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Biology > Cancer BIO Exam 2 > Flashcards

Cancer BIO Exam 2 Flashcards

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1
Q

10 Hallmarks of Cancer

A

*Sustaining proliferative signaling
*Evading Growth supressors
*Avoiding immune destruction
*enabling replicative immortality
*tumor promoting inflammation
*activating invasion and metastasis
*inducing angiogenesis
*genome instability and mutation
*revisiting cell death
*deregulating cell energetics

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2
Q

Sustained proliferative signaling

A

-The pedal is on
-signal is continuously on and proliferation is continuous

*proliferative signaling is normal and necessary, but if it is sustained and means the signal is continuous—that may pose as a problem and result in excess or abnormal proliferation

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3
Q

Resisting cell death

A

-brake is blocked–so stopping the cell cycle is inhibited—so if mutation happens, instead of cell cycle being stopped (arrested) and eventually heading to cell death—cell death is evaded and cell cycle continues despite the detected abnormality

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4
Q

Enabling replicative immortality

A

-in normal cells, telomeres shorten–which gives chromosomes a limited life
-in cancer cells-telomerase constantly elongates telomeres and gives cells an infinite lifeline-which enables lifetime replication ability

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5
Q

Inducing angiogenesis

A

-increased proliferation is supported by having more blood vessel formation–which fuels cancer cell survival and support more and increased proliferation

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6
Q

Evading growth suppressors

A

-The stop sign is present, but cells are ignoring the stop sign

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7
Q

Activating invasion and metastasis

A

-cells go to a new place they wouldn’t normally go

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8
Q

Deregulating cellular energetics

A

-cancer cells have a high metabolism
-cancer cells have different eating habits or take advantage of nutrients.
-tracing high glucose indicates having a high metabolism

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9
Q

Genome instability and mutation

A

-errors in the replication
-translocation of alleles that lead to abnormal and unstable genome
-mutation
-all the errors cause genome instability—which could be a potential start of cancer

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10
Q

Avoiding immune destruction

A

-abnormal cells who have increased proliferation or are ignoring stop signs are able to continue their abnormal behavior because they are able to evade immune cells that try to destroy them

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11
Q

Tumor promoting inflammation

A

thishappens when immune cells try to fight cancer cells, as they are foreign to the body, but then immune cells gets confused and sometimes they accidentally secrete signals that help the tumor grow even better and more

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12
Q

how does RTK gets activated

A
  1. growth factors binds to receptor
  2. then the two tyrosine kinases dimerize
  3. dimerize tyrosine kinases phosphorylate each other
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13
Q

2 ways cancer tends to activate proliferation:

A
  1. alterations that makes cell hypersensitive to growth factor ligands
    – (upstream) signal is louder. There might be an alteration in the receptor, that makes it easier for GF to bind to ligand, which encourages more activation
  2. Alterations that make GFs ligands irrelevant by being constitutively (always) active irrespective of growth factors
    – (downstream) the GF doesn’t really matter. whether GF is present or not, kinase is continuously activated

**mutations in normal cells (in their receptor)–can cause alteration in protein structure (like amino acid substitutions–red dots)–causes ligand-independent firing (kinase is activated even without the need for GF)
** If receptor proteins are overexpressed, there can be excessive numbers of normal structured receptor molecules–which can also cause ligand-independent receptor firing because of frequent collision of excessive receptors–which then causes spontaneous dimerization and on signals.

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14
Q

proliferative pathways in cancer

A
  • EGFR (RTK)
  • Ras- if this is mutated in a way that it is ligand-independent, then this will always activated, which makes the signal(GF) unimportant (on or off, Ras activates the downstream proliferation–which affects cell cycle progression and proliferation)
    *P13K–another gene that can be mutated–can affect protein synthesis and cell growth
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15
Q

RAS signaling pathway:

A

Ras signaling:

  1. Ligand binds to RTK.
  2. Signaling is initiated then by IRS
  3. IRS activates Ras
  4. Ras activates Raf
  5. Raf activates MEK
  6. MEK activates ERK

Result: cell cycle progression and proliferation

*every gene in this pathway is commonly mutated in cancer

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16
Q

P13K signaling

A

P13K signaling:

  • Ligand binds to RTK.
  • Signaling is initiated then by IRS
  • IRS activates Ras
  • Ras activates P13K
  • P13K activates PIP2
  • PIP2 activates PIP3

PTEN can inhibit PIP3 from activating downstream protein (if cell cycle has to be stopped when damage is detected in DNA)

BUT IF NO PTEN PRESENT:

  • PIP3 can activate AKT directly
    Or
  • PIP3 activates PDK1 and PDK 1 activates AKT
  • Activated AKT prevent inhibition of TSC1/ TSC2
  • inhibited TSC1/ TSC2 activates mTOR/Raptor complex (mTORC1) through Rheb

Result: protein synthesis and Cell growth

*every gene in this pathway is commonly mutated in cancer

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17
Q

Tyrosine Kinases example and its downstream signals

A
  • PTEN inhibits the pathway of P13K, thus inhibiting production of AKT
  • AKT inhibits BIM (which is pro-apoptosis /Tumor suppressor)

** If PTEN inhibits the production of AKT, then BIM is activated (so apoptosis is present, if needed)

  • ERK is pro-proliferation; so it inhibits BIM
    *AKT is pro-proliferation, so it inhibits BIM who is tumor supressor
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18
Q

when a growth factor binds, what happens downstream?

A
  1. Cytoplasm: GF binds to RTK (GF receptor)—GF receptor produces activated pre-existing translation factors and
  2. cytoplasm: activated GF receptor also leads to activation of serum associated mitogenic GF—to signal release of a diverse array of biochemical signals (PKC)
  3. Nucleus: release of biochemical signals leads to (activating pre-existing inactive translation factors)–so result: activation of transcription factors, which then leads to the production of immediate early genes
    —–immediate early genes + activated pre-existing translation factors lead to polyribosomes in cytoplasm releasing transcription factors in nucleus, and eventually production of delayed early genes in nucleus
    ** production of delayed early genes depends on transcription factors synthesized from immediate early genes
    ***delayed early genes are pro-growth, so binding of growth factor leads to more growth/proliferation
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19
Q

what happens downstream of phospho-ERK

A

** ERK is a regulator of other transcription factors and key players (ERK phosphorylates in a way that it activates downstream genes)
—ERK is pro-growth—if it’s off, then tumor suppressors may be inhibiting it

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20
Q

how does ERK gets phophorylated?

A
  1. Ras activates RAf
  2. Raf activates MEK
  3. MEK activates ERK 1 and 2
    *activation happens through phosphorylation
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21
Q

what does ERK phosphorylate in cytoplasm and in nucleus:

A

in cytoplasm:
***BIM (important)
*MCL
*RSK
*MNK
in nucleus:
*JUN
*FOS
*ELK
ETS
**MYC (important)
*MSK

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22
Q

How does P13K work?

A

*phosphatidylinositol (PI) is composed of 2 fatty acids with long hydrocarbon tails inserted in the plasma membrane, glycerol, and inositol

one way P13K works:
1. PI kinases can add phosphate groups to hydroxyls of inositols–which can yield PI (4,5)diphosphate or known as (PIP2)
2. Phospholipase C can cleave PIP2, which can produce DAG or activate IP3. Or PIP2 can be phosphorylated by P13K to yield PIP3

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23
Q

*Ras>Raf>Mek>Erk cascade phosphorylates a protein substrate
*P13K attaches phosphates to phospholipid

A
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24
Q

Cell/cell contact can stimulate signaling including via Notch/Delta interactions

A

Notch receptors on one cell can interact with Delta ligands on an adjacent cell, triggering a signaling cascade within both cells.

