Cancer Biology Part 2

Question 1

Ex of multistep pathway:

Answer 1

this is first slide- complete this if you can as review

Question 2

epigenetics

Answer 2

way to modifying the ability to express a particular gene through changes that can occur on the DNA; impact gene expressing w/o changing DNA sequence

Question 3

Histone connection

Answer 3

histones are proteins wrapped around DNA, and it is connected in DNA modifications with how DNA modifications work… (next card)

Question 4

DNA modifications can happen in two diff ways:

Answer 4

Methyl groups and tags

Question 5

Methyl groups

Answer 5

methyl groups can be added to increase compaction of DNA and histones; making the DNA not accessible as histones are blocking it from being accessed; gene turned off; this is heterochromatin

Question 6

Hypomethylation vs. Hypermethylation

Answer 6

hypomethylation is when methylation is removed and the expression of the gene or the removal of methylation causes chromosomal instability that has a negative impact on genome integrity

hypermethylation is the silencing of a gene to no longer be expressed

Question 7

Tags

Answer 7

A tag can be added to histone tails to relax them and spread them out to make DNA more accessible for transcription; turning on the gene; this is euchromatin

Question 8

Epigenetics and genetic changes

Answer 8

As there are two copies of a tumor suppressor gene in a diploid cell, those genes can be altered with due to a genetic change, such as a mutation, or/and an epigentic change, such as hypermethylation silencing the gene. The two tumor suppressor genes can have both genetic change, or both epigentic change, or one epigentic change and one genetic change (doesn’t matter the order). To review, both tumor suppressor genes not working (as its recessive) leads to the progression of cancer as tumor suppressor genes inhibit tumor behavior from happening

Question 9

epidemiology

Answer 9

goal is to investigate diseases in general; their frequency and where we find them: some cancers are found more in the US vs. Southeast Asia for ex

environment and lifestyle factors can influence progression of cancer in addition to hereditary factors

Question 10

Sources of DNA damage- chemicals from smoking

Answer 10

cigs are a source of cancer bc they are a source of DNA damage; trends of smoking and death are not layered on top of one another, there is a gap as there is accumulation of changes (as cancer takes a while to accumulate)

Question 11

Graphs of cancer trends

Answer 11

if you smoke a lot of cigs, that increases the concentration of damage through the form of the chemicals found in cigs (25 cigs); if you start at a young age (less than 15) increases chances of dying of lung cancer.

If you stop, after 20+ years, you have a less chance of getting lung cancer than right away; quitting helps!!

Question 12

Ames Test

Answer 12

Allows us to test for mutagenicity; mutagens mutate DNA, and this is linked to cancer as mutated DNA leads ot the progression of cancer

Carcinogens are cancer causing agents that could result from mutations, so testing whether a substance is a mutagen or not can help see if it is carcinogenic

Question 13

Sum up of Ames test:

Answer 13

bacteria that was added to growth medium needs histidine to grow and was not provided that. plate two had the substance being tested (to see if it has mutagens) with liver homogenate; many chemicals that can cause cancer happen after metabolic activation within the liver; so just helps provide the right conditions to help reveal the mutagenticity of the substance;

plate 2 had many bacteria colonies, which means the substance is a mutagen as it was able to mutate its DNA genome to produce histidine, which lets the bacteria grow.

plate 1 has no substance but still has some colonies made, but that is from random changes that occur ed within the bacterium, nothing to do with substance (as substance wasn’t used)

Question 14

Mutagenicity

Answer 14

the graph is kind of confusing but it shows on the x axis that the higher the mutagenic potency is, the less is needed to create 100 colonies per plate (not sure about this relation) (mutation allows for heightened cell proliferation).

This mutagenic potency connects to carcinogenic potency bc if we increase our mutagenic potency (how much mutagens), we’re also increasing carcinogenic potency. This makes sense as mutagens will likely behave as a carcinogen, but just bc it’s a carcinogen, doesn’t mean its a mutagen.

Question 15

Cancer Critical Gene: Ras

Answer 15

The set up of this signal transduction pathway is an enzyme linked receptor. The enzyme is Ras, a proto-oncogene , and the thing binding to the receptor is a growth factor. Ras is a proto-oncogene and a GTPase, like the GTP protein talked about before.

Question 16

Ras under normal conditions; being a proto-oncogene

Answer 16

when Ras behaves as a proto-oncogene the following process occurs:
the growth factor binds to the enzyme linked receptor. The receptor dimerized and there’s cross phosphorylation, which leads to an activated receptor. This activated receptor, with adaptor proteins, leads Ras, that has GDP attached to it, now have GTP. This is an activated Ras. The activated Ras w/ GTP activates a protein called Raf. Raf leads to downstream activity of proteins in the cytosol, and then in the nucleus. In nucleus, more downstream impact that leads o activation of certain genes, aka active transcription of these particular genes. A ton of activation of these genes leads to production of cyclin and Cdk. Cyclin and Cdk play a huge role in regulating cell cycle as they are a maturation promoting factor to go through cell cycle. So leads to cell proliferation, which makes sense of this downstream event as the growth factor that binds to this receptor is a growth factor which insinuates cell proliferation

Question 17

Ras being an oncogene

Answer 17

Ras becomes an oncogene due to a single point mutation that results in a diff amino acid upon translation, this means Ras in always activated because GTP is always hydrolyzed. This makes the protein super active and since oncogenes are dominant, you only need one copy (this mutation in this copy) to see an effect. The effect is cyclin and Cdk keep being produced, which would lead to inappropriate cell proliferation

Question 18

Normal receptor vs. mutant receptor vs. amplified receptor

Answer 18

receptors also have a role in cancer. normal receptor, the growth factor comes in, leads to activated receptor, and leads to appropriate downstream event. there can be abnormal behavior from the receptor side via a mutant receptor.

A mutant receptor can occur bc of an oncogene that codes for it. Receptor looks off, doesn’t have place for growth factor to bind. This receptor is in a constitutively active state, doesn’t require growth factor bc GTP is already on Ras so not relying on growth facto r to come in. hyperactive state that leads to excessive cell proliferation.

Amplified receptor is normal receptors but present in excessive quantity, so 3 times. the amount of receptors which means excessive receptor activity

Question 19

p53- another cancer critical gene

Answer 19

this is a tumor suppressor. is called the guardian of the genome and it is activated by the body when there are stressors, such as hypoxia, or radiation for example. p53 protein acts as transcription regulator and and ex would be inducing transcription of p21. p21 protein binds and inhibits Cdk; without Cdk’s cannot go through cell cycle. p53 has 4 pathways cells can go through bc of their stressors. Cells with cell damage can go through permanent cell cycle arrest (senescence), or return back to proliferation after DNA damage fixed, DNA repair, block of angiogenesis so it doesn’t have the oxygen/nutrients needed to proliferate, or apoptosis.

Question 20

p53 doing its role (not mutated) under stressful conditions

Answer 20

p53 under normal conditions are at low levels bc it activates another factor, mdm2, and mdm2 inhibits p53. during times of stress, like with radiation to a cell, DNA damage occurs. Sensors of that damage, such as 53PB1, and 𝛾-H2AX, will induce a signal transduction pathway and lead to phosphorylation of p53 protein. When p53 is phosphorylated, it prevents interactions btwn p53 and mdm2. this means p53 is no longer going to acitvate mdm2, and mdm2 can therefore not inhibit p53, which leads to p53 accumulation. p53 can then be used to address those stressors and either fix the cell, arrest the cell, kill the cell, or prevent angiogenesis.

for cancer cells, both p53 genes need to be mutated as it as tumor suppressor gene and is recessive, but once it is, we lose out of a high level of regulating cell responses in time of stress!

Question 21

DNA repair

Answer 21

although there is so much in the body that we see can go wrong, the body is not just sitting there and taking it. There is DNA repair pathways to reduce built up of DNA damage. When DNA damage occurs, there are sensors that pick up on it and communicate it to transducers, which allow for downstream events to take place as a result. These downstream events are very similar to p53, such as apoptosis, cell cycle arrest until it’s fixed or permanent, and DNA repair.

Question 21

DNA repair

Answer 21

although there is so much in the body that we see can go wrong, the body is not just sitting there and taking it. There is DNA repair pathways to reduce built up of DNA damage. When DNA damage occurs, there are sensors that pick up on it and communicate it to transducers, which allow for downstream events to take place as a result. These downstream events are very similar to p53, such as apoptosis, cell cycle arrest until it’s fixed or permanent, and DNA repair.

Question 21

DNA repair

Answer 21

although there is so much in the body that we see can go wrong, the body is not just sitting there and taking it. There is DNA repair pathways to reduce built up of DNA damage. When DNA damage occurs, there are sensors that pick up on it and communicate it to transducers, which allow for downstream events to take place as a result. These downstream events are very similar to p53, such as apoptosis, cell cycle arrest until it’s fixed or permanent, and DNA repair.

