5. Cancer II Flashcards
Hallmarks of Cancer Independence of \_\_\_\_ Resistance to \_\_\_\_ Evasion of \_\_\_\_ Limitless \_\_\_\_
Acquired ____ potential
Transplantability and invasion
Switch to ____ despite O2
Immune evasion
Enabling Characteristics:
• Genomic instability
• Tumor promoting
Inflammation
GF
growth inhibition
cell death
replicative potential
angiogenic
glycolysis
1 - Self Sufficiency of Growth
• Steps of cell proliferation
○ ____: growth factor binding
§ VEGFR, when bound by ligand, will lead to phosphorylation of RasGDP to RasGTP inducing downstream kinase activation
○ Signal ____ to the nucleus
§ Activation of second messengers
§ G-proteins and kinases
□ Phosphorylation of cytoplasmic proteins
○ Induction of nuclear regulatory factors
§ ____ factors
□ Genes are upregulated that are involved in the cell cycle
○ Entry into the ____
• Any of the above steps can be involved in the carcinogenic process
receptor
transduction
transcription
cell cycle
Growth Factors
Small ____
Bind receptors
Stimulate ____
Usually paracrine
Two mechanisms: Acquire ability to \_\_\_\_ growth factor \_\_\_\_ stimulation = PDGF - g\_\_\_\_ = TGF-a - \_\_\_\_
Stimulate ____ cells to produce growth factor
• Small peptides that are in the ECM, and secreted by stromal cells ○ Stromal cells use these to signal to each other and induce proliferation • Stromal cells are not \_\_\_\_
peptides proliferation produce autocrine glioblastoma sarcomas
stromal
cancerous
Growth Factors Receptors and Non-Y kinases
Mutant or ____ receptor
Constitutively ____
____ to low concentrations of GF
- Epidermal Growth Factor receptor ERBB1
- 80% of ____
- 50% glioblastoma
- 80-100% of epithelial tumors of ____
- HER2/Neu (ERBB2)
- -25% of ____ cancer
- 25% adenocarcinomas of lung, ovary and salivary glands
- ____ of HER2/NEU - poor prognosis
- ____ blocking receptor as treatment• In order for a cancer cell to grow you want activity to increase
○ Mutated in order to increase
○ Expression increases
§ This method is more commonly used
• Can still grow even in the presence of low concentration of GF because the receptors become hyperresponsive
• ERBB2, HER2/Neu
○ Overexpression in breast cancer - interesting clinical indications
§ Block the receptor with antibodies
□ The growth signal is not transmitted to the nucleus and the cells cannot grow
○ If the receptors are hyperresponding to GF the prognosis is poor
- ____ blocking receptor as treatment• In order for a cancer cell to grow you want activity to increase
overexpressed active hyperresponsive squamous cell carcinoma H+N
breast
overexpression
antibody
Downstream Signal-Transducing Proteins
____
Couple GF signaling to
nucleus
Common mechanism of ____
Examples
____
____
• Second messengers take the signal from \_\_\_\_ to the nucleus ○ Common mechanisms of growth autonomy § Not hindered by the levels of \_\_\_\_ • Will be activated in cancer cells
second messengers
growth autonomy
Ras
Abl
PM
GF
Ras
Small \_\_\_\_ nucleotide binding proteins Most common mutated \_\_\_\_ in humans -- GTP \_\_\_\_ -- GTP \_\_\_\_ 30% of all tumors
• Located on \_\_\_\_ side of PM ○ Binds GDP or GTP • Normally it is inactive when bound to \_\_\_\_ ○ When there is a signal coming from the GFR that is bound to GF, GDP is phosphorylated to GTP > activation of Ras § Short-term change to active Ras because the GF signalling you don't want turned on all the time § \_\_\_\_ inactivation by Ras itself (GTP hydrolysis) □ Any process that prevents this inactivation will lead to continued activation of Ras § \_\_\_\_ also converts GTP to GDP • Ras is one of the most commonly mutated 2nd messengers in carcinogenesis ○ Ras is an protooncogene ○ Have \_\_\_\_ functions in normal cells, but when mutated and activated they become oncogenic • Mutations can occur in the GTP binding pocket [???], or any step that prevents GTP hydrolysis (Ras' own activity to inactivate, or a deficiency in the GAP protein)
guanosine
proto-oncogene
binding pocket
hydrolysis
cytoplasmic GDP intrinsic GAP physiological
Ras signaling
Activates 2 kinase cascades Ras Mimics: -- \_\_\_\_ – 60% of melanomas -- \_\_\_\_ mutations very common -- Mutations in GTPase activating proteins -- e.g. \_\_\_\_
• Multiple kinases where they phos each other in sequence ○ How the signal from GFR gets transported to nucleus • Activates: ○ PI3K pathway § PI3K > \_\_\_\_ > mTOR ○ RAF pathway § RAF > \_\_\_\_ ○ Any overexpression in any of these kinases will be an oncogenic signal § "\_\_\_\_" • GAP (GTPase activating proteins) proteins are TSGs ○ Also a "Ras mimic" ○ Loss of NF1 leads to neurofibromatosis § Multiple tumors found within the \_\_\_\_
BRAF
PI3K
neurofibromin 1
AKT
MAPK
Ras mimics
CNS
Abl - Philadelphia Chromosome
Non-____ tyrosine kinase
Regulated by ____, ____ interaction, myristolation
t(____) – BCR:ABL fusion
Activates ____ targets
Targeted therapy:
– ____ (imatinib mesylate)
inhibits Y-kinase ABL
– Oncogene addiction
Early Step in Leukemagenesis for ____ and ____
Mutation of BCR-Abl underlies Resistance to Gleevac
• Non-receptor - not bound very closely to a GFR, but helps transmit the growth signal to the nucleus (like Ras) • Not always activated pathway; regulated heavily ○ \_\_\_\_ modification - myristolation • Abl is on chromosome \_\_\_\_, and bcr is on \_\_\_\_ and they fused together because of a balanced translocation ○ Normally there are regulatory elements internally, but bc of the translocation it is lost ○ Abl kinase is now active without any regulation § Activates Ras targets • First drugs against these "novel" genes - develop Gleevac ○ Very drastic effect - 90% of patients respond ○ Some tumors depend on \_\_\_\_ mutated pathway more than the others § Oncogene addiction □ The case with CML and AL ○ Eventually these tumors find a way to circumvent the drug, and mutate the fusion protein itself and become resistant to Gleevac
receptor phosphorylation protein:protein 9;22 Ras
Gleevac
CML
ALL
post-translational
9
22
one
Transcription Factors
Master Transcription factors
- - ____, Myb, ____, Fos, ____
- ____ of signaling oncogenes
- Regulate growth promoting genes like ____, cyclin dependent kinases
Myc
Activator and repressor
Activated genes include CDK and ____, glutamine utilization
Repressed genes include ____ inhibitors
Affects >2 Hallmarks of cancer
• Once signal reaches the nucleus, the TF can be affected • These TF are master TF, involved in multiple pathways ○ Critical in allowing the cell to get ready for division • Indirectly affect the inhibitors of cell cycle as well • Myc ○ Not only involved in cell division, but also in \_\_\_\_ ○ Affects two or more hallmarks of cancer
Myc Jun Rel downstream cyclins
aerobic glycolysis
CDK
metabolism
Myc
t(8;14) ____
- - ____ cell tumor
- - Myc under control of ____
Amplified in:
– ____, colon lung and
many other cancers
Related oncogenes:
- - ____ – neuroblastoma