Progrowth pathway–not all gf are secreted, these cells can be embedded so signal an be propagated—notch gets mutated so it doenst need ligate anymore or just go straight to nucleus or it can have mutation that makes it more sensitive to signals

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25
Q
  • cell number is regulated by factors that influence proliferation, differentiation, and survival
  • defective cell death contributes to cancer because of failure to eliminate pre-cancerous cells
  • too much oncogene also triggers apoptosis
A
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26
Q

mechanism (types) of cell death

A
  1. apoptosis
  2. non-programmed necrosis
  3. necroptosis
  4. autophagy
  5. entosis
  6. ferroptosis
  7. anoikis
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27
Q

describe mechanisms of cell death:

A
  1. apoptosis—programmed cell death, activation can be intrinsic (from inside the cell) or extrinsic
  2. non-programmed necrosis–triggered by external factors like trauma, hyporthemia, low O2, low pH, infection
  3. necroptosis–programmed form of necrosis
  4. autophagy–cell “eats” parts of itself to stay alive when food becomes scarce
  5. entosis–cell is “eaten” by another cell
  6. ferroptosis–iron-independent oxidative damage to membrane
  7. anoikis–anchorage dependent cells detach and float off
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28
Q

caspase:
what’s the purpose of procaspase and cleaved caspase

A

procaspase is not doing anything yet, it is basically like a sealed scissor
cleaved caspase–once released from the seal, will go to chop up other proteins as part of apoptosis

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29
Q

how does apoptosis happen?
steps:

A

*Pro-apoptotic (death) signals come in, which causes the outer mitochondrial membrane to open
—-Anti-apoptotic (survival) signal
*Outer mitochondrial membrane open = cytochrome c gets released
—Cytochrome C + Apaf 1 = apoptosome (+ procaspase 9)= caspase 9 (activated)–without procaspase 9, caspase 9 is not activated
—Caspase 9 turn on executioner procaspases 3,6,7 and convert it to executioner caspase 3,6,7
—executioner caspase 3,6,7 cleave death substrates (ICAD, vimentin, lamin, actin) = result in creating apoptotic cell phenotype
Outer mitochondrial membrane open = Smac/diablo gets released
–Smac/diablo inhibits inhibitors of apoptosis (IAPs)
–Inhibitors of apoptosis (IAPs) then activate executioner caspase 3,6,7 which cleave death substrates (ICAD, vimentin, lamin, actin)
**IAPs are pro-survival factors

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30
Q

Aspects of apoptosis
what happens when there’s apoptosis?

A
  • nucleus and cytoplasm start to condense during apoptosis
  • cells break up into membrane-bound fragments that have intact organelles (nonfunctional)
  • E. reticulum fuses and stuff inside the cell gets thrown off (splatters)
  • As the cell gets splashed outside, inflammation happens because of cleaning up—extracellular apoptotic bodies are phagocytosed by neighboring cells and degraded (by immune cells)
  • DNA is degraded non-randomly —DNA degradation is a hallmark of apoptotic cell death because of coiling around histone/nucleosome
  • BCL-2 is a pro-survival factor, when BCL translocates, apoptosis stops
  • caspase 3 is an effector
    *caspase 8&9 will cleave caspase 3, so caspase 3 can cleave other proteins
  • caspase 9 is pro-apoptosis
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31
Q

Apoptotic BH3-domain proteins

  • BH3 are proteins that help initiate apoptosis
A

*pro-survival members (cell lives):
—Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1
*Pro-apoptotic members (cells killed):
—multidomain effectors: Bax, Bak, Bok
—BH3-only proteins: Bim, Puma, Noxa, Bik, Bmf, Bad, Hrk, Bid

**BCl-2 is made up of proteins that contain conserved functional Bcl-2 homology domains

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32
Q
  • cancer cells are motivated to inactivate apoptosis

*what protein drives proliferation but is also able to trigger apoptosis?
*what protein is anti-apoptotic?
* what combination of protein is lethal because it drives excessive proliferation?

A
  • Myc (oncogene) drives proliferation, but too much proliferation also triggers apoptosis
  • BCL 2 and BCL-XL inhibits apoptosis–so the cell survives. These 2 can even override the ability of Myc to trigger apoptosis.
  • oncogenes that triggers more growth have a safety valve (apoptotic factor) that prevents excessive growth
  • so cancer select cells that inhibit apoptotic pathways early on, and combine with pro-growth pathways so it can be lethal and more active proliferation going on
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33
Q
  • what protein translocation leads to follicular lymphoma? How?
A
  • chromosome 14 and chromosome 18 translocation drives approx. 90% of follicular lymphoma
    *IGH (chromosome 14) is highly expressed in B cells
    *when BCL 2 (chromosome 18) is translocated with IGH, IGH drives the production/overexpression of more BCL 2—-since BCL 2 is pro-growth/anti-apoptotic, the translocation can result into lymphoma
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34
Q

10 pathways of apoptosis:

A

1) TRAIL ligand binding lead to caspase 8 directly activating caspase 3,6,7 > leads to apoptosis (cell dies)
2) RIPK1 is activated by TRAIL ligand binding > RIPK1 activates NF-xB > NF-xB activates MCL1, which inactivates BAX/BAK1, inactivated BAX/BAK1 activates BCL- X / BCL 2 > activated BCL- X / BCL 2 leads to closed outer mitochondrial membrane (no release of SMAC or cytochrome C) )which inhibits formation of caspase 9, but also activates IAP (inhibitors of apoptosis), so IAP also inhibits Caspase 9 and can inhibit caspase 3,6,7, and apoptosis (cell lives)
3) NF-xB activates FLIP, which inactivates caspase 8 > leads to inactivation of caspase 3,6,7 (no apoptosis = cell lives )
4) activated Caspase 8 activates BID > which activates BAX/BAK1 > activated BAX/BAK1 inhibits BCL X / BCL 2 leads to open outer mitochondrial membrane > open state releases cytochrome C ( formation of caspase 9) and release of SMAC (so IAP is inhibited-apoptosis happens), so caspase 9, 3,6,7 are activated and leads to apoptosis (cell dies)
5) BAD is pro-apoptosis–it inhibits BCL 2 because BCL 2 is anti apoptosis
6) P13K binds to AKT and inhibits apoptosis of BCL 2 by BAD (so cell lives)
7) AKT and ERK activates BCL X / BCL 2 > activated BCL- X / BCL 2 leads to closed outer mitochondrial membrane (no release of SMAC or cytochrome C) )which inhibits formation of caspase 9, but also activates IAP (inhibitors of apoptosis), so IAP also inhibits Caspase 9 and can inhibit caspase 3,6,7, and apoptosis (cell lives)
8) tumor microenvironment can directly initiate apoptosis through release of perforin from granzyme
9) ER stress, DNA damage can also directly initiate apoptosis
10) autophagy, anoikis, ferroptosis, Necrosis directly initiate apoptosis

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35
Q

what is involved in the intrinsic and extrinsic pathways:

A

extrinsic: caspase 8, TRAIL, TNF, FasL, FLIP
intrinsic: RIPK1,MCL1,BCL2/BCLX,BAX/BAK1,BID,Cyt. C, SMAC,CASPASE 9

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36
Q

how is necrosis related to vascularization?

A
  • hypoxia triggers necrosis
  • necrosis inside a tumor usually has less vascularized inner region and well vascularized outer region
  • blood vessels doesn’t go all the way in the necrosis area because it is ahrd for them
  • having no blood vessels means no immune cells and no nutrients present
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37
Q

how does necroptosis happen? what triggers it? what happens during necroptosis?

A
  • swelling of cytoplasm and organelles ( happens because of loss of proper pumps for maintaining osmotic balance)
  • swelling leads to ruptured lysosomes with the release of digestive enzymes, breaking up of histones and DNA randomly, decreased pH, and rupture of the plasma membrane
  • swelling causes an inflammatory response in cellular debris
  • persistent inflammation can lead to necroptosis
  • necroptosis is triggered by TNF binding to TNFR1
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38
Q

autophagy steps:

A
  1. phagophore formation (bubble forms around organelle)
  2. elongation of isolation membrane (membrane continues to envelope the organelle)
  3. maturation and fusion (cells have fully eaten their organelles)
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39
Q

autophagy complex explanation of how it happens? does it have a role in cancer development?

A
  • ULK1 is the initiator of autophagy. it is inhibited by mtorc1. mtorc1 complex is inhibited by ampk
  • initiation membrane forms. Vesicle nucleation is then promoted by the BECN/vps34 complex. Vesicle elongation is regulated by ATG12-UBL and LC3-UBL. When the vesicle closes (becomes autophagosome), it fuses with lysosome to produce autolysosome that digests autophagosomal content for cellular recycling.
  • there is evidence for autophagy as being a pro-cancer and anti-cancer process
  • autophagy is not really a form of cell death
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40
Q
  • steps of entosis:
  • what are the possible pathway of viable inner cell inside the outer cell?
A
  1. Internalization: E-cadherin engulfs actomyosin
    2: Cell-in-cell structure: viable inner cell
  2. entotic cell death: inner cell is fused with lysosome=inner cell death

*during viable inner cell: outer/inner cell can either proliferate, the inner cell can escape, or inner cell can commit apoptosis inside the outer cell

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41
Q

how does entosis work in cancer?

