Cancer I-III

Question 1

what are the stages of the cell cycle in order: function and time?

Answer 1

G1 phase: components of the cell excluding DNA are replicated (organelles, proteins, etc…)
- Each daughter cell is around 1/2 sized and has to grow to full size before the next cell division
~6-10 hours

S phase: DNA is replicated
~2-6 hours

G2 phase: methylation patterns are recapitulated and any DNA damage is repaired
~3-6 hours

Mitosis: when the cell actually divides
Prophase, metaphase, anaphase, telophase
~1-2 hours

G0 phase: cells are quiescent (aka no longer dividing)

Question 2

cancer definition

Answer 2

a disease caused by uncontrolled cell division and proliferation

Question 3

explain the difference between how long google claims DNA replication takes vs how long it actually takes and why

Answer 3

The human genome is 1.02 meters in length and is ~3 billion base pairs
google claims that the replication rate of a DNA polymerase complex is 0.1-1.2um/min
–> However, this seems problematic: 1m divided by 1 um/min = approximately 1 million minutes

In reality there are multiple, simultaneous “origins of replication”: around 1 per every 300,000 base pairs
300,000 base pairs = 1/10^4 of the human genome
And 1/10^4 of 1 million minutes is around 2 hours (which is consistent with the given LECTURE’s answer)
–> DNA replication actually takes ~2-6 hours (NOT 1 million minutes which is what google claims)

Question 4

the human genome is approx. how long and contains how many base pairs?

Answer 4

approx. 1.02 meters in length
approx. 3 billion base pairs

Question 5

what are the 2 activities/functions of the G1 phase?

Answer 5

1. recapitulation of parent strand methylation patterns on daughter strands takes place (aka copies methylation patterns from parent strand onto daughter strands)
2. DNA repair

Question 6

why is DNA repair necessary? use numbers

without DNA repair, what is the approx. number of mistakes per cell division made by DNA polymerase?
now with DNA repair, what is the approx. number of mistakes per cell division?

Answer 6

DNA repair is necessary because DNA polymerases are “only” 99.999% accurate → a 10^-5 error rate is NOT good enough since it means there are 30,000 mistakes per cell division

DNA repair fixes 99.99% of replication errors → the overall mutation rate is reduced from 10^-5 to around 10^-9 (aka around 3 mutations per cell division)

Question 7

If cells really did divide twice a day, as they can in theory, how long would it take for a fertilized egg to grow into an adult-sized person?

How frequently, on average, do cells actually divide from conception to adulthood?

Question 8

theoretically, what is the shortest amount of time it takes for a cell to divide?
how does it actually take human cells to divide?

Answer 8

the SHORTEST amount of time for a cell to divide is around 11 hours BUT 24-30 hours is typical for human cells

Gut progenitor stem cells do divide in around 11 hours though

Take home message: under normal conditions, almost all cells divide MUCH LESS frequently than they theoretically can (which is twice a day; around 12 hours per cell division)

Question 9

HOW and WHY cells divide slower than they theoretically can?

Answer 9

1. cell cycle stops in G0 phase (long “brake”)
   –> Although G0 can be reversible, it can last for 150+ years (ie. tortoise; and some cells in adult animals never divide)
2. cell cycle checkpoints (short “brakes”)
   G1 checkpoint: after G1
   Is the environment favorable? Is the DNA intact?
   G2 checkpoint: after G2
   Is all the DNA replicated? Is the DNA intact?
   M checkpoint

Question 10

what are the 2 things the cell cycle checkpoints check for?

Answer 10

1. DNA integrity (if the genome is damaged, cancer-causing mutations could occur)
   Sources of DNA damage:
   Metabolism: around 100,000 oxidative DNA lesions per day
   The environment: ie. sunlight, cigarette smoke, “chemicals”
   Cancer drugs: ie. cisplatin
2. the environment (in this case, we mean the microenvironment): the microenvironment controls checkpoint bypass

Question 11

biology of cell checkpoint bypass: Rb and E2F

Answer 11

checkpoint bypass for G1/S checkpoint

Rb: a tumor suppressor protein that binds to E2F to keep E2F INACTIVATED
→ this prevents E2F from activating the transcription of genes required for DNA replication and S-phase entry
E2F: a transcription factor required for DNA replication in S phase

