What are the four phases to the development of malignancy?
3. Local invasion
4. Distant metastasis
What three factors determine a tumors rate of growth?
1. Doubling time of the tumor cells.
2. Fraction of cells in cell cycle = growth fraction
3. Rate of loss of cells
NOTE: Cell cycle is not shorter in neoplastic cells, just more cells in it.
What are cancer stem cells and where have they been identified?
Cells able to self-renew, seen in breast cancer and AML.
Leukemic forms express the gene BMI1 --- represses cell cycle inhibitors: p161NK4a and p14ARF
Name and describe three pathways of tumor spread.
1. Direct seeding of body cavity or surface - carcinomas
2. Lymphatics - carcinomas
3. Hematogenous - sarcomas, liver and lungs most frequently involved
Name the four classes of normal regulatory genes.
1. growth promoting protooncogenes - dominant since only one needs to be damaged for transformation to occur
2. tumor suppressor genes - recessive since both alleles need to be hit
3. genes regulating apoptosis - can be dominant or recessive
4. DNA repair genes - usually recessive - both alleles need to be damaged
Name 7 essential alterations for malignant transformation.
1. Self-sufficiency in growth signals (ie. don't need external signals for growth)
2. Insensitive to inhib signals
3. Evasion of apoptosis (often d/t inactivation of p53)
4. Defective DNA repair
5. limitless replicative potential (maintenance of telomere length and telomerase fxn)
6. Sustained angiogenesis - VEGF
7. Ability to invade and met
Name the stages of the normal cell cycle.
G0 -- G1 -- S -- G2 --M
What drives cells through the cell cycle?
Cyclins and cyclin dependent kinases
CDKs phosporylate proteins, exrpressed constitutively in an inactive form
Cyclins synthesized during the cycle and rapidly decline after completion.
List the sequence of events in the cell cycle.
1. Signal (ex. GFs, integrins)
2. MYC, RAS, other genes
3. Production of cyclin D -- activation of CDK4
4. RB phosphorylation within RB/E2F/DP1 complex (when RB is hypophos it forms a tight inactive complex with trans factor E2F and DP1)
- RB/E2F/DP1 binds to promoter regions of E2F responsive genes needed for progression of cell cycle - RB recruits histone deacetylase - compacts chromatin
- when RB is phos, it dissasociates and allows transscription of genes needed for progression ex. cyclin E, DNA polymerases, thymidine kinase etc.
5. Cyclin E then activates CDK2 and cell moves from G1 to S (G1-S transition is restriction point) and DNA synthesis occurs
6. E2F then mediates transcription of cyclin A which activates CDK2 - complex regulates prophase
7. Cyclin B-CDK1 then causes breakdown of nuclear envelope and intiates mitosis
8. Exit from mitosis - need inactivation of cyclin B/CDK1
9. Return to G1 or to G0
So - D/4 then E/2 then A/2 then B/1
Name the cell-cycle inhibitors.
Cip.Kip: p21 (induced by p53), p27 (responds to TGFb)
INK4/ARF: p16INK4a (binds D/4) promotes inh effects of RB, p14ARF (incr. p53 levels by inh MDM2)
What are the two checkpoints of the cell cycle and how are they controlled?
1. G1/S - p53 - needed for p21 which inhibits cell cycle - slows or stops cycle if DNA damage
2. G2/M - mediated through p53 dependent and independent mechanisms
NOTE: ATM senses DNA damage
What are the 5 steps in cell proliferation?
1. GF binding
2. Activation of GF receptor - signal transduction
3. Signal transport via mesenger proteins to nucleus
4. Activation of nuclear regulatory factors -- DNA transcription
5. Entry to cell cycle --- cell division
What is an oncogene?
Genes that support autonomous cell growth in cancer cells. Protooncogenes are their normal counterparts.
Name the categories of oncogenes.
2. GF receptors
3. Signal transduction proteins
4. Nuclear regulatory proteins
5. Cell cycle regulators
Give examples of protooncogenes encoding a GF.
SIS - encodes b chain of PDGF, often same tumors express more of receptor as well - autocrine. But not enough for mal transformation but incr prol contributes to it.
Id'ed in OSA and astrocytomas
Also TGFa, HGF and Fibroblast GFs
Give examples and the mechanism of oncogenesis of protooncogenes encoding GFRs.
GFR are transmembrane proteins with GF binding site extracellular domain and intracellular domain with tyrosine kinase activity, when GF binds the receptor dimerizes and tyrosine phosporylation of signaling proteins.
Oncogenic versions often have constituent dimerization and become activated without binding of GF
Gives constant mitogenic signals to cell
ex. ERB B1 (EGF receptor gene) overexpressed in SCC, ERB B2 in breast cancer, GIST overexpress c-KIT
Name the most common protooncogene encoding signal transducing proteins and how it works.
RAS - most common oncogene - mutations reduce GTPase activity of RAS proteins