A

A) anti-tumorigenic effects—death of internalized tumor cell
B) Pro-tumourigenic effects—ploidy changes because of failed cytokinesis (happens when an outer cell fails to digest inner cell, so it leads to formation of multinucleated cell = genomic instability)
C) Cell competition—???

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42
Q

how does ferroptosis work?
remember these are all mechanisms of cell death (if they stop working, it can lead to tumor development: so no ferroptosis if needed, can contribute to tumorigenesis)

A
  • Signals: nutrients (amino acid, lipids), intra/intercellular signaling, environmental stress, environmental stress, selenium
    *Signals: nutrients (amino acid, lipids), intra/intercellular signaling, environmental stress, environmental stress activates cellular metabolism
    *cellular metabolism uses iron to activate PUFA-PLs or ROS, which activates phospholipid peroxidation, which leads to (either loss of membrane, lipid cross-linking, or further oxidative damage to macromolecules), which ultimately leads to ferroptosis
  • Signal: environmental stress can activate ROS, which activates phospholipid peroxidation, which leads to (either loss of membrane, lipid cross-linking, or further oxidative damage to macromolecules), which ultimately leads to ferroptosis
  • selenium: can inactivate ROS —in which case, no ferroptosis
    *selenium using GPX4 can inactivate phospholipid peroxidation step (leads to no ferroptosis)
    *cystine can also inactivate phospholipid peroxidation– so (no ferroptosis)
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43
Q
  • how does anoikis help prevent metastasis?
  • what mechanism or protein help a cell from resisting anoikis?
  • what is the consequence of resisting anoikis?
A
  • cancer cell from anchorage dependency sheds and float (during process of metastasis)–anoikis can initiate mitochondrial ROS caspase-mediated and mitochondrial-mediated apoptosis
  • what mechanism leads to survival (resistance to anoikis): TGF-beta, HIF, EGF-R, Integrin alpha5, Src, lactate, acidosis ascites, cancer associated fibroblasts
    *resistance to anoikis via epithelial to mesenchymal transition (EMT) can help metastasis
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44
Q

what is hayflick limit? How does hayflick limit relate to cancer?

A

hayflick limit is is a signal for cells to stop dividing, and when cells reach this point where they can’t divide further (experiencing senescence). Hayflick limit (signal to stop dividing) tends to be ignored by cancer cells

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45
Q

what did they found about the correlation of age and the ability of cells to divide?

A

found out that older people don’t double as much as younger ones

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46
Q

How do cancer cells get around senescence to grow indefinitely?

A

They avoid going into senescence and ignore hayflick limit

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47
Q

What role does p53 and rb serve in senescence?
What inhibits p53 and rb function, which also lead to inhibition of senescence?
When does population able to double and stop doubling?

A
  • p53 and Rb activates senescence
  • SV40 large T antigen inhibits p53 and rb function — which inhibits senescence
  • HEK cells with wild type large T antigen (inhibits p53 and rb, which ultimately inhibits senescence)— result: able to double it’s population
  • HEK cells with mutant LT antigen— which isn’t able to block p53 and rb function— result: population stopped doubling when senescence was reached
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48
Q

Where do you find telomeres situated?
Who characterized telomeres?

A
  • telomeres are usually at the end of the chromosome ( like caps at the end of shoe laces)

*McClintock, Blackburn, Szostak, Greider

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49
Q

Mechanism of Dna synthesis naturally leaves a small single stranded overhangs at the end. How?

A

Lagging strand have primers at each end to prompt dna nucleotide addition, but at the end of it, when primers are removed, the end has overhang as a result

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50
Q

Telomeres can shrink with each division. As cell continues to divide, telomeres shorten. What is the phenomenon called that happens when there is super short telomeres, that is not able to fully protect the chromosome ends?
How is telomeres related to overhang?

A

*Crisis
* telomeres make up for overhang— so with each cell division, that creates overhang, and over time telomeres can make up for that overhang— which could result in genomic instability as no protection is situated at the end

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51
Q

What happens when chromosomes are without telomeres?

A
  • without telomeres— chromatic ends are exposed— which could lead to end to end fusion (that makes a nonsense connection when chromatids separate during a a phase)
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52
Q

Explain the mechanism of telomere-free Chromosomal disruption

A
  • when telomere is not present at the end of chromosomes— chromosome ends are unprotected—then lead to end to end fusion—amd when chromosome separates during an a phase, there is a creation of one short and one long chromosome— then a non homologous chromosome can form a new fusion with the earlier point of fusion— during the next mitosis, a new breakage can arise
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53
Q

How can chromosomal disruption be prevented?

A

Cells have natural detection ability (called DNA damage sensing pathway)—to detect shortening of chromosomes, in which case activates p53 and rb function of triggering senescence— but chromosomal disruption cannot be prevented in cancer as cancer cells ignore

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54
Q

How does telomerase make up for the overhang?
How does telomerase act in normal cells?
How does cancer cells utiillize telomerase?

A
  • telomerase is an enzyme that adds the same repeating sequence to the ends of chromosomes to protect the overhangs— telomerase counteracts shortening
  • in normal cells, telomerase levels are low enough that chromosomes shrink until they reach the hayflick limit
  • cancer cells and stem cells can keep their telomeres longer as they increase the activity of telomerase. Cancer cells overexpressed telomerase, so they can keep lengthening telomeres for a long period of time
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55
Q

What protein turns up amount of telomerase? If telomerase goes up, how does it affect dna damage signal, p53 and senescence? What natural process turns up telomerase activity?

A
  • myc turns up amount of telomerase
  • high telomerase turns down dna damage signal
  • inactivated dna damage signal inhibits activationnof p53— so no senescence
  • cellular stress can also turn up telomerase or stress can add to the p16ink4a to activate rb and senscence
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56
Q

How do you make cell immortal?
What gene encodes telomerase that you can mutate or overexpressed to make cells grow indefinitely?

A
  • human TERT is the gene that encodes telomerase
  • to induce cell immortality— you overexpressed hTERT to help cells grow indefinitely
  • cancer cells mutate hTERT to amplify or activate it frequently, which leads to cell immortality
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57
Q

What alterations lead to cells growing forever?

A
  • alterations to TERT— overexpressing it causes cells to grow Indefinitely
  • in addition to this— losing p53 and rb, doesn’t stop cells from growing (even when it needs to)— this means no senescence occurring so cells grow forever
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58
Q

How does telomerase activity affect survival of someone with cancer?

A

*high telomerase activity leads to low survival in individuals with cancer
(telomerase + means no surviving tumor)

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59
Q

Describe angiogenesis’ normal process:

A
  1. Initiation of VEGF signaling
  2. Tip cells form between two vessels as they sense vegf
  3. Stalk cell develops in between to blood vessels
  4. Vessel grows— continues to connect two vessels
  5. Anastomosis and pefusion— fully formed vessels
  6. Maturation and stabilization
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60
Q

How does wound healing process go?

A
  • blood clotting plays a role in wound healing
  • two side in cut— now actin filament connect to anchor proteins, which then connects with cadherin dimers
  • cadherin dimers pulls on actin filament until plasma membrane of both side of cut is together
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61
Q

How does epithelial wound healing work?

A
  • tgf beta1 and mmps from stroma activate changes epithelial cells into mesenchymal cells (EMT)
  • EMT moves into the wound site, proliferate and cover wound
  • then changes back to MET (epithelial cells)
  • epithelium is reconstructed
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62
Q

How does stroma wound healing work?
Why do we need angiogenesis for wound healing?