Mid G1 phase: DNA synthesis CANNOT occur in early/mid G1 phase because even though E2F is PRESENT in a cell, it is NOT ACTIVE

Late G1 phase: in late G1 phase, the Rb protein becomes PHOSPHORYLATED when growth signals (cyclins, CDKs) are present and is inactivated
→ as a result, E2F is no longer sequestered and becomes ACTIVATED –> can now transcribe genes that drive the cell into S phase and the cell bypasses the G1 checkpoint

Question 12

describe the relation between the binding of Rb and E2F and their activations

Answer 12

initially: Rb is hypophosphorylated and in its active state when bound to E2F which is inactive right now (they start off bound together)
- It is energetically unfavorable for Rb and E2F to not be complexed together → allosteric interactions also stabilize the complex

after phosphorylation: Rb becomes inactive and unbinds from E2F, thus making E2F active
- Phosphorylation of Rb INCREASES deltaG and disrupts protein-protein interaction → causes E2F to be released and activate genes

Phosphate is removed from Rb after checkpoint has been passed

Question 13

how can cancer occur in the Rb and E2F process? (2 types of oncogenic mutations)

Answer 13

In cancer, point mutations may recapitulate the phosphate or nonsense mutations that may prevent E2F from binding to Rb –> Rb is constantly active and keeps transcribing genes that promote DNA replication –> unproliferated cell division

Cancer-associated mutations DEACTIVATE Rb
Oncogenic mutations include…
1. Point mutations that recapitulate phosphorylation
2. Nonsense mutations that remove parts of Rb required for interactions with E2F (creates truncated forms of Rb)

… as a result, E2F is ALWAYS turned ON since Rb is always inactive/turned off

Question 14

name 5 ways that phosphorylation modulates protein-protein interactions at the molecular level in GENERAL

Answer 14

Specific recognition
Protein dissociation
Ion transport
Order <–> disorder transition
Allosteric regulation

in summary, phosphorylation modulates protein-protein interactions by changing the conformation, binding affinity, or activity of proteins –> influencing a wide range of biological processes.

Question 15

Phosphorylation can promote SPECIFIC RECOGNITION via what 2 things?

Answer 15

ionic bonds
hydrogen bonds

Question 16

describe which type of phosphorylation effects applies to the protein-protein interactions of Rb/E2F complex

Answer 16

specific recognition: NO

protein dissociation: phosphorylation interrupts protein-protein interactions as happens for E2F-Rb by reducing the contact area between the two surfaces –> disrupting van der waals forces
- think in terms of entropy

allosteric regulation: phosphorylated Rb is folded in a “closed” conformation
- Phosphorylated Rb is folded in a “closed” conformation → disrupts its ability to bind to E2F → Rb releases E2F → E2F can activate the transcription of genes required for cell cycle progression
- Unphosphorylated Rb is in an “open” conformation → Rb can effectively bind to E2F and keep it inactive

Entropy plays a role in the formation of E2F-Rb complexes BUT E2F-Rb interactions are primarily determined by ALLOSTERIC REGULATION

Up to this point, we ruled out specific recognition in Rb-E2F interactions and instead we implicated allosteric regulation
HOWEVER… it is plausible that allosteric regulation involves INTRAMOLECULAR specific regulation

Question 17

describe how entropy affects the protein protein interactions of the Eb/E2F complex

Answer 17

Low energy state is energetically favored (high entropy); high energy state is energetically not favorable (low entropy)
Spontaneous: low entropy → high entropy

Entropy helps drive the formation of Rb-E2F complexes
Hypothesis: Rb-E2F complexes are energetically favorable due to the entropy of water
- Rb and E2F have hydrophilic and hydrophobic regions:
when they are unbound, their hydrophobic surfaces are exposed to water –> reduces entropy
when they are bound together, their hydrophobic surfaces are buried in the complex –> increases entropy

forming the Rb/E2F complex requires overcoming some enthalpic costs BUT the increase in WATER ENTROPY offsets these costs and overall makes the binding of Rb and E2F ENERGETICALLY FAVORABLE

Question 18

what forces are involved in protein dissociation?

