Neoplasia 2 8-10-15 Flashcards
What are the fundamental principles of cancer?
- cancer is a genetic disorder caused by DNA mutations
- most mutations are spontaneous or induced by environmental insults
- Some mutations are inherited in the germ line
- cancer arises from clonal expansion of a single progenitor cell that has incurred damage (monoclonal)
What are the 4 target regulatory genes?
- growth promoting
- growth inhibiting tumor suppressor gene
- genes that regulate apoptosis
- genes involved in DNA repair
What are proto-oncogenes?
normal cellular genes whose products promote cell proliferation
oncogenes
mutant or over-expressed versions of normal proto-oncogenes
- function autonomously
- encode transcription factors, growth regulatory proteins and cell survival proteins
- lost dependence on normal growth promoting signals
- potent carcinogenic factors
- dominant-mutation of a single allele can lead to cellular transformation
RAS the most commonly mutated proto-oncogene is a member of what family? What does it do?
-G protein that binds GTP(active) and GDP(inactive)
- active RAS stimulates downstream regulators of proliferation
- cell forced into continuously proliferating state
What are tumor suppressor genes?
normally prevent uncontrolled growth
- mutation leads to transformed cell
- usually both normal alleles must be damaged
What does RB do?
blocks G1—>S phase of the cell cycle
WHat are the associated tumor with mutation of RB?
-retinoblastoma, osteosarcoma
RB is the basis for the Knudson’s two hit hypothesis, what is Knudson’s two hit hypothesis?
cancer is the result of accumulated mutations to a cell’s DNA
What is a retinoblastoma?
intra-ocular neoplasm of children
- median age at presentation 2 years
- poor vision, strabismus, white-ish hue to pupil
- neuronal origin
What do you see in a higher-power view of retinoblastoma?
-Flexner Winterstein rosettes and numerous mitotic figures
How does RB affect E2F?
Hyperphosphorylated doesn’t bind to E2F
–>transcriptional activation
Hypophosphorylated binds E2F
—>transcriptional block
Whats the difference between the sporadic form of retinoblastoma and the familial form?
- sporadic-2 hits-older
- familial-1 hit- younger
What does P53, the most commonly mutated gene in cancer do? What are the associated tumors?
blocks G1–> S phase in cell cycle
- most human cancers
- Li Fraumeni Syndrome
What 3 things does the p53 do in face of stress?
- activates temporary cell cycle arrest(quiescence)
- induces permanent cell cycle arrest (senescence)
- triggers programmed cell death (apoptosis)
What is Li-Fraumeni syndrome?
- patient inherit one defective copy of p53 in the germ line
- one additional hit
- 25X greater risk of developing cancer by age 5-sarcomas, breast cancer, leukemia, brain tumors, adrenal cortex carcinomas, multiple primary tumors
What two proteins are anti-apoptotic?
BCL-2 and BCL-XL
What two proteins are pro-apoptotic, intrinsic pathway? How do they work?
Bax and Bak -poke holes in mito membrane -cyto c leaks out -activates caspases -nucleus starts fragmenting -cells starts pinching portions off -phagocytes come Apoptosis
What is the extrinsic death receptor pathway?
fas-death receptor
- caspases 8-9 initiators
- other caspase executioners
-responsible for elimination of self reactive lymphocytes
What happens if BLC-2 is activated by translocation?
perpetuation of anti-apoptosis
-follicular b-cell lymphoma
t(14;18)
What things lead need to happen for cancer to occur?
- loss of growth restraints
- limitless replicative potential
- activation of telomerase - sustained angiogenesis
- malignant neoplasms develop the ability to evade and metastasize
What do new endothelial cells secrete?
PDGF
insulin-like growth factor
What is an inducer and inhibitor of angiogenesis?
Inducer: VEGF
- Hypoxia inducible factor (HIF-1alpah) transcription factor
- von hippel lindau (VHL) suppressor
Inhibitor: Thrombospondin 1 (TSP-1)
Is there a homing mechanism that causes certain cancers to spread to certain places?
yes