A
  • damage to blood vessel lead to: 1)platelet aggregation 2) exposure of plasma to tissue (in parenchyma) 3) platelet degranulation
  • platelet aggregation leads to clotting
  • exposure of plasma to tissue (in parenchyma)— converts fibrinogen to fibrin— fibrin leads to clotting
  • platelet degranulation leads to activation of vascular factor, pdgf, and tgf beta
  • vascular factors lead to clotting
  • pdgf leads to fibroblast recruitment and (secretion of vegf, mmps, tgf beta) forming of new capillaries
  • pdgf can also recruit macrophages, which will secrete fgf, vegf, MMPs (activate other growth factor—proproliferative) that leads to angiogenesis
  • angiogenesis is needed to make a blood vessels in replacement of the broken vessels destroyed by wound
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63
Q

What is the role of blood vessels in recruiting TAMs and what role does TAM play in cancer?

A
  • the more vascularized (more blood vessels) lead to easier recruitment of Tumor associated macrophages (TAM)— (TAM) helps tumor grow
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64
Q

What are the molecules involved in angiogenesis?

A
  • carcinoma cells (becomes EMT-easier to move and cell to exit, become invasive and metastasize because it is flexible)
  • carcinoma cells release chemotactic factors (pdgf)
  • pdgf turns circulating monocytes to tumor associated monocytes, which becomes tumor associated macrophages
    *TAMs positively regulate EMT, secrete Egf, proteases (cathespins, mmps), and secrete angiogenic factors (vegf, IL8)
    *Egf positively regulate proliferation
    *proteases which positively regulate survival and proliferation, create space for new vessels and invading tumor cells, and lead to angiogenesis
  • vegf lead to angiogenesis
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65
Q

growth signals diminish over time.
So what’s the role of EGF in stimulating growth factor signals? what’s the effect of egf being continuously stimulated?

A
  • egf comes in and activates ras (for proliferation)
  • then erk turns on itself over time(downstream pathway)
    *egf’s role is to keep the pathway more activated (for proliferation)
    *so when erk is activated, it depletes over time, but egf keeps the pathway activated
    *everytime you add egf, there’s a spike in the amount of activated erk pathway
  • ras responds to egf to stimulate erk pathway
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66
Q

how does a negative feedback loop happen in the normal cell? how does it regulate normal cells to not turn into a cancer cell?
what happens when negative feedback loops are broken?

A
  • insulin (GF)– triggers kinase opening
  • phosphorylated IRS binds to P13K, which activates pip3, which activates Pdk1, which activates AKT
    *mtorc2 activates akt too
  • Akt inhibits tsc1/2 and pras40, to activate rheb and activate mtorc1, and activate s6k1
    *activated mtorc1activates grb10, which inhibits insulin receptor kinase
  • s6k1 results in irs1 degradation, so negative regulation–turns proliferative signaling off
  • cancer selects for alteration that inactivates negative feedback loops of growth signals(cancer cells want to keep proliferating, and not want to be turned off)
  • cancer cells get rid of grb10, so negative feedback loop is broken,–so on signal is continuous (no regulation)
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67
Q

how are growth suppressors regulated in the cell cycle? and how does it get mutated to lead to cancer?

A
  • growth suppressors regulate the cell cycle
  • cyclin-CDK, p57kip2, p27kip1, p21cip1 inhibits cyclin-cdk complex (so they are negative regulator of cell proliferation)
    *p16ink4a are tumor suppressors that also regulate cell proliferation
    *these negative regulators or (anti-growth signals) are deleted in cancer
  • cancer cells inactivate tumor suppressors like p27 and p21
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68
Q

What technology can you use to see area of metastases?
What methods can be used to take out / kill tumor cells?

A

*pet scan used to see areas of metastases
* surgery can get tumor cells out, but if cancer cells have metastasized, it can be hard to take them all out
* radiation— hitting radiation from different angles to attack the tumors from different sides in lower effect

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69
Q

What are the proteins involved in promoting metastases?

A

*cathepsin proteases cuts ECM to make space for tumor invasion

*CSF1 recruit macrophages

  • Macrophage—secrete pepsin, cleave surrounding tissue to help spread cancer cells by entering blood stream
    *P selectin and platelets are used to help slow down cancer cells in the blood stream— to make it easier for them to extravasate
    *metadherin enhances adhesion to endothelial cells to help prepare for extravasation
    *angptl4 help facilitate extravasation of cancer cells from blood stream into a new organ
  • Mmp (released by macrophage)-chews on extracellular space for cancer cells to move into (during metastasis to other organs)
  • Swtich to mesenchymal from epithelial (mesenchymal are more flexible— so cancer cells can squish through blood vessels)
    *SDF1 allows the metastatic cancer cells to survive in a new environment
70
Q

Motility of cell

A

Lamellipodium growing outward (way of extending itself)

Actin—like a skeleton

Integrin—involved in focal contact (bind to the floor)

Back portion contracts (job of myosin)

71
Q

Actin cytoskeleton and morphology

A

1) quiescent cell
2) rho activation—stress fibers starts to double in number
3) Rac activation—lamellopodium starts to extend
4) cdk42 activation—filopodia are spread throughout the outside of cell— activated

72
Q

effects of Rho-like proteins on actin cytoskleeton and cell adhesion

A

*Rho proteins like ras is in active state when bound to GTP and inactive state once bound to GDP
*Rho subfamilies: Rac protein, cdc42
* complex program of cell motility depends on the localized activation of each proteins, which enables the whole cell to move in one direction or the other
*Rho, rac, cdc42 control actin cytoskeleton and formation of adhesion
*micro-injection of Rac protein construct a single enormous lamellipodium
*micro-injection of GEF of cdc42 in a cell causes filopodia to extend in all directions

73
Q

cadherin shifts effect on melanoma invasiveness

A
  • when melanocytes are transformed into melanoma cells, E switch to N cadherin–this switch facilitates invasion of stroma because shut down of E cadherin enables cancer cells to extricate themselves from their keratinocyte neighbors
    *N cadherin allows tumor cells to form with mesenchymal cells (pro-invasion)
74
Q

role of MMPs in invasion?
How does siRNA help in stopping invasion?

A

14.34
* collaboration of mt1-mmp in carcinoma cell invasion: mt1-mmp enable carcinoma cells to degrade the basement membrane of stroma. Mt1-mmp cleaves pro-mmp-2 made by stromal cells and turns it into an activated mmp-2–that helps in further invasion

14.33
*cells that were forced to express control siRNA demonstrated a high degree of invasiveness (having non control siRNA allows repression of gene involved in invasion)
*mt1-mmp production was knocked down through (anti-MT1-MMP) siRNA

75
Q

Markers of epithelial cell and mesenchymal cell— how do they help in finding out information about cancer cells

A
  • epithelial— stable cell to cell junctions( apical-basal polarity)
    Markers: cdh1, epcam, grhl2
  • mesenchymal— ( front rear polarity)—migratory or invasive
    Markers: vim, cdh2, snai1/2, zeb 1/2, twist 1– high amount of these means mesenchymal and have higher chance of metastasizing
  • tumor cells tend to undergo EMT (switch from epithelial to mesenchymal)— could mean that it has or preparing to metastasize
  • you can biopsy, stain tumor, do ihc, rnaseq, westernblot to tell if cells are mesenchymal
76
Q

14.1 b
When does cell switch to mesenchymal and epithelial, why?

A
  • in progression of invasive carcinoma— epithelial have transformed into mesenchymal cell (for further invasion and also helps in intravasation and extravasation— makes it easier for cancer cell to squeeze through the blood vessels)
  • during micrometastasis— when cancer cell are starting to survive in a new organ/ environment—(mesenchymal switches to epithelial cell)
  • during macrometastasis— epithelial is also present, and this is to help stabilize the continuous proliferation of cell
77
Q

Micrometastasis lead to macrometastasis. What’s the effect?

A

Micrometastasis often has less survival compared to no micrometastasis after surgery. That is because micrometastasis often clusters and lead to metastasis, which is often considered deadly

78
Q

Micrometastasis lead to macrometastasis. What’s the effect?

