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
What is the sequence of events in the invasion of the epithelial basement membranes by tumor cells?
- E-cadherins mediate adhesion of epithelial cells-function lost in some cancers–>facilitates detachment from primary tumor
- degradation of basement membrane and interstitial connective tissue
- attachment of cells to ECM proteins
- migration of tumor cells through degraded basement membrane and zones of matrix proteolysis
Tumors start out as monoclonal but as new subclones arise what happens?
mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive
