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BIOC 212 > Cancer (TSG, oncogenes) > Flashcards

Cancer (TSG, oncogenes) Flashcards

1
Q

What does carcinos, carcinoma and oncos mean?

A

Carcinos = crab
Oncos = greek for swelling
Carcinoma → type of cancer that arises from epithelial cells

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2
Q

What theory about cancer was predominent around the 17th and 18 th centuries?

A

Infectious disease theory → cancer was infectious
Had separated hospitals for cancer patients and other patients

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3
Q

Now in modern days, what is know to cause cancer?

A

viruses, chemical carcinogens, radiation

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4
Q

What are the different acquired states of cancer cells?

A

GERESA DATI
IMPORTANT
1. Genome instability & mutation
2. Resitance to cell death
3. Sustained proliferative signaling
4. Evasion of growth suppressors
5. Enabling replicative immortality
6. Activating invasion & metastasis

NOT SO IMPORTANT
1. Avoiding immune destruction
2. Deregulation of cellular energetics
3. Tumor-promoting inflammation
4. Inducing angiogenesis

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5
Q

What was Peyton Rous’ study on?

A

On avian sarcoma in chicken being infectious → carcinogen was a virus called Rous sarmcoma virus (RSV)
1. Filtered tumor homogenate with sand
2. Collected the filtrate
3. Injected the filtrate → new tumors in healthy chickens
Conclusion: small quatities of cell-free filtrate have sufficed to transmit the growth to susceptible fowls (chickens)

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6
Q

What is the difference between cancer cells and normal cells when cultured in a Petri dish?

A

Normal cells stop dividing when they enter in contact → form a monolayer
Cancer cells/transformated cells → continue growing on top of each other → form a focus

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7
Q

Are transformed cells and tumors the same?

A

No, transformed cells can form tumours in the right conditions

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8
Q

What are the characteristics of a transformed cell? (7)

A

GGFLAMIT
1. Immortalization (not all immortalized cells are transformed)
2. Altered morphology (round shape)
3. Loss of contact inhibition (ability to grow over one another)
4. Anchorage-independent growth (growing without attachement to solid substrate, will grow in Jello)
5. Reduced requirement for growth factors
6. Increased transport of glucose
7. Tumorgenicity

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9
Q

How does a PET scan work?

A

Glucose is overly picked up by tumor cells
Inject radiolabelled glucose → picked up by tumor cells → positron-emission tomography (FGD-PET)
Makes it possible to visualize tumors in the body that have concentrated large amount of glucose

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10
Q

What is an example of cancer that virus driven?

A

HPV

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11
Q

What is a retrovirus? Give an example.

A

RSV is an example of a cancerous retrovirus
Use encoded enzyme (reverse transcriptase) to reversibly transcribe their RNA genome into complementary DNA (cDNA) which can then integrate into cellular genomes
Has the folowing coding regions:
- gag (core protein)
- pol (reverse transcriptase and integrase)
- env (envelope protein)

What charactertistic of RSV makes it a cancerous retrovirus compared to normal retroviruses?
Contains addition gene → src → has a role in triggering formation of sarcomas

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12
Q

Is src restricted to cancer cells?

A

No, found in DNA sequences in both RSV-infected and uninfected cells
c-src = proto-oncogene (in normal cells)
v-src = oncogene (viral gene)

dsDNA provirus (viral genome) → accidental integration next to c-src → co-transcription of viral and c-src sequences → fused ALV-src RNA trascript → packaging into capsid RSV virion carrying src sequences

*src = kinase

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13
Q

What are examples of oncogenes present in non-virally induced human tumours?

A
  • abl
  • erbB
  • raf
  • H-ras9
  • K-ras9
  • myc^i
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14
Q

What is the Src protein function?

A

Tyrosine kinase → phosphorylates speciifc Tyrosines in substrates
Src can also autophosphorylate

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15
Q

What is a kinase?

A

An enzyme that removes high-energy phosphate group from ATP and transfers it to a suitable protein substrate
By phosphorylating their substrates they change the functioanl state of the substrates
Kinases were determined frost for Src using anti-Src Ab that where phosphorylated after contact with Src
Many oncogenes are kinases

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16
Q

What are the effects of protein kinases signaling?

