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