Answer 18

van der waals forces

Question 19

Proteins that interact transiently have binding affinities that range from __ to ___?

Answer 19

Proteins that interact transiently have binding affinities that range from around -0.4 to -18 kcal/mol

Question 20

deltaG = -18 kcal/mol results in what type of binding?
deltaG values greater than -4 kcal/mol results what type of binding?

Answer 20

deltaG = -18 kcal/mol results in virtually IRREVERSIBLE binding whereas deltaG values greater than -4 kcal/mol results in virtually NO measurable binding interactions

Question 21

delta G relation to binding strength/affinity

Answer 21

In general…the more NEGATIVE the deltaG value, the TIGHTER the binding

Question 22

where does the name “Rb” come from?

Answer 22

The name “Rb” comes from retinoblastoma
The Rb protein was first associated with cancer from children with EYE CANCER
These children had congenital mutations in the Rb gene
In adults, sporadic mutations in Rb are associated with many types of cancer
–> Rb is a cancer gene

Question 23

what is the greatest cancer risk factor (according to cancer.net)?

Answer 23

age
And according to cancer.net, 60% of people who have cancer are 65 or older
However, as a counterpoint, “risk factors” are not (necessarily) informative for determining what CAUSES cancer

Question 24

Multi-hit theory/hypothesis of cancer progression

Answer 24

developed by Nordling
–> cancer requires the accumulations of 6 consecutive mutations

Key insight: cancer has NO SINGLE cause
Instead… cancer is caused by MULTIPLE contributing factors: ie. 6 based on Nordling’s mathematical analysis

a better way to put it: 6 RATE-LIMITING STEPS are needed for cancer

Question 25

what are the 6 original hallmarks of cancer?

Answer 25

Sustained proliferative signaling: cell cycle checkpoint dysfunction (ie. Rb mutations)
Evasion of growth suppressors: ie. mutations that suppress p21 and p53
Activating invasion and metastasis: cancer spreads throughout the body
Enabling replicative immortality: gain of telomerase activity
Inducing angiogenesis: growth factors (ie. VEGF) case blood vessels to infiltrate the tumor
Resisting cell death: ie. mutations that suppress p21 and p53

Question 26

hallmark 1: sustaining proliferative signaling

Answer 26

uncontrolled cell growth that is almost always due to cell cycle checkpoint dysfunction
- At each checkpoint, a chemical messenger tells the cell whether it can go onto the next phase; if the cell does not get that message, then it stays in that phase
HOWEVER, in cancer… checkpoint bypass occurs even without “getting that message”

ie. Mutations to Rb can recapitulate (aka mimic) phosphorylation
- In cancer, amino acid mutations can recapitulate the role of phosphorylation → permanently turning Rb OFF and permanently turning E2F ON → the G1 cell cycle checkpoint no longer functions and the cell “takes a step” towards uncontrolled growth

Question 27

hallmark 2: evading growth suppressors

Answer 27

growth suppressors: p53 and p21 –> they coordinate dozens of other proteins that collectively suppress cell growth under certain conditions (ie. in the presence of DNA damage or loss of cell cycle checkpoint proteins)
- Cells have safety mechanisms (ie. growth suppressors) to regulate the cell cycle even if something goes wrong with BOTH copies of Rb (or other cycle checkpoint proteins)
→ a major way that CANCER cells evade growth suppression is by experiencing mutations that INACTIVATE p21 and/or p53

Question 28

2 examples of growth suppressors

Answer 28

p21 and p53

Question 29

what percentage of all cancer types have p53 mutations?

Answer 29

over 50%

Question 30

hallmark 3: resisting cell death (apoptosis)

Answer 30

If the cell has unfixable DNA damage, then a normal cell will undergo apoptosis → no cancer risk
However, if a cell with unfixable DNA damage continues to divide, then this could lead to cancer

p53 plays a critical role in apoptosis

Question 31

hallmark 4: enabling replicative immortality (aka gain-of-function telomerase)

Answer 31

In normal cells…telomeres shorten each time a cell divides and when telomeres are too short (indicating too many cell divisions have taken place), a cell experiences senescence or undergoes apoptosis
- A LACK of telomerase activity can lead to DNA damage (ie. the chromosome structure “falls apart) → as a result, the cell cycle is blocked at the G2 checkpoint

HOWEVER, in CANCER, a gain-of-function for telomerase restores and rebuilds telomeres → providing cells with unlimited replication potential (aka replicative immortality)

Question 32

number of cells for a palpable tumor?
number of cells for a large tumor?