- - ____ – small cell cancers of lung• Mutation involving myc is a ____
○ Promoter region of myc is swapped with IgG
§ The new promoter is more sensitive and more likely to be turned on in response to GF
• Mutation also includes ____
• Neuroblastoma
○ Poorly differentiated ____ tumors
Burkitt lymphoma
B
IgG promoter
breast
NMYC
LMYC
translocation
amplification
CNS
Cyclins and Cyclin-Dependent Kinases (CDKs)
Regulate cell cycle progression
Cyclin:CDK checkpoints Cyclin D,E – ____ phase
Cyclin A - ____
Cyclin B - ____
• Cells in a resting state are \_\_\_\_ (G0) • In response to TF, GF and other stimuli they enter GI ○ Get ready to duplicate DNA ○ S > G2 > M • Several levels of regulation in the cell cycle: ○ CDK § CDK4, 6, 2, 1 § Do not act alone, must be bound by \_\_\_\_ § Can be categorized to the different phases when complexed with cyclins ○ Cyclins § D/E - involved in G1/S phase § A - involved in S/G2 transition § B - G2/M transition § You want these to be activated in order to travel through the cell cycle □ Will be either mutated or overexpressed in cancer cells ○ CDK inhibitors § \_\_\_\_, p15, p18, p19 § \_\_\_\_ p27, p57
G1-S
S-G2
G2-M
quiescent
cyclins
p16
p21
Alterations in Cell Cycle Control Proteins in Cancer Cells
All tumors disable ____ checkpoint
Increased expression of ____ or CDK4 is common
Cyclin D overexpression
– ____, esophagus, liver, ____
CDK4 amplification
– ____, melanomas and
____
Cyclin B and E also occur but more rarely
• Have to disable the mechanism which controls the G1 to S checkpoint ○ Upregulate cyclin D or CDK4 § More common then cyclin B/E because the transition point is more important (than the \_\_\_\_ transition)
G1-S
cyclin D
breast
lymphoma
sarcomas
glioblastomas
G2-M
Cyclin-Dependent Kinase Inhibitors
Monitor \_\_\_\_ integrity DNA damage triggers “stop” 2 families inhibit CDK activity: P21, p27 ,and p57 are broad \_\_\_\_ P16, p15, p18, and p19 inhibit Cyclin \_\_\_\_:CDK4 and \_\_\_\_ (INK4 A-D)
• Sense if the DNA is ready to replicate • Inhibitors in the teens (15, 16, 18, 19) ○ Inhibit cyclin D/CDK4 or cyclin D/CDK6 • P21, p27 and p57 are more broad, not specific to a certain CDK • Cancer cells will try to shut these down
DNA
CDK1
D
CDK6
Alterations of Cell Cycle Control Proteins in Cancer
\_\_\_\_ mutations of CDK inhibitors are frequent p16 (CDKN2A) -- 75% of \_\_\_\_ tumors -- 40-70% of glioblastoma -- 50% \_\_\_\_
These are Hallmark 2 changes as they lead to insensitivity to growth inhibitory signaling…
inactivating
pancreatic
esophageal
2 - Insensitivity to Growth Inhibititory Signals
Tumor suppressors -- Governors -- \_\_\_\_ \_\_\_\_ signaling Contact \_\_\_\_
Cancer cells have to overcome all of these for this hallmark of cancer to arise:
• During cell division there is a G1/S phase checkpoint that includes Rb (____)
○ One of the ways how the cancer cells become insensitive to the signals
• Any DNA damage that occurs in cancer
○ P53 (____)
• Antiproliferative signaling
○ Coming from the ____
• Contact inhibition
○ Tells cells to stop growing because of a lack of ____
guardians
antiproliferative
inhibition
governor
guardian
cell surface
space
Tumor Suppressors: Rb
\_\_\_\_ of the cell cycle -- Senses external environment Deregulated in most tumors -- Mutation of Rb, \_\_\_\_ -- Overexpression of cyclin \_\_\_\_, CDK4, oncogene signaling pRb: first tumor suppressor
Knudson’s ____-hit hypothesis
Mutation on ____
____ on sister chromosome
Syndrome: ____ in youth; sarcoma, breast cancer, lung cancer as adults
