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Year 2 EMS MoD > Carcinogenesis - Molecular Hallmarks of Cancer Cells > Flashcards

Carcinogenesis - Molecular Hallmarks of Cancer Cells Flashcards

1
Q

What is carcinogenesis?

A

The formation of cancer.

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2
Q

What 2 steps are necessary for neoplasia to develop?

A
  • Oncogene activation

- Tumour suppressor gene inactivation

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3
Q

What are the main causes of mutations leading to cancer? (2)

A
  • Spontaneous replication error

- Induced by carcinogens

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4
Q

What happens to mutated cells?

A

Clonal expansion.

-cells with a selective growth advantage (Darwin)

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5
Q

What is a common feature of most tumour cells?

A

Genetic instability.

-enables mutations to accumulate

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6
Q

What are the main tumour suppressor genes? (2)

A
  • Gatekeepers

- Caretakers

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7
Q

What is the function of gatekeeper genes?

A

Regulate normal growth.

  • negative regulators of cell cycle and proliferation
  • positive regulators of apoptosis and cell differentiation
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8
Q

What are gatekeeper genes negative regulators of? (2)

A
  • Cell cycle

- Proliferation

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9
Q

What are gatekeeper genes positive regulators of? (2)

A
  • Apoptosis

- Cell differentiation

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10
Q

What is the function of caretaker genes?

A

Maintain genetic stability.

  • repair damaged DNA
  • Control mitotic accuracy
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11
Q

How can carcinogens affect tumour suppressor genes?

A

Induce molecular abnormalities&raquo_space; decreased protein expression / inactivation.
-LOSS OF FUNCTION

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12
Q

What effect do mutations in caretaker genes have?

A

Don’t directly contribute to tumour phenotype.

-create conditions where gatekeeper mutations can arise

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13
Q

What does inactivation of TSGs require?

A

Mutations of both copies.

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14
Q

What normally causes the ‘1st hit’ in TSG inactivation?

A

Point mutation in coding sequence.

  • 1 in 10 million divisions
  • present in every cell in an individual with a familial cancer syndrome
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15
Q

What happens after a ‘1st hit’ in a TSG?

A

Remaining normal copy is capable of maintaining function.

-mutant version is recessive

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16
Q

What are the main processes that cause the ‘2nd hit’ in TSG inactivation? (3)

A

-Chromosomal non-disjunction
-Gene conversion
-Mitotic recombination
(-epigenetic inactivation)

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17
Q

Are the ‘2nd hit’ processes more or less common than point mutation?

A

1000x more common.

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18
Q

What does chromosomal non-disjunction lead to?

A

Aneuploidy.

-abnormal number of chromosomes

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19
Q

What is chromosomal recombination?

A

Crossing over.

  • in meiosis&raquo_space; genetic variation
  • in mitosis as 2nd hit&raquo_space; inactive TSB
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20
Q

Summarise the general process of TSG inactivation.

A

Requires mutation of both copies.

  • 1st hit : normally point mutation
  • 2nd hit : chromosomal non-disjunction / gene conversion / mitotic recombination
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21
Q

What are epigenetics?

A

A change in phenotype without a change in genotype.

-e.g. chemical modification

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22
Q

What epigentic process can cause TSG inactivation?

A

Promoter hypermethylation.

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23
Q

What do familial cancer syndromes involve?

A

Inheritance of a mutant copy of a caretaker / gatekeeper gene (TSG).

  • ‘1st hit’
  • 70-90% risk of developing cancer
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24
Q

FAMILIAL CANCER; what gene is involved in retinoblastoma?

A

RB1.