Answer 32

A palpable tumor requires around 10^9 cells (1cm diameter)
A large tumor has around 10^12 cells (1kg)

Question 33

average number of times a healthy human cell can divide before dying from telomere apoptosis

Answer 33

generally 2-10 times

Question 34

hallmark 5: inducing angiogenesis

Answer 34

A (highly simplified) mechanism of tumor angiogenesis: the GAIN of VEGF (a growth factor) expression is involved

Normally a helpful and important process that supports would healing and supplies oxygen-rich blood to organs and tissues
HOWEVER, it contributes to cancer since it supports tumor growth and spread by feeding tumors oxygen and nutrients

Question 35

angiogenesis definition

Answer 35

the biological process where new blood vessels form from pre-existing vessels
Angiogenesis is critical to supply rapidly growing cancer cells with nutrients (without vascularization, tumor cell growth is slow)
Angiogenesis involves the secretion of growth factors from the tumor (primarily VEGF) that spur the sprouting of blood vessels that grow toward the tumor

Question 36

hallmark 6: activating invasion and metastasis

Answer 36

the SPREAD of cancer throughout the body

Question 37

metastasis definition

Answer 37

The most critical step that divides benign tumors from malignant cancer
Metastasis itself is a multi-step process
There are still many unanswered questions about metastasis

Question 38

The metastatic cascade steps (7)

Answer 38

1 & 2. Local invasion and intravasation: angiogenesis, EMT, migration
3. Survival in circulation: immune evasion, CTC clusters, platelets binding
4. Arrest in distant organ: trapping/specific adhesion
5. Extravasation: physical barriers, seeding
6. Micrometastasis: survival on arrival, dormancy
7. Macrometastatic growth

Question 39

oncogenic mutations

Answer 39

genetic mutations that transform normal cells (proto-oncogenes or tumor growth factors) into cancerous cells

Question 40

describe the role p53 plays in cancer prevention and the steps it takes to protect against cancer

Answer 40

p53 plays a pivotal role in MULTIPLE hallmarks of cancer –> it is critical for CANCER SUPPRESSION

steps:
1. The environment can damage cellular components (ie. cigarette smoke contains over 6,000 damaging chemicals)
→ DNA damage is particularly dangerous and if left unrepaired, it can lead to oncogenic mutations (ie. Rb mutations)
2. p53 transduces DNA damage into cell cycle arrest
3. p53 provides DNA repair enzymes with extra time to repair damage caused by the environment (cigarette smoke, UV radiation)
–> Cell cycle arrest from step 2 extends the G phase from around 2-8 hours to 4-14 days (note: the exact upper limit is not well known)
4. If DNA or other cellular damage is repaired, cell cycle arrest is lifted; if DNA damage is NOT repaired after a few days, p53 coordinates APOPTOSIS
–> Either way, the body is protected against cancer progression (the system of course does not work perfectly and can be overwhelmed such that environment factors do increase cancer risk to some, but usually a limited, degree)

Question 41

describe Peto’s paradox in comparative oncology

Answer 41

Cancer incidence depends on size WITHIN a species but NOT ACROSS species (ie. larger humans are more likely to have cancer than smaller humans but elephants are not more likely to have cancer than humans)
WHY?? → other species may have more copies of tumor suppressor genes (ie. p53) in their genome → this is also why humans have relatively long lifespans compared to other specifies
HOWEVER, this comes with a tradeoff: increasing tumor suppressor genes decreases overall lifespans

Question 42

how does size play a role in cancer risk?

Answer 42

Sized-based differences do NOT hold ACROSS species (ie. size does not matter when comparing mice to people or people to elephants)

HOWEVER… there is evidence that size is a (usually modest) risk factor WITHIN a species

Ie. tall women have increased rates of colon cancer (cancer risk increases by about 80%)
Similarly osteosarcomas (bone cancer) occur in large dogs 200 times more frequently than in small breeds (again presumably because of the greater number of cells in the large done’s bones)
Hypothesis:
A taller person has more cells and since any particular cell will become cancerous, a larger number of cells increases the risk for cancer

Question 43

how would the graph look for cancer risk for a taller human, shorter human. and baseline model?

