Cancer

Question 1

[Slides 1-7 expectations of a normal cell] slide 1 and 2

Normal cellular responses and cell division. What is necessary for a multicellular society? What are the 4 outcomes of a cell after receiving signals or in the absence of a signal?

Answer 1

Cells must coordinate their behavior by sending, receiving and responding accordingly to signals. Cells must do everything at the right time

1) survive
2) divide
3) differentiate
4) apoptosis (usually when there is no signal)

Question 2

[Slides 1-7 expectations of a normal cell] slide 3.

How cancer disrupts a multicellular society. What is cancer? What causes these cells to err? Are any genes involved with cancer or is it specific genes? Do cancer cells receive signals? How do they respond to signals?

Answer 2

Cancer is a disease where a mutant clone of cells prospers at the expense of neighboring cells

Mutations causes the cell to behave abnormally and jeopardizes the health of the organism

Mutations have to happen to cancer critical genes (proto-onco gene to an oncogene, tumor supressor genes and genes involving genomic stability DNA maintenance)

Cancer cells do receive signals but they don’t respond accordingly, since they may have some signal transduction pathways already on/off.

Question 3

[Slides 1-7 expectations of a normal cell] slide 4.

When should cells divide? (4 cases)

Answer 3

1) repair (in the case of a wound)
2) fight infection (activation of B and T cells)
3) growth of the organism
4) replace (worn out cells)

Question 4

[slides 1-7 expectations of a normal cell] slide 5.

What molecules are necessary to trigger appropriate cell division?

Answer 4

Mitogens (from other cells, usually neighboring cells)

Growth factors: stimulate an increase in cell mass

Question 5

[slides 1-7 expectations of a normal cell] slide 6

What are the checkpoints that a cell must undergo during division? What is necessary at each checkpoint? What happens if the cell does not meet the standards during the checkpoint?

Answer 5

G1
- mitogens must be present
- cell size must be adequate
- nutrients must be available and sufficient
-DNA must be undamaged (makes sense bc S phase is next)

G2
- cell size must be adequate
- chromosome replication is successfully completed (makes sense because M phase is next and S phase came before)

Metaphase checkpoint
- all chromosomes must be attached to mitotic spindle (makes sense because sister chromatids must separate)

If criteria is not met, cell has to fix the problem. If it can’t fix it, it is better for that cell to commit suicide

Question 6

[slides 1-7 expectations of a normal cell] slide 7

How do cells stay at steady state (two things)? What are the 3 ways that cells can then form a tumor?

Answer 6

By having a cell division rate that parallels the apoptotic rate

1) increased cell division, normal apoptosis rate
2) normal cell division, decreased apoptosis
3) increased cell division, decreased apoptosis (condition of most cancers)

Question 7

[slides 8-9 characteristics of cancer in terms of mutations]

mutations to genes result in what deformed macromolecule? What happens if there is less chromosomal stability? Is cancer individual specific? What do mutations confer to the cell?

Answer 7

Mutations to genes cause defects in proteins that control the cell cycle and proteins that maintain chromosomal stability

Less chromosomal stability means more mutations

Cancer is specific to the individual because it takes a combination of mutations for cancer to occur.

Cancerous mutations confer a proliferative advantage to the cancer cell allowing it to outsurvive and outcompete its neighbors.

Question 8

[slides 8-9 characteristics of cancer in terms of mutations]

Do we accumulate many mutations? What proteins, if misfolded would have detrimental effects?

Answer 8

Yes, but only mutations to cancer critical genes

proteins that control the cell cycle and proteins that maintain chromosomal stability

Question 9

slide 10

What are the 3 normal responses of a cell to signaling via external molecules? What is contact inhibition

Answer 9

1) stimulate cell growth and division
2) inhibit cell growth and division (contact inhibition)
3) undergo apoptosis when necessary (cytotoxic T cells secrete signals)

Contact inhibition is when cells can sense how many neighbors it has and judge if it is suitable to divide. If it is too crowded, a normal cell won’t divide

Question 10

slide 11-12

What are the 7 properties shared by many potentially cancerous cells?

