Carcinogenesis - Molecular Hallmarks of Cancer Cells Flashcards Preview

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

Flashcards in Carcinogenesis - Molecular Hallmarks of Cancer Cells Deck (61):
1

What is carcinogenesis?

The formation of cancer.

2

What 2 steps are necessary for neoplasia to develop?

-Oncogene activation
-Tumour suppressor gene inactivation

3

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

-Spontaneous replication error
-Induced by carcinogens

4

What happens to mutated cells?

Clonal expansion.
-cells with a selective growth advantage (Darwin)

5

What is a common feature of most tumour cells?

Genetic instability.
-enables mutations to accumulate

6

What are the main tumour suppressor genes? (2)

-Gatekeepers
-Caretakers

7

What is the function of gatekeeper genes?

Regulate normal growth.
-negative regulators of cell cycle and proliferation
-positive regulators of apoptosis and cell differentiation

8

What are gatekeeper genes negative regulators of? (2)

-Cell cycle
-Proliferation

9

What are gatekeeper genes positive regulators of? (2)

-Apoptosis
-Cell differentiation

10

What is the function of caretaker genes?

Maintain genetic stability.
-repair damaged DNA
-Control mitotic accuracy

11

How can carcinogens affect tumour suppressor genes?

Induce molecular abnormalities >> decreased protein expression / inactivation.
-LOSS OF FUNCTION

12

What effect do mutations in caretaker genes have?

Don't directly contribute to tumour phenotype.
-create conditions where gatekeeper mutations can arise

13

What does inactivation of TSGs require?

Mutations of both copies.

14

What normally causes the '1st hit' in TSG inactivation?

Point mutation in coding sequence.
-1 in 10 million divisions
-present in every cell in an individual with a familial cancer syndrome

15

What happens after a '1st hit' in a TSG?

Remaining normal copy is capable of maintaining function.
-mutant version is recessive

16

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

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

17

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

1000x more common.

18

What does chromosomal non-disjunction lead to?

Aneuploidy.
-abnormal number of chromosomes

19

What is chromosomal recombination?

Crossing over.
-in meiosis >> genetic variation
-in mitosis as 2nd hit >> inactive TSB

20

Summarise the general process of TSG inactivation.

Requires mutation of both copies.
-1st hit : normally point mutation
-2nd hit : chromosomal non-disjunction / gene conversion / mitotic recombination

21

What are epigenetics?

A change in phenotype without a change in genotype.
-e.g. chemical modification

22

What epigentic process can cause TSG inactivation?

Promoter hypermethylation.

23

What do familial cancer syndromes involve?

Inheritance of a mutant copy of a caretaker / gatekeeper gene (TSG).
-'1st hit'
-70-90% risk of developing cancer

24

FAMILIAL CANCER; what gene is involved in retinoblastoma?

RB1.

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