Answer 43

taller human graph line will be shifted to the left from the baseline model
shorter human graph line will be shifted to the right from the baseline model
x-axis: age of cancer
y-axis: rate per 100,000

–> exponential graph

Question 44

compare incidence of cancer for humans vs whales, humans vs mice

Answer 44

incidence of cancer in humans is higher than in whales despite the fact that a whale has thousands-fold more cells than a human

A person has around 1000 times as many cells as a mouse and humans usually live at least 30 times longer than mice do
HOWEVER…the probabilities of cancer in mice and humans are similar
- In mice, over-expression of p53 reduced cancer by about 2-fold BUT accelerated aging

Question 45

describe how Peto’s paradox was solved by elephants

Answer 45

The elephant genome has 40 copies/alleles of genes that code for the p53 tumor suppressor gene (which is 38 more than humans); humans have 2 alleles that code for the p53 protein

larger animals have more copies of the p53 tumor gene to decrease the risk of cancer, but the downside of such high expression of p53 is that it accelerates aging and may also explain why young elephants have wrinkled skin

Question 46

cancer gene

Answer 46

any gene that contributes to the transformation of normal cells into cancerous cells

Question 47

what percentage of cancers are estimated to be linked to inherited cancer genes?

Answer 47

From 2-3% to around 66.67% of cancer is linked to “cancer genes” BUT only about 2-3% of incidences of cancer are estimated to be linked to INHERITED cancer genes

Question 48

name 5 cancer genes

Answer 48

Rb
p21
p53
VEGF
telomerase
BRCA1, BRCA2

Question 49

Proto-oncogenes definition and the 2 types

Answer 49

Proto-oncogene: the HEALTHY version of a gene/protein that when something goes wrong, is converted into an oncogene (aka a cancer gene)

2 major classes of proto-oncogenes:
Tumor suppressors: loss of function
Ie. p53 inactivating mutations
Tumor promoters: gain of function
Ie. VEGR expression in angiogenesis

Question 50

explain the role of tumor suppressor genes in cancer
explain the role of tumor promoter genes in cancer

Answer 50

Tumor suppressor genes experience a LOSS of function mutation to become oncogenes
- ie. BRCA1 and BRCA2, p53 - they normally inhibit growth

Tumor promoter genes or proto-oncogenes experience a GAIN of function mutation to become oncogenes
- ie. Ras, VEGF expression in angiogenesis - they normally growth

Question 51

Mutations that convert a normal gene into a cancer gene can be… (2)

Answer 51

Sporadic: they are acquired one by one throughout a person’s lifetime

Inherited (which is rare): they are estimated to contribute to around 2-3% of all cancers
However if present, inherited cancer genes GREATLY increase cancer risk

Question 52

How much do BRCA1 and BRCA2 gene mutations affect a person’s risk of cancer?
breast cancer statistic?
ovarian cancer?

Answer 52

a woman’s lifetime risk of developing breast and/or ovarian cancer is GREATLY INCREASED if she inherits a harmful mutation in BRCA1 or BRCA2

Actual data:
Breast cancer: 12% → 87% (about 700% increased risk)
Ovarian cancer: 1.2% → 50% (about 4,000% increased risk)

Question 53

what is the chance that any one of your cells will accumulate ALL of the mutations needed to become fully cancerous?
overall what is the chance of you getting cancer?

Answer 53

For any particular cell…
The chance that a particular oncogenic mutation will occur randomly in any cell in your body over a particular time period (ie. 50 or 60 years): (1/100)
The chance that BOTH of the mutations will accumulate in the SAME cell in your body over the time period: (0.01)*(0.001) = 10^-5
NOTE: these numbers are made up but are reasonable “guesstimates”
The odds that the multiple mutations required for cancer progression will occur in any particular cell become increasingly SMALL

In this contrived but somewhat realistic example, there is a 10^-14 chance that any one of your cells will accumulate ALL of the mutations needed to become fully cancerous
→ thus… since an adult has around 10^13 cells in their body, overall there is approx. a 1 in 10 chance of getting cancer: (10^-14 chance per cell)*(10^13 cells) = 0.1

10^-14
1 in 10 chance

Question 54

How does an inherited cancer gene DRAMATICALLY increases cancer risk?

