (non-familial).
I.e. mutation in both alleles is required for loss of function of a TSG
Examples of TSGs
p53, APC, Rb, BRCA1/2
What do proto-oncogenes encode?
Encode for proteins that promote cellular proliferation
Examples of proto-oncogenes?
RAS, RAF, Myc, EGFR, Her2 signalling.
Are proto-oncogenes dominant or recessive?
Dominant - therefore mutation in 1 allele required
What are the 3 mechanisms of proto-oncogene activation?
- Translocation –> the oncogene can be translocated to an active transcriptional site
- Amplification –> the oncogene can undergo amplifications and result in increased expression, as seen in Her2 in breast cancer.
- Insertion –> proto-oncogene kras can be inserted into a promoter site leading to activation
Which inherited cancer syndrome is associated with MLH1 (mismatch repair) mutation?
Hereditary non-polyposis colorectal cancer (HNPCC)
What is the APC gene?
APC is classified as a tumor suppressor gene.
Which disease is mutation is APC gene linked to?
FAP
What is MLH1?
Tumour suppressor gene (one of a set of genes known as the mismatch repair (MMR)
Mutations in MLH1 gene are known to cause what?
Lynch syndrome
What faulty allele have FAP patients inherited?
APC allele
What causes HNPCC?
Due to microsatellite instability - germline mutations in DNA mismatch repair genes (MSH2 or MSH1)
What is microsatellite instability?
Loss of DNA mismatch repair (MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability (MSI)
What gene is involved in retinoblastoma?
Rb1
Function of Rb gene?
Regulates and stops the cell cycle at the G1 checkpoint