Answer 10

1) many disregard external and internal signals that regulate cell proliferation (they wear headphones)

2) altered responses to apoptotic signals and other stress-associated signals (bad at dying)

3) many circumvent programmed limitations to proliferation and escape replicative senescene and dedifferentiating

4) most are genetically unstable (chromosomes are messed up so they exhibit aneuploidy)

5) Many escape their home tissue (they are invasive because they express proteins that function as scissors)

6) Some survive and proliferate in foreign sites (metastasize). It is not easy to metastasize because cancers need specific environments and this may not be present in the foreign location

7) Many induce help from nearby cells (angiogenesis) and modify nearby cells (they are bullies)

Question 11

slide 11-12

What is replicative senescence?

Is it easy to metastasize?

Answer 11

occurs when ends of telomeres are shortened bc of lack of telomerases. It is basically retirement

In the case of cancer, they avoid replicative senescene by turning on their telomerases

It is hard to metastasize

Question 12

[slides 13-15 in vitro culturing of normal and cancer cells]

What is PDGF? What does the control prove (-PDGF +basic growth media with normal cells)?

Answer 12

PDGF is platelet derived growth factor. It is a signal/growth factor/mitogen that allows the cells to grow

The control proves that normal cells, in the absence of signaling, cannot proliferate.

Question 13

[slides 13-15 in vitro culturing of normal and cancer cells]

What are some reasons that the cancer cells have grown in just the basic growth media (-PDGF)? Do all cancer cells work this way?

So, why are cancer cells easier to grow in the lab?

Answer 13

These cells have turned on the signal tranduction pathways downstream of where PDGF binds to the receptor (In other words, no need for PDGF if pathway is already on)

Not all cancer cells share this mechanism. Some may actually require PDGF.

They have a proliferative advantage. They have adapted to outdivide, outcompete and outsurvive regular cells since they do not require as many of the perfect conditions as norma cells.

Question 14

[slides 13-15 in vitro culturing of normal and cancer cells]

How do cells sense density? Do normal cells divide or stop dividing if they are touching other cells? What is anchorage dependence? What is density-dependent inhibition? Which one of these do cancer cells exhibit?

Are cancer cells within a tumor heterogenous or homogenous?

Answer 14

Cells sense density by engaging receptors of adjacent cells

Cells stop dividing if their receptor is engaged (receptor engagement is negative inhibiton)

Anchorage dependence: cells must attach to a surface to divide

Density-dependent inhibition: When density of surrounding cells is too high, cells stop dividing

Cancer cells exhibit neither density-dependent inhibition or anchorage dependence

Cancer cells within a tumor can differ, thus they are heterogenous

Question 15

[video] what is confluence? under normal conditions, how many layers thick do cells grow in a dish? What is a focus?

Answer 15

When cell death rate parallels division rate so number of cells stays the same

monolayer

a clump of cells that grows past the monolayer

Question 16

[slide 17-18 invading cancer cells]

Why can cancer cells invade to other tissues? What are the two routes that cancer cells can enter circulation?

Answer 16

They express enzymes that cut through the basolamina that keeps them contained to an area

1)via blood vessels or lymph vessels

Question 17

[slide 17-18 invading cancer cells]

What are some factors that allow cancer cells to adhere to foreign tissue

Answer 17

1) pattern and direction of bloodflow from primary tumor
2) blood vessels at the secondary site must be able to trap the cancer cells
3) tumor cells may have adhesive proteins on their surface allowing binding
4) microenvironment at the foreign region must be supportive

Question 18

[slides 19-20 cancer cells with unstable chromosomes]

What are the consequences of breakage and fusion

Answer 18

Genes can be overexpressed or silenced

Question 19

slide 21

What are the 3 main classes of cancer critical genes

Answer 19

1) genes that trigger cell growth and division by initiating specific phases in the cell cycle: proto-onco genes

2) genes that stop or slow the cell cycle: tumor suppressors

3) genes that maintain genomic stability: DNA maintenance genes. Mutation results in aneuploidy and uncontrolled cell division

Question 20

[slides 22-24 and 29 proto-oncogenes]

What mutation turns a proto-oncogene into an oncogene? What kinds of proteins are coded by a proto-oncogene?

How is this mutation achieved (4 ways)

Answer 20

A gain of function mutation

Any protein within a cell growth and division pathway is coded by a proto-oncogene (ex. secreted protein, RTK, G proteins, relay proteins, kinases

1) gene amplification. This can occur when there is a replication error resulting in too many copies of a gene. (produces normal protein)

2) point mutation to a control element. Changes the transcription factors that bind to the control element which allow it to be more active. (produces normal protein)

3) translocation or transposition. Gene is moved to a new place because of breakage and fusion.
(produces normal protein)

4) point mutation to the gene itself. (produces an abnormal protein that is more active)

Question 21

[slides 22-24 and 29 proto-oncogenes]

How many copies of a proto-oncogene must suffer the gain of function mutation to be turned into an oncogene?