Answer 54

Let’s say that at step 3, it is an INHERITED (mutant) cancer gene → the odds for this step are now 1-to-1 instead of 1-to-100
→ as a result the chance that any one of a person’s cell will accumulate all of the mutations needed to become fully cancerous increases approx by 100-fold (ie. from approx. 10^-14 to 10^-12)

→ overall as a result, the chance of getting cancer increases from about 1 in 10 to about 10 to 1 (using “fuzzy math” from approx. 10% to 90%)

Another way to look at cancer risk is that an inherited cancer gene decreases the number of rate-limiting hits from 6 to 5
–> the graph for k=6 and k=5 are very different

Question 55

explain why mice have a rate-limiting step of k=5 compared to humans k=6

Answer 55

Recall hallmark 4 key point: human telomeres can only sustain about 2-10 sequential cell divisions without gain-of-function telomerase expression
New info: in mice, telomeres are about 10x longer than in people and they shorten approx. the same amount as in people during each cell division
Implication: in mice, telomeres are NOT a rate limiting step for tumor development because murine cells can undergo approx. 10x more divisions than human cells (ie. from 20 to 100)
→ this in essence, reduces the number of rate-limiting steps (“k”) from 6 to 5 for mice

Question 56

what is the chance of a “hit per cell” for a human?
— mice?

Answer 56

For humans, the risk of cancer per cell is approx 10^-14
If all hits have the same probability (note: this is a different assumption than previously used) and there are 6 hits required…
The chance of a “hit per cell” is… 0.0046 (aka approx. 1 in 215 chance of a hit per cell)

For mice, the risk of cancer per cell is approx 2*10^-11 (assuming mice have 1000x fewer cells and approx double the occurrence of cancer as people)
The chance of a “hit per cell” is… 0.0072 (aka approx. 1 in 139 chance of a hit per cell)

Question 57

the risk of cancer for mice vs humans is approx how much higher?

Answer 57

Bottom line: on a per cell basis for each hit, the risk is approx 57% higher in mice, NOT a million or billion-fold difference as proposed by Dr. Peto

Question 58

what are the 4 next generation hallmarks of cancer?

Answer 58

7. Genome instability and mutation: ie. single base substitutions that inactive tumor suppressor genes or activate proto-oncogenes
8. Deregulating cellular energetics: Warburg effect (switch to glycolysis) before tumor is vascularized
9. Avoiding immune destruction: immune checkpoints (ie. PD-L1) on cancer cells prevent T-cells from being activated and destroying the cancer cells
10. Tumor-promoting inflammation

Question 59

hallmark 7: genome instability and mutation

Answer 59

Over time, cancer cells (almost always) accumulate gross genetic abnormalities
ie. a single point mutation can inactivate tumor suppressor genes and constitute a “hit” in cancer progression (p53, Rb)

Question 60

hallmark 8: deregulating cellular energetics (aka Warburg effect)

Answer 60

The Warburg effect: a phenomenon observed in cancer cells where they preferentially utilize glycolysis for energy production even in the presence of sufficient oxygen for oxidative phosphorylation
- To survive, early stage cancer cells exploit the “Warburg effect”

aka uses glycolysis instead of oxidative phosphorylation despite there being sufficient amounts of oxygen available because glycolysis promotes the production of lactate with produces vast amounts of carbon building blocks to create more daughter cells → tradeoff: less ATP produced, but more carbon monomers produced → increases cancer cell growth significantly

This is in contrast to most normal cells which primarily use oxidative phosphorylation under aerobic conditions due to its higher efficiency in ATP production

Question 61

hallmark 9: avoiding immune destruction

Answer 61

Mechanism: over time, cancer cells “evolve” such that…
1. The cancer cells are no longer recognized by the host immune system AND/OR…
2. The cancer cells are capable of actively suppressing it

Main lesson: the environment is important

Question 62

why and how can tumors with similar biochemical and genetic features remain relatively benign in one person and highly malignant in another?
why a metastasizing cancer cell homes to and thrives in one site of the body (ie. a vertebrae; Lake Michigan) but not others (ie. a finger bone; the lake shown in Ukraine)?

