Neoplasia 3 Lecture Flashcards
Tumor suppressor genes
Inactivation of genes that normally suppress cell proliferation
- loss of function of these genes are key in what initiates carcinogenesis in majority of human cancers
Tumor suppressor retinoblastoma gene
Active when dephosphorylated or underphosphorylated and inactivated when hyperphosphorylated (prevents S phase by binding to E2F)
- Growth factors induce phosphorylation and growth inhibitors dephosphorylate
Pathogenesis of Retinoblastoma
Sporadic form: both mutations acquired after birth
Familial form: inherited one mutation and the second was acquired after birth
– Has to be homozygous for the gene, one is not enough
p53
Guardian of the genome, gate keeper against tumor genesis, mutated in greater than 50% of all cancers
- Homozygous loss, DNA damage goes unrepaired and cells carrying mutant genes continue to divide –> cancer
How does p53 prevent neoplastic transformation?
Activation of temporary cell cycle arrest
Induction of DNA repair
Activation of permanent cell cycle arrest (senescence)
Induction of apoptosis
What happens if DNA is damage and p53 is activated and binds?
Transcription dependent and independt effects on targets
p21 and GADD45 lead to successful repair (normal cell again) BUT BAX and GADD45 lead to repair failure (apoptosis)
What happens if DNA is damage and p53 is not activated?
No cell arrest, no DNA repair –> mutant cells that go through expansion and additional mutations leading to a malignant tumor
What happes in DNA is damage and p53 is activated and binds involving microRNA?
mir-34 is transcribed and processed leading to inhibition of translation of growth-promoting genes (senescence) OR inhibits translation of anti-apoptosis genes (apoptosis)
Define senscence
Process of deterioration with age
Telomerase activity?
Telomers are shortened and the ends will fuses
p53 would recognize this and kill it but if you do not have it this moves on and divides –> possibility of uncontrolled breaks leading to mitotic catastrophe or formation of new doubel stranded breaks + more telomers leading to reexpression and ultimately cancer
miRNA possibilities?
Reduce activity: inhibit translation of oncoproteins
Over-activity: inhibit tumor suppressor genes leading to cancer
—-Depends on where the microRNA binds
APC
beta-catenin controlled by APC prevent genes stimulate cell division
- Wnt signaling inhibits the destruction of complex and nuclear translocation of beta-catenin
- When APC is mutated or absent, the destruction of beta-catenin cannot occur so it cannot enter the nucleus
BRCA-1/2
DNA repair genes
- 80% of breast cancer cases as well as ovarian cancers and if within the germ lines than ovaries and male breast cancer
NF-1
Loss impairs the conversion of active GTP bound ras to inactive ras –> continuously stimulated to divide
Cell surface receptors (TGF-beta)
Upregulates the growth inhibitory genes
- Cancer: mutated receptors prevent the growth-restraining effects of TGF-beta
WT-1
Tumor suppressor gene
– Development of Wilms tumors
Genes that regulate apoptosis
BCL-2 prevents programmed cell death
- Over expression leads to extended cell survival —> proliferation
BAX controls by regulating the exit of cytochrome C from the mito, activating caspase 9 (proteolytic enzyme) –> apoptosis
Mut-S-Homolog 2 and human Mut-L-Homolog1
Involved in DNA mismatch repair
- Accumulation of mismatch –> cancer
Kinetics of tumor cell growth
Doubling time of tumor cells
Growth Fraction
Cell production and loss
Doubling time of tumor cells
Cell cycle has the same five phases
Usually equal to or longer than normal cells
Growth fraction
Proportion of cells within the tumor population that are in the replicative pool
– Usually about 20%
Cell production and loss
Imbalance between cell production and cell loss
- More rapid growth
- Unwanted growth = tumor (but can be benign)
Two tumor angiogenic factors are?
Vascular endothelial growth factor
Basic fibroblast growth factor (angistatin, endostatin, vasculostatin)
- Tumor growth is controlled by the balance between angiogenic and antiangiogenic factors
Detachment of tumor cells from each other?
Cell remain attached to each other by adhesion molecules (cadherins)
Down regulation of E-cadherins, reducing the adhesiveness of tumor cells
Attachment to matrix components?
Tumor cells detach from each other because of reduced adhesiveness and cells then attach to the basement membrane via the laminin and fibronectin cell surface receptors
Degradation of extracellular matrix?
Tumor cells secrete proteolytic enzymes that degrade the matrix components and create passageways for migration
Migration of tumor cells
Autocrine motility factors and cleavage products
How does a cell move through circulation and get to another site?
Detach from each other
Attach to the membrane
Degrade the matrix
Migrate via autocrine motility factors and cleavage products