• Governor - it is the first point where the signal coming from the external environment is interpreted and the cell says it's not going to grow anymore ○ Mutated itself or the \_\_\_\_ are overexpressed (cyclin D/CDK4) • LOH ○ Two copies of Rb (one from father and one from mother) and if one is mutated you have a defective copy as offspring ○ In order to inactivate the TSG you need to KO both alleles ○ Due to random chances, you may lose the other allele, leading to loss of heterozygosity and makes the cell have a non-functional Rb § Which originally prevents cell from moving from \_\_\_\_ phase ○ Also happens with p53 and other TSG's
governor CDKN2A D 2 13q11 LOH retinoblastoma
regulators
G1-S
Retinoblastoma
60% \_\_\_\_ Usually before 3 Tumor of the retina Appears as “\_\_\_\_” Pain in eyes and poor vision Surgery, chemo, radiation
• If you get not from your parents, it's AD (AD-cancer syndrome) ○ Considered to be sporadic (did not inherit mutant/damaged copy from parent) • Will appear as a cat's eye regardless or whether sporadic or inherited ○ In one eye - more likely to be \_\_\_\_ § More likely to occur in \_\_\_\_ ○ In two eyes - more likely to be \_\_\_\_ § More likely to occur \_\_\_\_ • The eye must be removed to remove the tumor ○ The tumor can also invade the \_\_\_\_ • Also happens in adults
sporadic
cat’s eye
sporadic adults familial/inherited earlier CNS
Rb Regulation
____ protein
Regulates G1-S via E2F
Controls cell decision to become ____, Senescent, Differentiated, Apoptotic
Target of ____ and oncogenic DNA viruses (____)
• Controls G1 to S phase transition ○ Binds to \_\_\_\_ (a TF that upregulates gene that are necessary to make proteins for cell division) and keeps it from binding its targets ○ Remove Rb, E2F is free and goes through the cell cycle ○ Rb becomes \_\_\_\_ by cyclin/CDK complexes § Overexpression of cyclin \_\_\_\_ will be similar to suppressing Rb □ Prevents it from binding E2F • There are also DNA viruses that bind to Rb, preventing it from binding E2F and promoting cell division
ubiquitous
quiescent
oncogenes
HPV
E2F
phosphorylated
D/CDK4
p53: The Guardian of the Genome One of the most commonly mutated in human cancer Functions to induce: \_\_\_\_ Senescence Apoptosis
Internal stress sensor:
____ damage
____ activity
____
• \_\_\_\_ from Rb ○ P53 is involved in whether cell has to enter quiescence, senescence or apoptosis • Will push the cell out of cell division (quiescence - G0), or it will say that there is too much damage (induce senescence - the genome is inhibited that it cannot return to cell division; or induce apoptosis)
quiescence
DNA
oncoprotein
anoxia
downstream
p53 Regulation
p53 is a ____
It is degraded due by ____-mediated ubiquitination
Disruption of this ____ by DNA damage, hypoxia, etc. induces quiescence, senescence, or apoptosis
Quiescence - p53 induces -- \_\_\_\_ CDKI-arrests cells -- miRNAs to block cyclin expression -- DNA \_\_\_\_ enzymes – repairs DNA -- \_\_\_\_ – degrades p53 and resume cycle
• Bound by MDM2, which puts ubiquitin on p53 - which are small molecules that tag it for degradation by the proteosome ○ Which is why it has a \_\_\_\_ half-life (15-20 min) • P53 begins to accumulate in the \_\_\_\_ and controls the genes for quiescence, senescence or apoptosis • Quiescence ○ Induces CDK inhibitors - p21 § Cell is now arrested in whatever step in the \_\_\_\_ it is in ○ Increases miRNAs to inhibit specific targets - degrade RNA of target proteins § Degrades mRNA of cyclin A/D/B/E ○ Upregulates DNA repair enzymes • Ultimately MDM2 finds a way to degrade p53 so the cell cycle resumes