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25
FAMILIAL CANCER; what gene is involved in Li-Fraumeni?
p53.
26
FAMILIAL CANCER; what gene is involved in familial adenomatous polyposis?
APC.
27
FAMILIAL CANCER; what gene is involved in familial breast cancer?
BRCA1 | BRCA2
28
FAMILIAL CANCER; what genes are involved in HNPCC?
hMLH1 | hMSH2
29
What are the main functions of proto-oncogenes?
- Promote cell proliferation, survival and angiogenesis | - Negative regulation of apoptosis
30
What can proto-oncogenes become if they are over-expressed or mutated?
Oncogenes. - gain of function - potential to cause cancer
31
What do oncogenes cause?
- Increased levels of cell proliferation, survival and angiogenesis - Inhibition of apoptosis
32
How many copies of the gene need to be activated to cause a gain in function of proto-oncogens?
Only one copy. | -mutated gene is dominant
33
What are the main mechanisms of oncogene activation? (3)
- Translocation - Point mutation - Amplification
34
What is the minimum number of genetic alterations required to transform a normal cell into a tumour cell?
3 genetic alterations.
35
What does tumorigenesis involve?
- Activation of oncogenes | - Inactivation of TSGs
36
Describe the general process of colon carcinoma progression.
``` Normal epithelium >> hyperplastic epithelium >> adenoma >> carcinoma >> invasion / metastasis ``` NB. p53 mutation
37
What are the main hallmarks (characteristics) of cancer cells? (6)
- Self-sufficiency in growth signals - Insensitivity to antigrowth signals - Tissue invasion and metastasis - Limitless replication potential - Sustained angiogenesis - Evading apoptosis
38
What do normal cells require before entering the cell cycle and dividing?
Stimulus of positive growth factors. | -signal transduction
39
What is signal transduction?
Transmission of a signal from outside the cell to inside. - growth factors bind to GF receptors - deregulated in cancer cells
40
Why don't cancer cells require a signal from growth factors?
Oncogene-encoded proteins make cell think they have encountered a growth factor. >> proliferation
41
What are common causes of cancer cells not requiring signals from growth factors? (4)
- EGFR overexpression - EGFR mutation - Ras mutation - B-Raf mutation
42
What is Ras?
Common oncoprotein. - inactive when normal cell is not proliferating - stimulation >> drops GDP and acquire GTP >> active - inactivates after
43
How do Ras oncogene mutations affect their function in cancer cells?
Unable to revert to inactive state after acquiring GTP. | >> continual positive growth signal
44
What happens in normal cells once the required level of cell division has occurred?
They respond to negative growth signals and leave cell cycle. -tumour cells cannot respond
45
What is the function of the retinoblastoma(RB) protein in normal cells?
Binds to transcription factors, preventing progression from G1 to S phase. - negative growth factors activate it
46
How can cancer cells escape inhibition by negative growth factors?
Mutational inactivation of retinoblastoma protein.
47
What are epithelial cells held tightly together by?
E-cadherin.
48
How do cancer cells invade and metastasise?
- Loss of E-cadherin >> break through epithelium | - Secrete proteases to break through basement membrane
49
What happens to normal cells after 50-60 cell divisions?
They deteriorate and die due to loss of DNA from telomeres. | -hexanucleotide sequence loss
50
How do tumour cells have a limitless potential for replication?
Tumour cells express telomerase. | -replaces lost DNA from telomere
51
What is the main gene involved in apoptosis, and what is the general process?
TP53 gene. - codes for transcription factor - P53 induces cell cycle arrest when cell damage, and apoptosis (if too much damage)
52
How do cancer cells evade apoptosis?
TP53 inactivation. | -Li-Fraumeni cancer sydrome
53
What size tumours need to stimulate angiogenesis in order to survive?
>2 mm.
54
What growth factor is often produced by cancer cells in order to stimulate angiogenesis?
Vascular endothelial growth factor (VEGF). | -especially invasive tumours
55
What are tumour markers?
Biomarkers found in blood / urine / tissues that can be elevated by the presence of cancers.
56
How are tumour markers used clinically?
- Screening - Diagnosis - Prognosis - Therapy - Monitoring
57
What is a tumour marker used for prostate cancer diagnosis?
Prostate specific antigen (PSA). | -however, 1/3 with raised PSA don't have prostate cancer
58
What cancer is CA-125 serum antigen present in?
Ovarian cancer. | -good for monitoring, but not for detecting early disease
59
What is a problem with current serum protein markers?
They lack sensitivity and specificity.
60
What are predictive markers used for?
Prognosis and deciding therapy. | -e.g. acute myeloid leukaemia
61
What cancer is HER2 (predicitive marker) associated with, and what is the treatment?
Over-expression in 30% breast cancer >> more susceptible to +ve growth factors. -treatment : Herceptin

Year 2 EMS MoD (20 decks)

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