A

Gene transcription (which causes):
- proliferation
- angiogenesis
- apoptosis
- protein synthesis

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17
Q

What is the definition of an oncogene?
What is the definition of a proto-oncogene?

A

An oncogene is a gene that increases the selective growth advantage of the cell in which it resides
A proto-oncogene is a normal gene that can become an oncogene as a result of mutations or increased expression
*Gas pedals

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18
Q

What is a tumor-supressor?

A

A tumor-supressor is a gene that, when inactivated or lost, leads to an increase in the selective growth advantage of the cell in which it resides
*Its the brake pedal

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19
Q

What is a selective growth advantage?

A

The difference between birth rate and death rate in a population (of cells for oncogenes)
It allows cancer cells to outgrow the surrounding «normal» cells

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20
Q

How can a proto-oncogene turn into an oncogene?

A
  1. Amplification → Genetic alteration producing a lare number of copies of a small segment of the genome (more mRNAs)
  2. Insertion/deletion (Indel) → of a few nucleotides
  3. Translocation → Specific type of rearrangement where regions of 2 nonhomologous chromosomes are joined (ex: Philadelphia chromosome)
  4. Point mutations → single nucleotide substitution (can cause insertion of stop codons)
    *These can happen in healthy individual and will not automatically cause cancer
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21
Q

What are Driver and Passenger mutations?

A

Driver mutation → direclty or indireclty confers a selective growth advantage to a cell
Passenger mutation → does not confer selective growth advantage

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22
Q

How does tumor mutation burden vary?

A

Some cancers have a much higher mutation burden, does not mean that all the mutations are driver mutations
Ex: Breast cancer has a low relative mutation burden compared to melanoma

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23
Q

What are examples of cellular oncogenes that were studied?

A
  1. BCR-Abl
  2. erbB2/HER2
  3. Ras
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24
Q

How is chronic myeloid leukemia (CML) driven by an oncogene? How was it discovered?

A

Dicovered by doing karyotyping → philadelphia chromosome → translocation between chromosome 9 and 22 (small Philadelphia chromosome 22)

Abl = tyrosine kinase (proto-oncogene in chromosome 9)
Bcr = breakpoint cluster region in chromosome 22
Fusion of the 2 genes leads to Abl kinase constitutive activity → emiting strong growth-promoting signals

25
Q

What therapy was found to inhibit BCR/ABL fusion gene hyperactivity? (involved in CML)

A

Imatinib (Gleevec):
Competitively binds to the kinase domain/ATP binding pocket of BCR/ABL fusion protein (constitutively active kinase) → can’t phosphorylate downstream protein → tumor cell can’t proliferate

26
Q

How does erbB2 signaling work?

A

Receptor Tyrosine Kinase (ligand binding domain + hydrophobic TM domain + intracellular kinase domain):
- responds to epidermal growth factors
- also called neu or HER2
- Dimerization activates proliferation and survival gene expression signaling pathways
- RTK overexpression → hyper-responsiveness to low growth factor concentration and/or cause ligand-independent RTK dimerization because too many on the cell surface (proximity)

27
Q

How can gene copy number be assessed by fluorescence in situ hybridization? (FISH)

A
  1. Take DNA probe against HER2 gene for example
  2. Denature DNA of the cell (single stranded)
  3. Add ssDNA probe —> hybridize
  4. Look under fluorescent microscope (normal cells show 2 copies because diploid)
    In breast cancer cells —> a lot more copies if the gene is amplified
28
Q

How can dysregulation of ERBB2/HER2 be assessed if the gene is not amplified?

A

By Immunohistochemistry IHC → looks at protein levels instead of DNA levels
Staining with specific Ab against the protein
Can assess overexpression instead of amplification

29
Q

What is Traztuzumab (Herceptin)?

A

It is an example of personnalized medicin for treatement of HER2
It binds to an extracellular domain of the receptor and inhibits HER2 homodimerization → prevent HER2-mediated signaling

30
Q

Which missense mutation is comon in Ras oncogenes?

A

G12 and 61 is mutated to D → constitutively active → turns Ras from proto-oncogene to oncogene
Found in 95% of pancreatic cancers and 50% of colorectal cancers

31
Q

What are example of tumor suppressor genes that often play a role in tumor formation?