TF
MDM2
interaction
p21
repair
MDM2
short
cytoplasm
cell cycle
p53 Regulation
Senescence
Changes in ____
and gene expression
Mechanisms unclear but global ____ changes permanently alter gene expression
Apoptosis
Increase proapoptotic proteins such as ____ and PUMA
Induce miRNAs to block ____ expression
• Senescence ○ There is no \_\_\_\_ for senescent, but there is a permanent change in the shape ○ There are fewer active genes • Apoptosis ○ If the cell cannot be kept in the other states ○ Increases at the transcriptional level the levels of proapoptotic proteins (Bax and PUMA) ○ Can increase miRNA to decrease mRNA levels of antiapoptotic proteins (BCL2)
morphology
chromatin
BAX
BCL2
marker
p53 Regulation
• Regulated by MDM2 oncogene • \_\_\_\_ target • Impacts Rb via: --• \_\_\_\_ expression --• \_\_\_\_
• Stress conditions: \_\_\_\_ radiation, hypoxia, ox stress > p53 initially bound to MDM2, and then this interaction prevented by binding of \_\_\_\_ or ATR > stabilizes p53 and not degraded and turns on downstream \_\_\_\_ ○ Activates \_\_\_\_ (CDK inhibitors) and inhibits cyclin D/CDK4 activity > Rb/E2F dissociation and cell cycle arrest [???] • If ATM is dysregulated it results in carcinogenesis • Impacts Rb via: ○ Upregulating \_\_\_\_ expression ○ Segregating MDM2 from \_\_\_\_ § Because if unbound by p53 it can now bind Rb instead!
ATM
p21
MDM2
UV
ATM
p21
p21
Rb
p53 in Tumors
Loss of both p53 copies leads to malignancy 70% of human cancers have mutated p53 Remaining inactivate p53 Leads to \_\_\_\_ Target of \_\_\_\_ viruses with pRb
Mutated in \_\_\_\_ syndrome LOH at p53 locus Predisposed to \_\_\_\_ tumors (25x higher than population) \_\_\_\_ mutation sites Occurs at \_\_\_\_ age
• Can be either lost or mutated: ○ Loss § Need to lose both copies > malignancy ○ Li Fraumeni syndrome § LOH § Malignant tumors in various sites of body (vs. just the \_\_\_\_ in Rb) □ Breast to sarcoma § Younger age - colon cancer at 20 y/o, normally this arises later in life □ Should indicate that there may be a \_\_\_\_ predisposition • Leads to further accumulation of mutations, translocations and dsDNA breaks
genomic instability
DNA
Li Fraumeni
malignant
varied
young
eyes
familial
Growth Inhibitory Signaling - TGFb Transforming growth factor b Growth inhibitory in \_\_\_\_, hematopoietic, and \_\_\_\_ cells Induces \_\_\_\_ like p21 Represses \_\_\_\_, CDKs and cyclins Mutations in \_\_\_\_ or receptor type II
• Common in cells that divide quickly - TGFb ○ Turn on through type \_\_\_\_ receptors > \_\_\_\_ proteins > induce CDK inhibitors like p21 • Mutation in SMADs or type 2 receptors > carcinogenesis
endothelial epithelial CDKIs myc SMADs II SMAD
TGFb in Cancer: Effects on Multiple Hallmarks
SMAD4 is mutated in 100% of ____ cancers of 83% of ____ cancers
Mutations in the receptor are seen in colon, stomach and endometrial tumors
If intact, TGFb can promote ____, immune evasion and epithelial to mesenchymal transition that facilitates, migration, invasion and ____
• Sometimes it's overactive, and happens secondary to cell growth ○ Need controlled growth where growth inhibitory pathways should be involved; it's activated in angiogenesis, immune evasion, etc. [???] • TGFb is a hallmark, but it's contribution can be by \_\_\_\_ or \_\_\_\_ depending on the stage of the cancer