A

Micrometastasis often lead to less survival compared to no micrometastasis after surgery. That is because micrometastasis often form clusters and lead to metastasis, which is deadly

79
Q

Metastases tend to travel in cluster/group

A
80
Q

Process of tumor going from primary site into metastasis

A

*from primary organ site— ctc are attracted into blood vessel
* from blood vessel, ctc can either go to brain, bone, lungs (or different organs)
* metastatic cancer cells can further circulate in blood vessels to find more organs to arrest and situate to
* il6 and il8 help attract macrophages— which allows ctc to intravasate into blood vessels
* ctc functions: infiltration (through mmp), stroma recruitment( stroma promotes integrity of epithelial cells, but once cells become metastatic, they change sides and starts promoting growth, invasion, and metastasis), angiogenesis (CXCL1 secreted from human tumor epithelial cells may promote tumor-associated angiogenesis)

81
Q

How does cell adhesion affects the ability of cancer cell to survive thin capillaries?

A

*circulating tumor cells (ctc) are able to squeeze through thin capillaries (make themselves smaller to fit and reform when out of thin capillaries)
*clusters can form single file through thin capillaries
* strength of cell adhesion matters:
Strong adhesions (high stickiness)—bad at getting into thin blood vessels as the cohesive aspect resist getting in, they stretch and try to stay together which resist the force of coming in
Moderate adhesions (moderate stickiness)—they go by a single file chain but more successful
Weak adhesions (less sticky) — most successful as cells go individually

82
Q

Circulation patterns influence metastasis. How?

A

ex: colon (primary site) metastasize to liver
the high proportion of liver metastases deriving from primary colon cancers likely reflects the drainage via the portal vein of blood from colon directly to liver

*not related to circulation: metastasis can go to areas not commonly the route of metastasis, but in lower frequency

83
Q

What factors help a breast cancer cell metastasize to the bone?

A
  • breast cancer cell release PTHrP, which causes osteoblast nearby to change the mix of signals that they release: osteoblasts now increase RANKL synthesis and decrease OPG synthesis
    *increased RANKL synthesis–induced maturation of osteoclast precursors into fucntional osteoclasts (lead to osteolysis or bone degradation, which exposes ecm of bone)
    *exposure of bone lead to release of tgf beta, calcium,BMPs, pdgf, fgf,igf1
    *igf1 and calcium enable cancer cell proliferation and survival. TGF beta induces cancer cells to release more PTHrP (positive feedback loop of osteolytic metastasis)
84
Q

Role of tgf beta signaling in metastases?

A

*Tgf beta comes in to bind to tgfbr1/2 receptor
* tgfbr1/2 becomes phosphorylated and activate smad complex or non smad pathway (ras-erk, p13-akt, gtpases)
*smad complex can bind to tgf beta target genes to help induce cell response and metastasis
* non smad pathways bind to coactivator and corepressor, additionally non smad complex can directly induce— tgf beta induced cell responses and metastasis ( all these three ways lead to metastasis)

Pubmed:
In early stages of cancer, TGF-β exhibits tumor suppressive effects by inhibiting cell cycle progression and promoting apoptosis. However, in late stages TGF-β exerts tumor promoting effects, increasing tumor invasiveness, and metastasis.

85
Q

Tgf beta dual purpose:

A

Tgf beta function in:
*epithelial cells— proliferation, apoptosis, adhesion, cytokine pdtion, ecm prdction
* fibrobalsts— ecm production, cytokine secretion, proliferation
*endothelial cells— migration, morphogenesis, proliferation
* immune cells— inhibit t cell proliferation, inhibit nk cell function, inhibits antigen presentation
* emt/ metastasis—increased invasion and motility

** tgf beta when cells are still normal fucntion to suppress cell growth, motility and invasion
** tgf beta when cancer cells metastasize promotes cell growth, motility and invasion
* it starts on acting as TS, then over time becomes oncogene

86
Q

immune microenvironment and metastasis
explain briefly the role of TAM, csf1, egf in invasion:

A

reciprocal interactions between breast cancer cells and macrophages:
* macrophages are often close to microvessels
*stimulation by TAMs of breast cancer cell motility and invasiveness may contribute to cancer cell intravasation

to understand the whole picture: [carcinoma cells express egf receptor, activation of this receptor allows invasion and secretion of csf1, which attracts macrophages. Macrophages respond to csf1 by proliferating and releasing egf, which activates the cancer cells

87
Q

Explain the transwell assay experiment, the involvement of mena inv, macrophages in tumor cells migration:

A
  • in a transwell assay—there is a top and bottom part— top part is starvation area (no nutrients), bottom part is nutrients area
    *macrophage are attached to the membrane (gate between top and bottom part)
  • then macrophage starts to invade endothelial cells— then carcinoma cells also starts following macrophages
  • mena(inv) — actin regulatory proteins expressed in tumor cells that enables macrophage to invade endothelial cells ( it makes actin more mesenchymal— to enable macrophage to go through endothelial cells)
  • exp. Result:
    — control didnt allow migration
    — control ( no tumor cells with mena inv) but with macrophages also didnt allow migration, thats because mena inv will transform endothelial into mesenchymal to allow it to be more flexible and so macrophages can easily go through
    —only mena(inv) didnt allow migration — because even when mena imv with tumor cells are present and there were mesenchymal cells, macrophages was needed to allow migration
    — mena inv + macrophages allowed for migration, which means mena inv plus macrophages have stronger capability to be able to invade— thats because macrophages are able to attract tumor cells by being able to squeeze through mesenchymal cells
  • although macrophage are pro-tumorigenic, they are not 100% required for invasion— tumor cells are just stronger or more likely to invade when macrophage are present
88
Q

Signaling factors that influence EMT/Metastasis
14.24

A

*signaling channels originate from stroma and influence epithelial cancer cells to undergo a partial or complete EMT
* EMT is triggered in response to confluence of signals that carcinoma cells receive from stroma and intracellular signals (released by ras)

  • shift to EMT is initiated by a collaboration between specific mutant alleles in cancer cell genomes (like ras and p53), these signals are received by boundaries between tumor epithelia and stroma (where cells become mesenchymal)
  • tgf beta, wnts, pge2, tnf alpha are released by cells in reactive stroma (that trigger shift to EMT)
  • egf and hgf can also elicit changes to cancer cell invasiveness and EMT

ex:
*fibroblast release fgf, hgf , which activates ras, which activates tgf beta, which activates emt and lead to invasion
*macrophages release egf, which activates ras, lead to invasiveness
tnf alpha activates NF-kb, lead to emt and invasiveness

89
Q

Metastatic transcriptional signatures
14.51

A

*great majority of cells in certain primary tumors expressed a gene expression signature associated with metastasis –meaning the signature was acquired early in primary tumor progression and inherited by great majority of descendant cells

90
Q

epigenetic regulation of metastasis

A

*in primary tumor site: switch to mesenchymal from epithelial (sign of local invasion and intravasation)
*transfer of cancer cells from primary tumor site is transferred into target tissue (sign of colonization/extravasation)

epigenetic control of gene expression:
*depending on accessibility of DNA for transcription: it can affect tumor cells undergoing EMT, ctc becoming anoikis resistant, tumor cells growing in metastasis

91
Q

Metastatic evolution
Where is pten most likely found?

A
  • pten thrives in the lung
  • pten shows that 9.2% of lung cells have genomic lesion
  • For example, in the patient being tested PTEN deletion is found only in lung metastases
92
Q

Normal oxidative phosphorylation of ADP to ATP

A

Nadh, fadh2 enters eelectron transport chain to turn adp into atp (in the process turning hydrogen and oxygen into water)

93
Q

Normal oxidative phosphorylation of ADP to ATP
how?

A

*high nutrient supply = high energy demand–result in: high glucose consumption, redox homeostasis, proliferation, low atp yield, induced glutaminolysis (catabolizes glutamine to generate ATP and lactate)—cancer cells
*less nutrient supply = less energy demand/consumption–result in: low glucose and glutamine consumption, broken redox defense, blockade in nutrient acquisition pathways, high ATP yield, metabolic vulnerability in mitochondria—normal cells

94
Q

Cancer cells consume more nutrients than normal cells
and they process nutrients in a different way—what effect hypothesize this?