Question 21

DNA repair

Answer 21

although there is so much in the body that we see can go wrong, the body is not just sitting there and taking it. There is DNA repair pathways to reduce built up of DNA damage. When DNA damage occurs, there are sensors that pick up on it and communicate it to transducers, which allow for downstream events to take place as a result. These downstream events are very similar to p53, such as apoptosis, cell cycle arrest until it’s fixed or permanent, and DNA repair.

Question 22

DNA repair method: non-homologous end joining

Answer 22

non-homologous end joining addresses the double stranded break when there’s DNA damage. There is recruitment of proteins called Ku and DNA-PK. There will also be minimal DNA processing, which means it will chew off a little bit of both ends and ligand back together via DNA ligase.
non-homologous end joining results in not exactly the same DNA it once was prior to damage so it can lead to scarring that can be negative on the genome, but that shouldn’t be an issue unless there’s an accumulation of scarring over a lifetime

Question 23

DNA repair method: homologous recombination (HR)

Answer 23

• only able to create homologs when we achieve replication, so can happen during S phase- G2 phase, not M phase bc then homologs split.
• homologous recombination (HR) addresses double stranded breaks
• when there’s a break, there are sensors that recruit other factors to process DNA, processing is extensive
• high level of fidelity so pretty accurate just restricted on when we can use it as we rely on having homologous chromosome present
• many factors involved in HR, but BRCA1 is an important one as it is also a cancer associated factor, so if BRCA1 is mutated, can’t help with DNA repair, and can help lead to cancer

Question 24

DNA repair defects cause disease

Answer 24

people with BRCA1 and BRCA2 deficiency means their DNA repair system of homologous recombination (HR) is not working as you need BRCA1 and BRCA2 as a factor in it. As a result, they are more susceptible to breast and ovarian cancer as the DNA damage accumulates.

Question 25

The impact of mutations

Answer 25

two diff kinds of mutations with respect to cell types in our body: germline mutations and somatic mutations

Question 26

germline mutations

Answer 26

germline mutations are present in egg or sperm of parent and can get passed onto child, is hereditary. If this happens, all cells are affected in the offspring.

Question 27

somatic mutations

Answer 27

somatic mutations are non-germline mutations and cannot be inherited

Question 28

Retinoblastoma

Answer 28

eye cancer that develops in young children. use this to talk about the role of spontaneous mutations vs. inherited ones.
Inherited Side:
-If you inherit a mutated RB gene from either egg or sperm (mom or dad), you already have one faulty RB gene in every cell in your body.
-Since you need both RB copies in diploid cell to be faulty, bc its a tumor suppressor that plays a role in inhibiting cell proliferation by controlling the transition btwn G1-S phase (replication), all that person needs is one more mutation to the good RB gene in order to lose the tumor suppressor gene.
-If they get this mutation, they are on the path to develop familial retinoblastoma as they lost both copies of RB

Spontaneous:

• a person with no familial history, has no mutated RB gene starting out
• therefore, they need to separate mutation events to happen, one for each copy of RB gene in order to develop retinoblastoma.

As a comparison, someone with familial history it is easier for them to go down the path of getting the cancer of retinoblastoma as they already are predisposed with one faulty RB gene

Question 29

Prevention of cancer

Answer 29

epidemiology helps us see that cancers can have an increased risk due to certain lifestyle choices; smoking, eating bad diet, alcohol etc

Question 30

Diagnosis

Answer 30

Diagnosis have approved for catching early cancer through sensitive molecule experiment to detect tumors when they’re small and have yet to metastases

• can look for differences in appearance (histology)
• can look for where there is a huge glucose uptake
• can look for expression/upregulation of things we ascribe to cancer (ex. HER2+ for breast cancer cells)

Question 31

Staging

Answer 31

T: identify the size of the tumor and if it appears to be contained in one tissue or spread to local tissues from 0-4
N: identify the presence of tumor cells in lymph nodes; which are immune system organs that tend to collect cancer form 0-2
M: “1” indicates metastasis, “0” indicates no metastasis

Question 32

Treatment option: Surgery

Answer 32

• to see if surgery is viable, it depends on location if the tumor, if that tumor forms a mass in which surgery can even be done, and if there’s many metastases is it even worth putting patient under all the stress for massive surgery(s)
• when you do surgery, you excise the region where the tumor and the cancer cells are located till the last of that cancer has been removed
• need to make sure you have clean margins so all of tumor cells are removed