pancreatic
colon
angiogenesis
activation
inhibition
Contact Inhibition
Cell:Cell contact blocks growth
Mediated by cadherins
– Cell surface proteins that ____ between cell surfaces
– Bind ____
• Cancer cells want to shut down this pathway by inhibiting \_\_\_\_ • Bind b-catenin, which promotes cell proliferation ○ If E-cadherin is on cell surface, it binds b-catenin, and b-catenin cannot induce cell proliferation § If lose E-cadherin, b-catenin will turn on \_\_\_\_
dimerize
b-catenin
E-cadherin
cell proliferation
Contact Inhibition
E- Cadherin causes contact inhibition in epithelial cells Mechanisms -- Some are not clear -- E-cadherin - NF2/merlin – \_\_\_\_ -- E-cadherin-b-catenin - \_\_\_\_
• Loss of NF2 > neuronal tumors in the CNS • Normally, b-catenin is in \_\_\_\_ and when it goes into nucleus it will activate gene expression by activating TCF ○ But when in cytoplasm it is bound by E-cadherin, but also can be kept in place by \_\_\_\_ so that it doesn't go to the nucleus and it's continually degraded § "\_\_\_\_" degrades b-cat ○ If there is a growth signal, interpreted by \_\_\_\_, will lead to dissociation of APC from b-cat > travels to nucleus and turns on gene expression for proliferation ○ In absence of wnt signaling, in tumors, b-cat can be turned on: § \_\_\_\_ can be lost § \_\_\_\_ can also be lost □ No direct link between the two
neurofibromatosis 2
APC
cytoplasm
APC
destruction complex
wnt
APC
E-cadherin
Adenomatous Polyposis Coli (APC)
____
– LOH
By teens or 20’s, thousands of adenomatous polyps in the ____
Almost invariably one will convert to ____
70-80% of spontaneous colon cancers have mutation of ____, the rest have mutations in ____
• No contact inhibition due to loss of APC or E-cadherin
TSG colon malignancy APC E-cadherin
Adenomatous polyposis coli (APC)
Numerous adenomatous polyps in the colon
High rate of ____
Loss of APC tumor suppressor
transformation
Adenomatous Polyposis Coli
____ mediates degradation of b-catenin – no proliferation
b-catenin has many functions
– Binds cadherins
– ____
____ signaling disrupts b-catenin interaction with APC so b-catenin can move to the nucleus
Induces expression of:
– ____ and cyclin ____
– ____ and ____ – decrease cadherin/reduce contact inhibition
• If b-cat goes into nucleus, it will turn on expression of protooncogenes ○ In normal cells, there are checks and balances that prevent it from turning it on indefinitely • B-cat \_\_\_\_ twist and slug > once the levels go up, they decrease the levels of cadherins and then reduce contact inhibition
APC
TF
Wnt myc D1 twist slug
upregulates
• Wnt binds to receptor, and dissociates ____ so b-cat can enter the nucleus
○ Eventually APC will get a hold of b-cat to prevent it from activating the nucleus factors
• No APC > no ____ feedback
• In cancer, no wnt, but also no APC, and b-cat will still enter the nucleus
APC
regulatory
3 - Evasion of Cell Death
____
____
apoptosis
autophagy
Apoptosis
Extrinsic
– Tumor necrosis/Fas
– ____
Intrinsic
– ____ membrane
permeabilization
– ____ formation
Effector ____
• Two arms of apoptosis: ○ Extrinsic § Receptor involved to induce death □ TN/Fas > activation of a complex □ Procaspase 8 > caspase 8 (\_\_\_\_), can talk to mitochondria via \_\_\_\_, or will activate caspase \_\_\_\_ which will induce apoptosis § Starts on \_\_\_\_