A

warburg effect

95
Q

explain warburg effect:

A

*in normal cells: they are in a catabolic mode, and uses efficient generation of ATP in the mitochondria–tend to go through oxidative phosphorylation, if oxygen is present. They go through anaerobic glycolysis and use lactate when oxygen is not present
*in cancer cells: they tend to favor glycolysis over oxidative phosphorylation as means of generating energy (ignoring even when oxygen is present–aerobic glycolysis)—Glycolysis is faster, which is important because cancer cells have high energy demands (needed for proliferation), and they prioritize high energy for now for speed, rather than ATP production for later use

96
Q

glycolysis rate of cancers? also kras mutant lung cancers

A
  • to measure glycolysis rate, acidification rate is used (often result from acidification also indicate the same for glycolysis)
    *switch to glycolysis can lead to the accumulation of lactate and protons, resulting in an acidic microenvironment
    *normal lung cells have less glycolysis, lung cancer cells have higher glycolysis rate, and kras mutant lung cancer cells have the highest glycolysis rate
97
Q

KRAS and metabolism and how it affects cancer cell growth?

A

*oncogenic KRAS influence the increase of glucose influx via GLUT1, increased glucose also increases glucose metabolism, which increases pyruvate, and increases tca cycle
*increased pyruvate, increases lactate, which lead to cancer cell growth
*Oncogenic kras increases glutamine metabolism in TCA cycle
*increased activity in TCA cycle lead to macromolecular biosynthesis, which influences cancer cell growth

98
Q

Nutrient processing in cancer

A

*growth factor directs uptake of nutrients (glucose and gluatmine) in cells that are proliferating (they enter anabolic mode to create biomass)
*cancer cells have mutations that lead to constitutive growth factor signaling and metabolic reprogramming

*cancer cell has metabolic disruption:
–increased rate of glycolysis
–mitochondrial dysfunction and disruption of the TCA cycle
–accumulation of metabolites (lactate, fumarate)
–increase in reactive oxygen species (oxidative stress)

99
Q

how does insulin signaling regulates glucose? what effect does insulin have on rate of glucose? what effect does the amount of glucose have?

A

*Activated PI3K/Akt signaling leads to enhanced glucose uptake and glycolysis via increased glucose transporter expression and activation of hexokinase to capture glucose inside of the cell through phosphorylation

*when insulin comes in, it activates AKT, which activates GLUT1 (glucose transporter) and HK2 (hexokinase)–so more glucose comes in (increased in glucose metabolism)

100
Q

MYC oncogene induces addiction to glutamine over glucose: why?

A

*Cells overexpressing oncogenic Myc are addicted to glutamine and undergo apoptosis when deprived of glutamine
*when MYC is on, glutamine is preferred over glucose
*MYC off, glocose is preferred over glutamine

101
Q

p53 sense glucose amount in cell: differentiate how normal and cancer cells each acts based on glucose amount

A

*in normal cells: when they are glucose deprived–they undergo senescence and proliferation is inhibited

*in cancer cells: when p53 is deleted or mutated, cells continue to grow even with the absence of glucose (because they use glutamine)
–glutamine is preferred because it better supports TCA cycle, and TCA cycle is needed for energy production

102
Q

effects of insulin in tumor:

A

*pancreas releases insulin
* insulin is distributed to liver, adipose, muscle, and (tumor)
*in liver: when insulin is provided, there’s increase in glucose uptake and decrease in gluconeogenesis (or making glucose / process of making glucose (sugar) from its own breakdown products or from the breakdown products of lipids (fats) or proteins)
*in adipose: when insulin is provided, fatty acid production and triglyceride synthesis increases, and decrease in lipolysis (breakdown of triglycerides)
*in muscle: when insulin is provided, there’s an increase in glucose uptake and utilization, and decrease in fatty acid oxidation
*in tumor: when insulin is provided, glucose uptake increase, and cell survival/proliferation increases

*insulin is pro-oncogenic

103
Q

how does low insulin increase the efficacy of P13K inhibition

A
  • only ketogenic diet (low sugar, low carbs), but P13K pathway is still on = increases tumor volume
  • no ketogenic diet, but P13K pathway is inhibited = slow but growing tumor volume
  • ketogenic diet + P13K inhibitor = decreased tumor volume

*ketogenic diet + P13K inhibitor + insulin (injection) = increased tumor volume
–adding insulin increases efficacy of processing sugar, so cancer grows again

*ketogenic diet helps with P13K inhibition because cancer cells are being starved of food source, adding that to inhibition of cell growth = less chances of growing tumor volume
–ketogenic diet inhibits consumption of dietary glucose, which also inhbits delivery of glucose to liver, pancreas, and eventually to supplying tumor
–if only p13k inhibitor is present, yes you’re inhibiting insulin from being delivered to tumor, but glucose is still delivered through non-ketogenic diet (so low sugar diet is important)

104
Q

relation of pkm1 and pkm 2 to normal and cancer cells:

A

*PKM1 -involves in normal cells as it promotes oxidative phosphorylation
*PKM2 regulates the rate-limiting step (last step) of glycolysis that can shift the glucose metabolism from normal to lactate production in tumor cells
–less active dimer form of PKM2 lead to increased aerobic glycolysis (warburg)–preferred by cancer cells
–more active PKM2 lead to increased oxidative phosphorylation (normal cells)

105
Q

explain the difference in pyruvate kinase M (1 and 2) splicing

A

*pkm1:
–most adult tissues have this (gene 9)
–pyruvate enters the citric acid cycle (or tca cycle)
*pkm2:
–cancer cells have this (gene 10)
–c myc levels are increased
–pyruvate is converted into lactic acid (warburg)

*PKM2 splice variant is the major isoform in embryonic tissues and in many cancer cells

106
Q

metabolomics purpose:

A
  • metabolomics is used to see if there’s an unusual metabolic activity in certain organs
  • Metabolomics quantify metabolites in any tissue
107
Q

IDH1/2 mutations cause 2HG accumulation:

A

*asp and glu are metabolics–AML with IDH2 shows that there’s 2HG accumulation in IDH2 mutant cells
–IDH1 mutations specifically cause massive 2-hydroxyglutarate (2HG) accumulation
*2HG accumulation leads to cancer

108
Q

deep sequencing tumors:

A

*they tested AML, and found that genes IDH1, IDH2, TET2, WT1 are somehow mutated in AML
* mutual exclusivity of mutations (separate relations of these genes) helped identify linear pathways in cancer

109
Q

Accumulation of 2HG leads to cancer: explain relation to idh1/2, tet2.wt1

A

*Dna methylation—affects transcription
*5mc–represses gene transcription
*5mhc–means the gene is stable

*normal cell: idh1/2 activates alpha-KG, which allows TET2 to bind to WT1 (when TET2 is bound to WT1, gene is stable due to work of 5hmC)

*in AML: IDH1/2, TET 2, and WT1 could all be mutated, when that happens, gene switches to 5mc, and there’s altered proliferation and tumorigenesis

110
Q

IDH1/2 functions

A
  • IDH1/2 increases levels of 2HG
  • 2HG inhibits DNA demethylases, histone demethylase, histone methyltransferase, prolyl hydroxylases (the first 3 changes hypermmethylation pattern of CpG islands, the last one leads to HIF1 (aids in tumor proliferation)
111
Q

how does high metabolism help in detecting if cancer is present?

A

*Cancer’s reliance on glucose can be exploited for imaging
*Cancer cells utilize large quantities of glucose

*18F-deoxyglucose positron emission tomography (FDG-PET) detects glucose use, mostly in metastatic tumors

*helps us know if cancer is present, and where

112
Q

Transition mutations vs transversion mutations

A

*Transition mutations create a change from purine to purine, or from pyrimidine to pyrimidine
*Transversion mutations create a change from purine to pyrimidine, or from pyrimidine to purine

113
Q

Stem cell maintenance vs. differentiation

A

Stem cell mutation can be passed on or affect the subsequent steps compared to when only differentiated cells are mutated, which only affects the last step

114
Q

Cancer risk correlates with stem cell divisions

A

More cell divisions = more opportunities for DNA fidelity errors

115
Q

Mutation rate across tumor types correlates with carcinogen exposure

A

Melanoma has a high rate of mutation due to also exposure to carcinogens (sun)
Lung cancer comes next with a high mutation rate (even when we don’t smoke, the air we breathe is full of smoke—high carcinogen exposure)

116
Q

Reactive Oxygen Species

A

*oxygen free radical (has unpaired electron)–unpaired electron is highly reactive and can bind to DNA causing damage

117
Q

Types of damage: Oxidation of DNA bases, often by reactive oxygen species (ROS)