Question 33

Treatment option: Radiation

Answer 33

• Radiation therapy utilizes high energy X rays or ionizing radiation that kills cancer cells
• kills cancer cells by increasing the DNA damage to those cells to the extent that they will die
• they will either die by the radiation activating the p53 pathway, if it is available and not already turned off by that cancer; p53 gene will lead cell to apoptosis
• another way is onslaught of chromosomal damage so that the cell cannot physically progress through mitosis and cells die trying to divide
• radiation doesn’t know the difference btwn cancer cells and normal cells so appropriate dosage is essential to make sure you’re not damaging normal cells

Question 34

Treatment Option: Chemotherapy

Answer 34

• diff than radiation as radiation therapy is more localized and chemotherapy is more systemic
• chemotherapy focuses on the destruction of replicating cells; drugs meant to destroy things that re actively dividing
• again, cannot differentiate cancer and normal cells so will target cells that have a high cell turnover the most in addition to cancer cells
• chemotherapy plays a role in angiogenesis, cell division, in cell death, and by creating and in dividing cell by altering cell structure

Question 35

Ideal Treatment Therapy

Answer 35

We can exploit genetic instability in cancer cells and use it to kill cancer cells but leave normal cells intact, which is the main goal in treatments. An example of doing this is by synthetic lethal. Cancer cells have a mutation that mutates pathway 2 in DNA repairs. As a result, if we target pathway 1, the drug will target both pathway 1 in cancer and normal cells, as it can’t differentiate btwn the two, however normal cells still have pathway 2 to fix DNA damage while the cancer cell now has none. This leads to accumulation of DNA damage which will lead to cell death.

Question 36

Targeted Therapies: Gleevec

Answer 36

• Gleevec is an example of target therapy for leukemia.
• A very common translocation we see in leukemia is fused BCR-Abl gene (from chromosome 22 and Abl from chromosome 9) that leads to BCR-Abl fusion protein. The BCR-Abl has a pocket where ATP binds to, which causes the trouble. -The ATP binding results in substrate level phosphorylation to activate the substate protein binding to the BCR-Abl protein. This results in a signal for cell proliferation and survival which leads to leukemia.
• Gleevec, a therpay drug, is used to bind to the BCR-Abl so that ATP can’t bind which stops the substate level phosphorylation and thus stops the signal from going out to proliferate. This results in no leukemia as it is able to stop cell proliferation.
• This treatment understand the pathway of the drug proliferating and stops it, making it very successful!!

Question 37

Drug resistance

Answer 37

• Similar to antibiotics, cancer cells may resist the drug being used and a small portion may mutate and proliferate now that it’s not competing with any other cancer cells as a result and drug A may not be useful. Drug B can be used to target that mutated cancer cell but again a small section may mutate and proliferate.
• One way to combat that is to use a bunch of cancer drugs at the same time, simultaneous treatment
• trial and error to see how cancer cells respond and take it from there with supplementing diff drugs in a cocktail

Question 38

Cancer and the Immune System

Answer 38

• Cancer suppresses the role the adaptive immune response has, especially the T-cell by creating an immunosuppressant environment
• it does this by modifying its proteins on the surface of the cancer cells to activate proteins found on the T cell
• this activation results in T cells becoming inhibited, which means that when it binds to cancer cell specific antigen, it is not able to kill it

Question 39

Cancer and the Immune System- how the immune system can evade cancer cell tactic

Answer 39

• If antibodies are there to already bind to the proteins on the T-cell, the modifying proteins on the cancer’s cell surface are unable to activate it, and thus the T-cell will not be inhibiting and will be working
• This leads to a highly activated T-cell response and is able to recognize the cancer cell as foreign and attack it
• downside is that there is risk of autoimmune side effects as cancer cells and normal cells are similar form a molecular perspective so having it attack cancer cells can also mean it attacks itself (normal cells)

Question 40

Cancer and the Immune System: HER2+ in breast cancer

Answer 40

HER2 is a receptor that sends signals to cell to divide and grow normally

• HER2 normal breast cancer cell has norma amounts of these HER2, still dividing because its cancer but at a normal rate (still bad tho)
• HER2+ has too many HER2+ receptors so the cell grows too quickly
• A drug like Herceptin is a monoclonal antibody that attach to HER2 receptors and inhibit its ability to dimerize, and as HER2 is an RTK, this prevents the signal from traveling down, which slows down cell proliferation as less HER2 receptors are activated