Answer 62

differences in each person’s immune system

Question 63

immunosuppression definition

Answer 63

a century-old idea that the immune system effectively eradicates most cancer cells

But HOW effective?: 9 out of 10? 999/1000? or 999,999/1,000,000? → no one is sure!

Immunosuppression: the reduction or inhibition of the immune system’s ability to mount an effective response against harmful agents or abnormal cells (can occur naturally, be induced therapeutically, or be a pathological consequence)

Question 64

Immunosurveillance

Answer 64

Immunosurveillance: the process by which the immune system continuously monitors the body for abnormal or harmful cells and eliminates them

Question 65

Whether or not the T cells will kill the cancer cell depends on which 2 things?

Answer 65

1. T-cell activation depends on TCR recognition of a tumor antigen
2. BUT… an immune checkpoint prevents T-cell activation (ie. PD-1 binding to its ligand PD-L1)
   Immune checkpoint inhibitors (ie. PD-1 inhibitor) reverse a cancer cell’s ability to avoid immune description

Question 66

explain PD-1 receptor and PD-L1 ligand and their role on the immune system

Answer 66

PD-1: a receptor expressed on T cells
PD-L1: ligand for PD-1

When PD-1 binds to PD-L1 or PD-L2, it INHIBITS T cell activity to REDUCE immune responses
HOWEVER, many tumors exploit this by upregulating PD-L1 to suppress T cells and evade immune attacks

Question 67

immune checkpoint

Answer 67

a regulatory pathway in the immune system that modulates the intensity and duration of immune responses (essentially act as “brakes” on immune responses to ensure the immune system does not overreact to stimuli)

Question 68

immune checkpoint inhibitors definition and give 1 example

Answer 68

Immune checkpoint inhibitors: a class of drugs that are designed to “release the brakes” on the immune system to allow it to attack cancer cells
- Immune checkpoint inhibitors (ie. PD-1 inhibitor) reverse a cancer cell’s ability to avoid immune description

ie. Keytruda

Question 69

what is a caveat to immune checkpoint inhibitor drugs?

Answer 69

this type of therapy (immune checkpoint inhibitors drugs) will NOT work if the patient does NOT have or CANNOT MAKE T cells with specificity for a target antigen on the cancer cells

Question 70

describe CD19 and B cell-derived leukemia and a solution (therapy) for it

Answer 70

CD19 is over-expressed in cancer but it is also expressed on normal B cells
→ thus it is a self-antigen and a patient does not have CD19-targeting killer T cells to fight B cells leukemias –> cannot use immune checkpoint inhibitor drugs to solve this issue

a solution: CAR T cell therapy

Question 71

CAR T cell therapy and the steps (4)

Answer 71

used to treat primarily blood cancers: ie. CD19 and B cell-derived leukemia
CAR = chimeric antigen receptor
- in THEORY, the CAR can recognize ANY antigen

steps
1. T cells are extracted from a cancer patient

2. Viral vector is used to transfect T cells with genes for chimeric antigen receptor (CAR) which consists of antibody domain to recognize cancer cells, hinge and transmembrane domain to tether antibody to T cell, and costimulatory and essential activity domains that signal T cells to divide
   –> CAR enables T cells to specifically recognize and bind to antigens on the surface of cancer cells
3. Reprogrammed (aka modified) T cells are grown in a bioreactor with antibodies that promote T cell proliferation
   –> Aka the modified T cells are multiplied in the lab to produce millions of CAR T cells
4. Chemotherapy is given to the same patient as well to suppress their immune system and thus increase the chance that the immune system will accept the modified T cells
5. The reprogrammed T cells are infused back into their blood where they seek out and destroy cancer cells expressing the target antigen

Question 72

When did CAR T cell therapy become FDA approved?

Answer 72

2017 - present

Question 73

cancer immunotherapy is a “hot” area: what are several approaches under development?

Answer 73

NK cells
Activated T cells
Antibody-dependent (ADCC)
BiTE.bispecific antibody
Genetically engineered T cells: CAR T cells
Macrophage