A

*oxidation can lead to unstable base and can lead to deamination
*unrepaired damage can be mutagenic

118
Q

Types of damage: Deamination

A

*(nucleotide sequence change) U looks enough like T that this sometimes is not repaired and results in a C to T mutation (like in melanoma cancer)
*deamination reactions affect purine and pyrimidine bases

119
Q

Types of damage: Depurination and depyrimidination

A

*Mutation via the DNA backbone losing a base (G)
*Depurination affects guanine within DNA and leaves behind deoxyribose

120
Q

Types of damage: Stuttering errors in repetitive “microsatellite” DNA sequences

A

*More repeats—easy for DNA to make mistakes/confusion (because a lot of repeats are lookalikes)—so mutations formed
*stutter–meaning skips a base when copying a repeating sequence of DNA, so the newly synthesized strand may acquire an extra base that increases the length of the repeating sequence or may lack a base

121
Q

Types of damage: Breaks at replication forks

A
  • during DNA replication–DNA molecules are vulnerable to breakage in single-stranded portions near replication forks that have not undergone replication
    *breaks result from chemical alteration of a base, so dna polymerase is unable to recognize the altered base–resulting in region of single-stranded DNA that may exist as is before it gets replicated
    *breakage of single stranded region is equivalent to dsb in double helix
122
Q

Types of damage: Ultraviolet radiation can create covalent crosslinks between bases

A

*Uv can induce dna strand break
*Ultraviolet (UV) radiation produces
covalent cross-links between adjacent (sometimes forming a four-carbon ring)
–These are mutagenic, inappropriate connection of bands, and affect genome stability

123
Q

Types of damage: DNA damaging chemicals like ENU or MNU can induce cancer

A

*Enu—highly carcinogen—mutates guanine
*Mgmt—tumor suppressor that can turn back into guanine (a DNA repair enzyme)
*Counteract DNA damage by overexpressing mgmt.
*Low mgmt.—cancer
*Too much mgmt.-can repress genes and reduce the risk of cancer

*Enforced overexpression of DNA repair enzyme MGMT can counteract chemical damage

124
Q

Smoking-induced carcinogens can drive mutations

A

*BPDE can attack many chemical sites in the dna (like guanine or ring of nitrogens)
*BP of BPDE may be mutagenic

*Sometimes, these DNA mutations happen in oncogenes and tumor suppressors, leading to cancer
*bpde gets into cell, hit part of dna, bpde gets fused to guanine, which causes repair error

125
Q

Lung cancer mutations in p53 (what nucleotide is involved?)

A

*carcinogens from smoking are likely to cause G to T mutations

126
Q

Smoking influences KRAS mutation patterns in different tissues

A

*Because carcinogens in cigarette smoke induce more G to T transversions, KRAS mutations caused by G to T occur more frequently in lung cancer than in other tissues
*This is important for patients because cysteine is the only mutant KRAS allele that is directly treatable (for now)
*G12C (amino acid changes in lung cancer mutation)
*Kras inhibitors that work for lung cancer may not for colon or other cancers

127
Q

Mutational signature analysis–give example and what is the importance of analysis

A

*KRAS G12C mutations are strongly associated with mutational signatures caused by cigarette smoke
*Mutation signatures provide clues about the potential causes of that particular tumor

128
Q

other types of dna damage:

A

*translocations (IGH and myc)
*amplifications and deletions of genes and chromosomes
*telomere degradation that causes chromosomal catastrophe induced breaks and fusions

129
Q

chromothripsis—what is it caused by?

A

*chromothripsis is caused by random fusion
*when catastrophic chromosomal breakage happens, there are resulting 10 to 100 DNA fragments—then there’s attempted chromosomal repair, but if breakage keeps happening, there may be a few fragments that are lost and never fused back again, which leads to progression towards cancer

130
Q

aneuploidy

A
  • the kinetochore of an individual chromatid may be connected inappropriately to two opposite spindle fibers or may not be connected at all (be lost in the end)

from pubmed:
*when cells—especially cancer cells—divide, the chromosome pairs separate unevenly, leaving one cell with more chromosomes than the other. The resulting aneuploidy generally wreaks havoc on the cells, causing widespread problems with metabolism, protein production, and growth—genomic instability

131
Q

Mechanisms of DNA damage repair

A

Proofreading—pencil analogy
Mismatch repair—one strand gets changed, the other sided dint get repaired—
Base excision repair—cuts up the wrong base, and replace it with correct one
NER—replaces nucleotide backbone
NHEJ—dsb, whole cleavage, bind two breaks together
MMEJ– homology between two end help rewires the two breaks
HR—cell use the other cell’s template, to take the other copy from other chromosome to repair the mistake

132
Q

DNA damage sensing pathways

A

*(cellular metabolism, uv light exposure, replication errors, ionizing radiation, chemical exposure)=leads to dna damage
*DNA damage sensors scan and look for breaks
* DD Mediators—help connect signal from transducer to p53 (which triggers DNA damage repair)
*Transducer—continuing the signal from sensors and passing the signal to mediators
*DD repair effectors are responsible for eliciting solution (DNA repair, cell cycle arrest, apoptosis, senescence)
*Brca mutation—dna repair pathway is less effcient because BRCA is not included in dna damage repair pathway
*Inherited brca can lead to cancer–because again, no dna damage repair pathway available
*Brca mutations are not a sure thing
*Sensors, mediators, transducers depend on level of damage, and it base itself to that to produce more dna damage repair signal
*there are different pathways for dsb and non dsb repair pathway

133
Q

how does Proofreading by DNA polymerases work?

A
  • there are number of polymerase that have proofreading ability that allows them to minimize the number of misincroporated bases
    *dna polymerasewill use existing 3’OH of the strand to keep adding nucleotide, but if something went wrong, dna polymerase will degrade in a 3’ to 5’ direction and moves forward to correct its mistake
134
Q

Mutations in DNA pol inactivating proofreading cause cancer–how did they prove it?

A

*Mice with proofreading deficiencies die of lymphoma, lung carcinoma,
squamous cell carcinomas of the skin, or other cancers

135
Q

Mismatch Repair (MMR) Pathway

A
  • Muts alpha and mutl alpha collaborate to initiate repair of mismatched DNA
    *Muts alpha scans the dna and locates the mismatch
    *mutl alpha scans the dna for single-strand nicks
    *mutl alpha triggers degradation of the strand back through the detected mismatch and then proceeds to allow for repair DNA synthesis
136
Q

*Tumors with deficiencies in MMR genes have high mutation rates
*gliomas treated with DNA-damaging chemotherapeutic temozolomide had less mutations now

A
137
Q

homology-directed repair

A

*repair begins with the removal by an exonuclease of one of the two strands at each ends formed by dsDNA break.
*the resulting ssDNA invades undamaged sister chromatid, whose double helix was unwounded by the repair apparatus to pair invading ssDNA with complementary sequence in undamaged sister chromatid
*the ssDNA strands from damaged chromatid are elongated in 5’ to 3’ direction by polymerase using the strands of the sister chromatids’ DNA as a template
from picture:
*dsDNA break
*exonuclease performs removal of strands
*damaged sister chromatid base pairs with unwound DNA of sister chromatid (that is undamaged)
*strands are extended
*once undamaged sister chromatid’s template are used, damaged chromatid disengage and pair to fill in gaps, ligate, and restore wild-type helix

138
Q

NHEJ

A

*there’s DSB
*removal of single strands by exonuclease
*DNA strands are brought together, and there’s a possible limited base pairing between them
*strands are filled in and joined by ligation
* double helix is reconstructed
* several base pairs are present in original; wild-type are missing

139
Q

nhej vs hdr

A

nhej, you cant recover wild-type sequence because you just fused dsb together
hdr, you can recover wild-type sequence since you copied the same sequence from a sister chromatid

140
Q

Molecular Players in DNA Damage Repair

A

*Inducing radiation (in therapy) can lead to dna damage repair by triggering apoptosis and senescence—this is backward purpose of treating cancer (but it is most active when p53 is also active)
* HR pathways either leads to cell cycle arrest or HR dependent DNA repair/tumor cell survival
*NHEJ pathway –accumulation of dsb in brca pathway leads to genomic instability/tumor cell death

141
Q

Inactive BRCA genes lead to chromosomal abnormalities

A

*These include fusions
between chromosomal arms, resulting in chromosomal translocations that often
manifest aberrant chromatid pairings at the metaphase of mitosis.
*The fusions are often caused by unrepaired or improperly repaired dsDNA breaks.