Answer 21

only one copy is necessary

Remember: One gene turning oncogenic does not immediately mean that it is cancerous but that it is approaching cancer, it will take a combination of other mutations to be cancerous

Question 22

slides 25-28 (Philedelphia chromosome (Bcr-ABL) An example of a proto-oncogene causing cancer and therapies)

What is chronic myelogenous leukemia? What is ABL and What is BCR-ABL? What is gleevec and how does it work? Is gleevec considered targeted therapy?

Why does chronic myelogenous leukemia confer growth factor independence?

Answer 22

Chronic myelogenous leukemia cancer to the lineage of white blood cells. Breakage and fusion within the quelle arms of chromosome 9 and 22 (9q+, 22q-)

Both are tyrosine kinases but BCR-ABL is an overactive tyrosine kinase. Gleevec is a competitive inhibitor that blocks ATP (a substrate) from binding. It is considered targeted therapy because it only works for individuals that have this specific cancer.

Having a tyrosine kinase already on results in the cell not having a need for a growth factor since the growth factor pathway is always on.

Question 23

[slides 30-34 tumor supressor genes]

When are tumor suppressors transcribed? What do tumor suppressor genes do? Do you have to lost one or both copies of a tumor supressor gene?

Answer 23

Tumor supressors are transcribed when the cell notices damage or when the cell hasn’t met requirements environmentally to progress through the cell cycle.

Tumor supressors stop the cell from continuing into the cell cycle

Both

Question 24

[slides 30-34 tumor supressor genes]

What are the 5 ways that we lose funciton of a tumor supressor gene? What happens if you dont have tumor supressors and DNA damage occurs

Answer 24

1) point mutation that inactivates allele (point mutation can lead to stop codon making a protein too short)

2) deletion of the gene due to error in replication (deletion error, after duplication the gene is entirely absent on the chromosome)

3) Loss of chromosome due to nondisjunction (when the sister chromatids to not separate, so one of the daughter cells did not get an entire chromosome)

4) epigenetic silencing of promoter (heterochromatin because of DNA histone methylation)

5) Viral proteins (viral proteins inhibit the tumor supressor proteins, which is advantageous for the virus if it needs the cell to be dividing to complete its own replicative cycle)

If tumor supressors are absent in the presence of DNA damage, the cell will divide and give off two damaged cells.

Question 25

[slides 35-40 p53, a tumor supressor gene]

What is p53? What are its functions?

Answer 25

p53 (protein) is a transcription factor that regulates expression of cell cycle regulatory genes and expression of proteins used for apoptosis

Question 26

[slides 35-40 p53, a tumor supressor gene]

What are the 4 signals that activate p53?

Answer 26

1) hyperproliferative signals (overexpression of oncogenes)

2) DNA damage

3) telomere shortening (as cells age)

4) hypoxia

Question 27

[slides 35-40 p53, a tumor supressor gene]

is there usually a high concentration of p53 in healthy cells? What modification stabilizes and activates p53

Answer 27

In a healthy cell, there is not much p53 available because it gets thrown out by a proteosome in the cell

Any of the signals cause the phosphorylation of p53, making it stable and active

Question 28

[slides 35-40 p53, a tumor supressor gene]

What are the 3 outcomes of p53 activation

Answer 28

1) cell cycle arrest
2) senescence (retirement)
3) apoptosis

Question 29

[slides 35-40 p53, a tumor supressor gene]

What happens after p53 stimulates the arrest of G1? What happens if that fails? How does p53 tell time (how does it know when to stop working)? How does p53 resist degradation?

Answer 29

p53 stimulates genes that arrest G1 and genes for DNA repair.

If repair fails, the cell commits apoptosis

p53 stimulates a gene, MDM2 that inihbits itself (by encouraging ubiquitylation and degradation in proteasomes). However, phosphorylation kicks of MDM2.

Question 30

[slides 35-40 p53, a tumor supressor gene]

What is p21? When does it get activated and what does it do ?

Answer 30

p21 gets activated after p53 activation.

p21 codes for a CDK inhibitor protein. CDKs bound to cyclin (complex) is necessary to move through the different stages of the cell cycle but p21 inactivates them.

