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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
Q

FAMILIAL CANCER; what gene is involved in Li-Fraumeni?

A

p53.

26
Q

FAMILIAL CANCER; what gene is involved in familial adenomatous polyposis?

A

APC.

27
Q

FAMILIAL CANCER; what gene is involved in familial breast cancer?

A

BRCA1

BRCA2

28
Q

FAMILIAL CANCER; what genes are involved in HNPCC?

A

hMLH1

hMSH2

29
Q

What are the main functions of proto-oncogenes?

A
  • Promote cell proliferation, survival and angiogenesis

- Negative regulation of apoptosis

30
Q

What can proto-oncogenes become if they are over-expressed or mutated?

A

Oncogenes.

  • gain of function
  • potential to cause cancer
31
Q

What do oncogenes cause?

A
  • Increased levels of cell proliferation, survival and angiogenesis
  • Inhibition of apoptosis
32
Q

How many copies of the gene need to be activated to cause a gain in function of proto-oncogens?

A

Only one copy.

-mutated gene is dominant

33
Q

What are the main mechanisms of oncogene activation? (3)

A
  • Translocation
  • Point mutation
  • Amplification
34
Q

What is the minimum number of genetic alterations required to transform a normal cell into a tumour cell?

A

3 genetic alterations.

35
Q

What does tumorigenesis involve?

A
  • Activation of oncogenes

- Inactivation of TSGs

36
Q

Describe the general process of colon carcinoma progression.

A 
Normal epithelium
>> hyperplastic epithelium
>> adenoma
>> carcinoma
>> invasion / metastasis

NB. p53 mutation

37
Q

What are the main hallmarks (characteristics) of cancer cells? (6)

A
  • Self-sufficiency in growth signals
  • Insensitivity to antigrowth signals
  • Tissue invasion and metastasis
  • Limitless replication potential
  • Sustained angiogenesis
  • Evading apoptosis
38
Q

What do normal cells require before entering the cell cycle and dividing?

A

Stimulus of positive growth factors.

-signal transduction

39
Q

What is signal transduction?

A

Transmission of a signal from outside the cell to inside.

  • growth factors bind to GF receptors
  • deregulated in cancer cells
40
Q

Why don’t cancer cells require a signal from growth factors?

A

Oncogene-encoded proteins make cell think they have encountered a growth factor.
» proliferation

41
Q

What are common causes of cancer cells not requiring signals from growth factors? (4)

A
  • EGFR overexpression
  • EGFR mutation
  • Ras mutation
  • B-Raf mutation
42
Q

What is Ras?

A

Common oncoprotein.

  • inactive when normal cell is not proliferating
  • stimulation&raquo_space; drops GDP and acquire GTP&raquo_space; active
  • inactivates after
43
Q

How do Ras oncogene mutations affect their function in cancer cells?

A

Unable to revert to inactive state after acquiring GTP.

|&raquo_space; continual positive growth signal

44
Q

What happens in normal cells once the required level of cell division has occurred?

A

They respond to negative growth signals and leave cell cycle.
-tumour cells cannot respond

45
Q

What is the function of the retinoblastoma(RB) protein in normal cells?

A

Binds to transcription factors, preventing progression from G1 to S phase.
- negative growth factors activate it

46
Q

How can cancer cells escape inhibition by negative growth factors?

A

Mutational inactivation of retinoblastoma protein.

47
Q

What are epithelial cells held tightly together by?

A

E-cadherin.

48
Q

How do cancer cells invade and metastasise?

A
  • Loss of E-cadherin&raquo_space; break through epithelium

- Secrete proteases to break through basement membrane

49
Q

What happens to normal cells after 50-60 cell divisions?

A

They deteriorate and die due to loss of DNA from telomeres.

-hexanucleotide sequence loss

50
Q

How do tumour cells have a limitless potential for replication?

A

Tumour cells express telomerase.

-replaces lost DNA from telomere

51
Q

What is the main gene involved in apoptosis, and what is the general process?

A

TP53 gene.

  • codes for transcription factor
  • P53 induces cell cycle arrest when cell damage, and apoptosis (if too much damage)
52
Q

How do cancer cells evade apoptosis?

A

TP53 inactivation.

-Li-Fraumeni cancer sydrome

53
Q

What size tumours need to stimulate angiogenesis in order to survive?

A

> 2 mm.

54
Q

What growth factor is often produced by cancer cells in order to stimulate angiogenesis?

A

Vascular endothelial growth factor (VEGF).

-especially invasive tumours

55
Q

What are tumour markers?

A

Biomarkers found in blood / urine / tissues that can be elevated by the presence of cancers.

56
Q

How are tumour markers used clinically?

A
  • Screening
  • Diagnosis
  • Prognosis
  • Therapy
  • Monitoring
57
Q

What is a tumour marker used for prostate cancer diagnosis?

A

Prostate specific antigen (PSA).

-however, 1/3 with raised PSA don’t have prostate cancer

58
Q

What cancer is CA-125 serum antigen present in?

A

Ovarian cancer.

-good for monitoring, but not for detecting early disease

59
Q

What is a problem with current serum protein markers?

A

They lack sensitivity and specificity.

60
Q

What are predictive markers used for?

A

Prognosis and deciding therapy.

-e.g. acute myeloid leukaemia

61
Q

What cancer is HER2 (predicitive marker) associated with, and what is the treatment?

A

Over-expression in 30% breast cancer
» more susceptible to +ve growth factors.
-treatment : Herceptin

Year 2 EMS MoD (20 decks)

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