A

Retinoblastoma and p53
TSG = brake pedal

32
Q

What is the Knudson 2-hit hypothesis?

A

Familial Rb supression → 1 random events → bilateral high risks of recidives
Sporadic Rb supression (no family history) → 2 random events
Rb is haplosufficient so need both copies KO to have loss-of-function

33
Q

What is the Quiescent phase?

A

It is a stage where cells remain metabolically active, but do not proliferate unless called to do so.
G0 (after M, before G1, could eventually go back to G1)
Monitored by the Cell cycle clock → considers growth factors, genome integrity, integrins, cell metabolism

34
Q

What is the role of Rb in the cell cycle?

A

Rb regulates the restriction (R) point:
- point where the cell must commit to advance through M phase, remain in G1 or go into G0
- Rb = cell cycle gatekeeper → prevents from entering the cell cycle by inactivating E2F1, acts as a trascriptional repressor that determines if cell enter S phase
- Can be phosphorylated by mitogenic signaling pathways

35
Q

What is mitotic recombination? What is its effect?

A

It can lead to Loss of Heterozygosity (LOH) in TSG eliminating the WT copy
- Can occur during G2 phase of cell cycle
- Subsequent segregation of chromatics may yield a pair of daughter cells with LOH
1. Heterozygosity at Rb locus (1 mutant, 1 WT)
2. S phase → chromosome replication
3. G2 and M phases → mitotic recombination → 1 mutant on each chromosome (chromatid sisters not identical anymore)
4. Segegation in daughter cell → possible lack of Rb WT copies

36
Q

How can loss of tumor supressor genes occur?

A
  1. Many familial cancers can be explained by inheritance of mutant tumor supressor genes (1 copy mutant, 1 WT)
  2. Mitotic recombination can be responsible for Loss-of-Heterozygosity
37
Q

What are different mechanisms by which Loss-of-Heterozygosity can occur? (causing complete loss of WT copy of TSG) («other ways the 2nd hit can happen»)

A
  1. Terminal deletion of a chromosome (WT copy deleted) → hemizygous with only mutant copy
  2. Mitotic recombination
  3. Point mutation in WT copy
  4. Indels → frame shift → loss of proper coding sequence of WT copy + probability of premature stop codon insertion
  5. Disruptive translocation
  6. Epigenetic silencing (ability of DNA to be expressed, no change in actual DNA sequence)
38
Q

n what cas is only 1 hit needed for inactivation of the WT copy of a tumor supressor gene?

A

When the mutation is dominant negative

39
Q

What are the levels of compaction/structure in chomatin silencing?

A
  1. DNA sequence + DNA methylations
  2. Rolled into nucleosomes (beads on a string)
  3. Histone modifications + histone variants (H3K9me3, H3K27me3, H3K4me3, H3K36me3)
  4. Compaction of nucleosomes or DNA-binding proteins
40
Q

How can loss of TSG be achieved without mutation nor mitotic recombination?

A

Epigenic silencing → Promoter methylation can lead to TSG inactivation without mutation
(Hypermethylated CpG)
*DNA methyltransferase (DNMT3B) is highly regulated in cancer cells

41
Q

What type of gene is p53? How does it accomplish its function?

A

Tumour suppressor genes
1. DNA damage and dysregulated growth signals → p53 stabilization
2. p53 forms a homotetramer to function
3. Functions as TF (not as transcriptional repressor) that halts cell cycle
4. p53 target genes = growth arrest genes, DNA repair genes, regulators of apoptosis —> favour senescence over proliferation

42
Q

Does the 2 hit model apply to p53?

A

No, because as tetramerizes → 1 mutation in p53 affects the whole tetramer
*It is a haploinsufficient gene

43
Q

What are 2 example of haplosufficient TSG? (follow the 2-hit model)

A

Rb and BRCA1

44
Q

What is a dominant negative mutation?

A

Mutation whose gene product adversly affect the normal/WT gene product within the same cell
Usually when mutant can still interact with others, but blocks other part of the function

ex: p53 mutatn can still tetramerize, but mutation in DNA-binding domain

45
Q

What is synthetic lethality? What is its importance?