○ Intrinsic § \_\_\_\_ light/chemotherapy turns on events in mitochondria § Starts on \_\_\_\_ membrane § Holes appear in mitochondrial membrane > leakage of \_\_\_\_ and procaspase \_\_\_\_ > activates \_\_\_\_ in cytoplasm and activates caspase \_\_\_\_ > activates caspase \_\_\_\_ > apoptosis
caspase 8
mitochondrial
apoptosome
caspase
cleavage
Bid
3
cell surface
UV mitochondrial Apaf-1 9 cytochrome c 9 3
Apoptosis
Mitochondrial membrane permeability
Antiapoptotic - ____, BCL- XL
Pro-apoptotic - ____, BAK
BH3-only neutralizers - ____, BID and ____
Overexpression of BCL2 — 85% of ____ (t(____)(q32:q21))
Reduced ____
Increased ____ (inhibitor of caspase 8 activation)
p53, pRb and myc
• The proteins involved with mitochondrial membrane permeability are targets of cancer cells ○ Overexpression of anti-apoptotic, or inhibiting pro-apoptotic proteins • BH3 only neutralizers try to neutralize the effect of \_\_\_\_ proteins • P53 turns on expression of genes involved in \_\_\_\_, and Rb needs to be shut down because it's bound to E2F, if shut down Rb E2F turns on transcription of \_\_\_\_ genes
BCL2
BAX
BAD
PUMA
follicular B-cell lymphoma
14;18
CD95
FLIP
antiapoptotic
apoptosis
antiapoptotic
4 - Limitless Replicative Potential
Somatic cells divide ____ times and then senesce
Low ____ levels
Shortened telomeres signal ____
Senescence is mediated by ____ and ____
Short telomeres are seen as \_\_\_\_ DNA breaks Non-\_\_\_\_ endjoining is activated \_\_\_\_ chromosomes form \_\_\_\_ cycle Genomic instability
• During cell division and replication, the telomeres shorten, because DNA replication is not very efficient at the ends of the chromosomes ○ If they continue to divide, they'll lose the \_\_\_\_ themselves as they divide ○ \_\_\_\_ cells have low telomere levels • Want to have p53 and pRb to stop cell division upon short telomere lengths • When dsDNA break they try to fuse when there are two cases > non-homologous endjoining ○ Even if not complimentary, they will try to adhere to each other
60-70 telomere senescence p53 pRb
ds
homologous
dicentromeric
bridge-fusion-breakage
genes
senescent
Limitless Replicative Capacity
____ is elevated in 85-95% of tumors
Makes genomic changes ____
• Normally, a cell dies because the telomeres are shortened ○ If have p53/Rb > telomeres are too short > senescence § Checkpoint activation: no meta to anaphase transition, no mitosis occurs § In cancer cells, no p53, the ends of chr's begin to adhere □ You have two centrosomes in one chromosome, and during meta to anaphase they will break and fuse and continue to do so ® \_\_\_\_ cycle ® Can continue many times, and normally leads to cell death, but in cancer they need to grow \_\_\_\_ longer again in order to get out of cycle ◊ Express \_\_\_\_ which elongates these regions, and then the cells will be able to survive and continue to divide endlessly § Once have telomerase, they will accumulate more and more mutations § Seen more-so in \_\_\_\_ stages of cancer, in early stages you do not see the upregulation of telomerase ○ If a cancer cell does not have telomerase it will eventually \_\_\_\_ out § An \_\_\_\_ response of the cancer cell to continue dividing
telomerase
permanent
bridge-fusion-breakage telomere telomerase later die adaptive
Limitless Replicative Potential
Telomere activity seems to be a late event in carcinogenesis suggesting:
____ proliferation
____ shortening
Genomic instability (due to ____ cycle)
____ upregulation
uncontrolled
telomere
telomerase
bridge-breakage-fusion