142
Q

Base excision repair

A

*wrong base needs replacing
*DNA glycosylase removes the wrong base
*AP endoculease removes the ucleotide backbone of the base
*beta + ligase = short patch repair (nucleotide is inserted and ligase seals the gaps
*long pathc repair is whenyou move the whole nucleotide either to the right or left depending on the direction you’re replacing

143
Q

Nucleotide excision repair

A

*wrong nucleotide is distorting the helix
*DNA fragment is cleaved (the backbone)
*the whole nucleotide backbone is added (this time, with the correct nucloetide)

144
Q

cancer is not transferable from one to another person because the immune system of the recipient destroys the cancer cell

A
145
Q

Antibody diversity by random recombination–purpose

A

Each B cell makes different chunks of antibody for different virus
Vdj is for heavy chain, vj is for light chain

146
Q

function of antibodies

A

*prevents viral adsorption
*prevents bacterial adherence

–antibodies bind the virus receptors, to stop them from binding to other receptors and eliciting effect

147
Q

Macrophages eat and digest antibody-coated invaders
*invaders are then eaten by macrophages and degraded inside by the lysosome

A
148
Q

Natural killer (NK) cells lyse their targets
*antibodies bind to receptor of the invader target cell
*NK cell then bind to receptor—so NK cell becomes activated
*activated NK cell releaase perforin and granzymes to lyse the invader cell

A
149
Q

Bcells recognizes antigen, breaks it down, and present them through MHC II—present the chunk of destroyed virus and show it to other cell (helper Tcell), to make other antibodies find more of that antigen and destroy it

A
150
Q

dendritic cells are also apc
they phagocytose antigens and present it through MHC II

A
151
Q

cytotoxic T cells

A

*Cytotoxic T-cells are trained to look for cells displaying antigens that “aren’t supposed to be there”
that was picked up by dendritic cells and Helper T-cells
*Dc activates helper t cells through presentation of antigen
*DC still have to present itself and its own contents through MHC I in cytotoxic t cells
*active cytotoxic T cells attack apcs with antigen not ood for the body

152
Q

Cytotoxic T-cells induce cell death in target cells via extrinsic apoptosis pathway
*cytotoxic T cells have FasL on their surface, while target cells have Fas receptors
*once cytotoxic T cells have bound to the target cells, pro-caspase 8 are activated, which when bound to active caspase 3 will trigger apoptosis

A
153
Q

Effector T-cells (CD4, CD8/cytotoxic T-lymphocytes) vs. Regulatory T-cells (Treg)

A
  • CD4 T cell release IL2, which stimulates CD8 T cells—CD8 activate CTL (similar with cytotoxic T cells)–which degrades apc (target cell)
    *CD4 T cells can also directly connect with apc and destroy apc
    *CD4 cells can activate CD8 cells–which is responsible for checking self-presenting cell
    *T reg cells–are tolerating infecting cells
    *T reg cells are allowing apc to inhibit CD4 T cells from killing apc and T reg cells
    *T reg cells eat IL2, so they won’t signal CD8 and won’t stimulate attack
154
Q

*Helper T cells are activates by antigen presented by dendritic cells—only if a right match happens
*Activated helper T-cells go on to activate B-cells with matching antigens
to differentiate and secrete appropriately targeted antibodies

A
155
Q

Cells bound by many antibodies attract complement, which pokes holes in cell membrane to lyse cells

A
156
Q

Tumor infiltrating lymphocytes (TILs)

A

*TILs are also frequently
found in invasive non-small-cell lung carcinomas
*Those patients whose tumors had high levels of TILs (blue line) fared significantly better than did those whose tumors lacked significant concentrations of TILs
*low TIL–less responsive in therapies because immune cells aren’t able to attack cancer cells

157
Q

*Tregs suppress cytotoxic T-cells,
thus helping cancer thrive
*CD25 (Treg) mask FOXP3 (cancer cell?) from being recognized by CD8 cells
*high Treg is associated with low survival

A
158
Q

*The immune system attacks and kills “foreign” cells
*when a foreign (cancer) cell was injected into allogeneic cell (which has different genetic background)–immune cells attacked the cancer cell bc it recognized it’s foreign

A
159
Q

*Rag2-/- mice do not make B- or T- cells —they are immunocompromised, thus cancer forms
*wild-type has immune system, capable of destroying cancer cells
* tumors that did arise in wt mice were already selected for being weakly immunogenic and thus capable of forming new tumors in other wt mice

A
160
Q

*Macrophages can have anti-tumor or pro-tumor activity
*macrophages activated by diverse signals like interferon and lps, are able to present antigen to helper t cells and trigger tumor killing
*hypoxia and other signals activate macrophages and cause them to foster tumor progression

A
161
Q

Polarization gradient of Tumor-Associated Macrophages (TAMs)

*M1-like TAM: tumor suppressing
*M2-like TAM: tumor promoting

A
162
Q

Natural Killer (NK) cells sense stress via alarm proteins

*Alarm proteins (MICA/MICB) on other the surface cells signal cell stress to the NKG2D receptor on NK cells
*Binding of these proteins to the NKG2D receptor results in strong activation of an NK cell’s cytotoxic response and is therefore followed rapidly by killing of cells that express these stress-associated pro- teins on their surfaces.

A
163
Q

Neutrophil extracellular traps

*NETs have been linked to cancer progression, metastasis, and cancer-associated thrombosis

A
164
Q

How can cancer evade immunosuppression?

A

*recruitment of immunosuppressive cells (like tregs and MDSCs)
*ineffective presentation of tumor antigens to the immune system (due to downregulation of MHC expression or suppression of APC)
*release of immunosuppressive factors (these factors/enzymes directly or indirectly suppress immune response
*T-cell check point dysregulation–

165
Q

Cancers can downregulate MHC-I

*prostate and breast cancers have the highest downregulation of MHC I, which also resulted into high percentage of tumor development

A
166
Q

NK cells try to get around cancer’s “downregulate MHC I” trick

*When the killer inhibitory receptors (KIR) is active, binding to the constant region of MHC I sends a “no attack” signal
*when KIR can’t bind to the potential target cell because no MHC I is present, it attacks the cell
*so even if cancer cells can downregulate and limit presentation of mhc I, NK cells learned this and try to attack a cell that won’t exhibit mhc I

A
167
Q

Interactions between antigen presenting cells (APCs) and Helper T-cells

*CTLA-4 receptor on TH cells inhibits their stimulation by APCs
*negative regulator of activation of TH cells–without this

A
168
Q

PDL1 on tumor cells tells the PD1 on T-cells signal “leave me alone”

  • When programmed cell death protein 1 (PD1) on the surface of T cells binds to programmed death-ligand 1 (PDL1) on cancer cells, it sends a signal to the T cells to avoid attacking the cancer cells. Blocking this interaction, typically through the use of PD1/PDL1 checkpoint inhibitors, can unleash the immune system’s ability to recognize and kill cancer cells.
  • Pdl1-pd1 is high, signal is off

Tumor cell upregulates pdl1

*ZEB1 upregulates signal of pdl1 to bind to pd1
*microrna200 helps downregulate signal of zeb1— so this is useful if we want t cell to recognize cancer cells
* mutations in EGFR or KRAS can activate downstream signaling pathways that lead to increased ZEB1 expression. This upregulation of ZEB1 contributes to cancer progression by promoting epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and immune evasion.

A
169
Q

Dominant negative mutant of TGF Beta RI

  • In the presence of both the mutant and wild-type TGF BetaRI, the wild-type receptor is preferred for signaling, as it retains its ability to transmit signals downstream upon ligand binding (erk pathway activation—cancer progression). However, if the wild-type TGF BetaRI promotes tumor progression, then the dominant negative mutant could potentially interfere with its oncogenic signaling, thereby inhibiting tumor growth and progression.
A
170
Q

Dominant negative TGFBRI in lymphocytes helps them attack cancer

*having wt tgfbri—lymphocytes are killed but tumor cells survive
*having dn tgfbri(mutant)—melanoma cells are destroyed

A

Biology (3 decks)

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