A

Used to target «untargetable» tumour suppressor gene mutants cancer cells
2 mutated alleles are non-lethal independently, but their combination → lethality
*Most mutations = loss-of-function mutations → difficult to develop drugs to restore the function of a missing/altered protein → can achieve indirectly by inhibiting activity of a protein that acts downstream of the missing TSG product along a signaling pathway
Want normal cells to be good, but cancer cells to be lethal

46
Q

What are the benefits of using synthetic lethality-based strategy to treat TSG mutations?

A
  1. Synthetic lethality is selective for cancer cell-specific genetic mutations
  2. Can be applied to any type of cancer mutation → tumour suppressors, mutation deemed «undruggable»
47
Q

How is synthetic lethality used in clinics for cancer treatement? (With ovarian and breast cancer for example)

A
  1. DNA damage repair:
    - block specific DNA repair process
    - cancer cells rely on one mechanism because the other one is mutated in cancer cells → by blocking the functional mechanism, normal cells have another option, but cancer cells don’t
    → PARP (polymerase) inhibitors

PARP (poly(ADP-ribose) polymerase) inhibitors + DNA damage repair
For patients with BRCA1-mutant or BRCA2-mutant

Normal cells have DNA repair by Base-excision repair (PARP1) OR Homologous recombination (BRAC)
Cancer cells don’t have Homologous recombination as BRCA is mutated → by inhibiting PARP1 → no DNA repair → cell death for cancer cells
Normal cells can still have DNA repair through BRCA homologous recombination even if PARP1 is inhibited

48
Q

What does screening for synthetic lethal interactors involve?

A

Treat Ras WT and Ras mutant with lethal compounds → find one that is only lethal for Ras mutant and not Ras WT

49
Q

What are HELA cells?

A

Cells from Henrietta Lacks (had cervical cancer) → where transformed and immortalized for study

50
Q

What are the 2 major obstacles to cellular immortalization?

A
  1. Replicative Senecescence:
    Irreversible halt in cell proliferation with retention of cell viability over extended periods of time
    - Metabolically acitve, but cell has exited the cell cycle for ever
  2. Crisis:
    «genetic catastrophe» → leads to death by apoptosis
51
Q

What is the difference between Senescence and Quiescence?

A

Senescence is permanent → metabolically active, but lost ability to reenter the cell cycle
Quiescence = G0, waiting to return into G1 eventually

52
Q

What is the Hayflick limit?

A

The number of times a normal human cell population will divide until cell division stops —> before entering senescence (~50 divisions, ~50 doubling of the population)
*Not the same for all tissues and all cell types

53
Q

What are possible roads to senescence?

A

TOCCOD (6)
1. Oncogene activation (HRAS —> HRASv12)
2. Telomere dysfunction
3. Cell culture (cells get in contact with each other)
4. Oxidative stress
5. DNA damage
6. Cytotoxic drugs
*To immortalize cells, senescence has to be bypassed

54
Q

How does oncogene-induced senescence occur?

A

Presence of oncogenes/other types of stress activates TSG (Rb, P21, p53) → promote cell cycle arrest → senescence

55
Q

How does telomere dysfunction induce senescence?

A

Telomere shortening → Senescence → Bypassed by disruption of tumour suppressive pathways → cells undergo crisis = chromosomes fuse leading to apoptosis (p53-INdependent)

Telomeres get very short → cell keeps going through mitosis → chromatid ends with no telomeres start fusing with each other → breakage fusion during anaphse (Breakage-fusion-bridge cycles)
Eventually leads to apoptosis (crisis)

56
Q

By what mechanisms do cells escape crisis induced by telomere dysfunction?

A

Cancer cells escape crisis by overexpressing telomerase enzyme to keep long telomeres (85-90% of human tumors = telomerase positive)
When cells have escaped crisis → immortalized (not enough to be transformed)

57
Q

What charactertistic of RSV makes it a cancerous retrovirus compared to normal retroviruses?

A

Contains addition gene → src → has a role in triggering formation of sarcomas

58
Q

What are the inputs/outputs the cell cycle clock?

A

Inputs:
- Growth factors
- Monitors
- TGF-b receptors
- Integrins
- monitors of cell metabolism

Ouputs:
- Entry into Go (quiescent state) OR into cell cycle (G1)
- Entry into different phases of cell cycle

BIOC 212 (15 decks)

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