Neoplasia II Flashcards
What are the 4 classes of genes that are targets of damage that can lead to cancer?
– Growth promoting proto-oncogenes
– Growth inhibiting tumor suppressor genes
– Genes that regulate apoptosis
– Genes involved in DNA repair
What are proto-oncogenes?
Proto-oncogenes are normal cellular genes whose products promote cell proliferation
What are oncogenes?
Oncogenes are mutant or over-expressed versions of normal proto-oncogenes.
Are oncogenes dominant or recessive and what does this mean?
Oncogenes are considered dominant – a mutation of a single allele can lead to cellular transformation
What kind of mutation in an oncogene can lead to cancer?
Gain of function mutation
What is the most commonly mutant proto-oncogene in tumors?
RAS
What is the function of RAS?
RAS is a signal transducer that relays receptor activation to the cell nucleus
It is a member of family of small G proteins that bind GTP and GDP.
What are the active and inactive forms of RAS and how do mutations in RAS specifically cause it to become an oncogene?
In its inactive state RAS is bound to GDP.
In its active state RAS is bound to GTP.
GTPase activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDP-bound state. Mutations interfere with GTP hydrolysis trapping RAS in its activate GTP bound form.
Active RAS stimulates downstream regulators of cell proliferation and the cell is forced into a continuously proliferating state.
What are tumor suppressor genes?
Tumor Suppressor Genes normally prevent uncontrolled cell growth.
Are tumor suppressor genes dominant or recessive and what does this mean?
Tumor suppressor genes are considered recessive: both alleles must be mutated/lost for cancer to develop
What kind of mutation in a tumor suppressor gene can lead to cancer?
Loss of function mutation
What is the function of retinoblastoma (Rb)?
Rb controls the G1 to S transition of the cell cycle.
What is the active form of Rb and how does it function?
In its active form Rb is hypophosphorylated and binds to E2F transcription factor.
This interaction prevents transcription of genes, like cyclin E (cyclins are proteins that regulate progression through the cell cycle), that are needed for DNA replication. The cells are therefore arrested in G1.
What is the inactive form of Rb and how does mutation of Rb lead to cancer?
E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex.
RB mutation results in constitutively free E2F allowing progression through the cell cycle and uncontrolled cell growth.
What is a characteristic of Sporadic Retinoblastoma?
Sporadic RB mutations are characterized by unilateral retinoblastomas. Retinoblastoma is an intra-ocular neoplasm of children which is neuronal in origin.
What is a characteristic of Familial Retinoblastoma?
Germline RB mutations are characterized by bilateral retinoblastomas as well as primary bone malignancies called osteosarcomas.
What is the function of p53?
It regulates cell growth: progression from G1 to S phase of the cell cycle.
What are the 3 responses p53 has for DNA damage?
- Activates temporary cell cycle arrest (quiescence)
- Induces permanent cell cycle arrest (senescence)
- Upregulates DNA repair enzymes
What does p53 do when DNA repair cannot occur?
It triggers apoptosis
What is Li-Fraumeni syndrome?
p53 germline mutations that have an additional hit will result in Li-Fraumeni syndrome that leaves the person with 25x greater risk of developing a malignancy by age 5.
How does the Intrinsic Pathway (mitochondrial) of apoptosis occur?
DNA damage leads to inactivation of BCL2. Disruption of BCL2 allows Cytochrome C to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases – leading to the activation of apoptosis.
How does the Extrinsic Pathway (death receptor) of apoptosis occur?
FAS ligand binds to the FAS death receptor (CD95) on the target cell, activating caspases and leading to the activation of apoptosis.
What is the function of BCL2?
BCL2 normally stabilizes the mitochondrial membrane blocking release of Cytochrome C.
What is the mechanism for the elimination of self-reactive lymphocytes?
Extrinsic Pathway of Apoptosis
What is the function of telomerase in relation to neoplasms?
Neoplasms develop limitless replicative potential via the up regulation of telomerase.
How do tumor cells achieve angiogenesis?
Inducers of angiogenesis such as VEGF are commonly produced by tumor cells.
Hypoxia inducible factor (HIF-1a)
Hypoxia inducible factor (HIF-1a) is a transcription factor which increases VGEF production.
Von Hippel-Lindau (VHL)
Von Hippel-Lindau (VHL) is a tumor suppressor gene which inhibits HIF-1a. When VHL is lost it leads to the increased developed of VGEF.
How do tumor cells achieve metastasis?
Downregulation of E-cadherin leads to dissociation of attached cells as E-cadherin is an adhesion molecule for cells.
How do cells invade the basement membrane and metatasize?
Cells attach to laminin and destroy/degrade the basement membrane (key component is collage type IV) via collagenase.
Cells attach to fibronectin in the extracellular matrix and spread locally.
Cells invade the vascular and/or lymphatic spaces which allows for metastatic spread.