Question 31

[slides 35-40 p53, a tumor supressor gene]

what are the outcomes when DNA damage happens in the presence/absence of p53

Answer 31

present: either damage gets repaired and cell can still divide or cell undergoes apoptosis

absent: cell cycle does not arrest
1) either cell undergoes mitotic failure OR
2) it replicates even withthe damage present

Question 32

slide 42 retinoblastoma gene, a tumor supressor

How do children get cancer despite cancer requiring many mutations?

Answer 32

Children getting cancer is because they have a hereditary disposition to cancer. In other words, they have a mutation to begin with.

Question 33

slide 44 HPV

How is the chromosome of papillomavirus arranged?What is necessary for papillomavirus to turn cancerous

Answer 33

ds circular DNA that exists as an extrachromosomal piece, it replicates w cell’s chromosomes. If the DNA does not integrate, the cell divides more rapidly but it is not cancerous.

Integration of the extrachromosomal piece produces proteins that inhibit tumor supressors

Question 34

slide 45 HPV

What are the major proteins of HPV

Answer 34

E6 plucks p53 (transcription factor) off the DNA and destroys it

E7 binds to Rb (a protein that sequesters a transcription factor). This activates the transcription factor and causes cyclin E transcription. Cyclin finding its CDK pulls the cell into the cell cycle.

Question 35

slide 48 shows that multiple mutations are necessary by looking at colon cancer (multiple hit model)

What genes are involved in colon cancer

Answer 35

oncogenes (ras)

tumor supressor gene (APC, DCC, p53)

Question 36

cancer metabolism

What is the normal goal of lactic acid fermentation? which pathway do cancer cells prefer

Answer 36

To replenish concentrations of NAD+

Cancer cells do not send their pyruvate into CAC and ETC, instead they mostly do lactic acid fermentation because the product, lactate, can be used as building blocks for other molecules.

Question 37

cancer metabolism

Does cancer uptake more or less glucose

Answer 37

Cancer, which does not go thru the ETC, cannot produce ATP in high amounts, but they still have ATP demands.

To meet this, they just do a lot of glycolysis

Question 38

abilities of cancer

What is angiogenesis? Why is it important for cancer cells? What do cancer cells secrete?

Answer 38

Angiogenesis refers to the ability of a cancer cell to draw blood vessels to them/stimulate growth of new vessels

Angiogenesis is important bc gas exchange, delivery of nurtients, removal of waste is required for proliferation

Cancer cells secrete a cytokine VEGF (vascular epithelial growth factor) or they can bully other cells to secrete VEGF

Question 39

Is telomerase on in differentiated cells? What happens with every division? What about cancer cells? Why can stem cells divide indefinitely?

So are cancer cells stem cell in origin?

Answer 39

telomerase is off or expressed in low amounts in differentiated cells

With every division telomeres shorten

Cancer cells have telomerase on

they keep their telomerase on and thus do not shorten their chromosomes

Fully differentiated cells can turn cancerous

Question 40

Slides 55-61 (What are the 3 ways in which cancer cells avoid detection by the immune system? What is the normal T cell inactivation pathway? What do the monoclonal antibodies YERVOY and OPDIVO do?)

Answer 40

3 ways
1) If a tumor cell does not produce vastly different proteins but it produces the normal one in excess, it can get away with displaying it on its MHC1

2) If a tumor cell does produce vastly different proteins, it can get away with it since it stops expressing the one MHC1 allele capable of showing the peptide

3) Some cancer cells turn off T cells by expressing PD-L1 and PD-L2

Normal T cell inactivation pathway
1) Antigen presenting cell presents an antigen to a CD4 cell

2) Antigen binds to the T cell receptor

3) Binding of the antigen to the T cell receptor sends a stimulatory response to the nucleus

4) Activation results in PD-1 (programmed death-1), CTLA-4 (cytotoxic lymphocyte antigen), and LAG-3 to appear on the T cell

5)PD-L1 & PD-L2 bind to PD-1, GAL-3 and LSECtin bind LAG-3, CD80/CD86 binds CTLA-4 and binding inhibits the T cell

So, antigen presenting cells as well as tumor cells (with PD-L1 and PD-L2) can turn off T cells to make sure the response is controlled

-Monoclonal Antibodies YERVOY and OPDIVO bind CTLA-4 and PD-1, respectively. This sequesters the inhibitory receptors from the complimentary ones on the tumor cell/APC.