5. Cancer II Flashcards by J L

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

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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

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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

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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

overexpressed
active
hyperresponsive
squamous cell carcinoma
H+N

breast
overexpression
antibody

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

Study These Flashcards

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

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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

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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)

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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

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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)

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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!

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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

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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

Study These Flashcards

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

5. Cancer II Flashcards

(37 cards)