Carcinogens: Molecular hallmarks of cancer cells

Question 1

Why is genetic instability important and how can it be caused?

Answer 1

• Caused by mutant forms of caretaker genes
• Important for enabling specific genetic alterations to accumulate in carcinogenesis
• Common feature of tumour cells

Question 2

What are the two types of tumour suppressor genes?

Answer 2

• Gatekeeper

- Caretaker

Question 3

What is the function of gatekeepers?

Answer 3

• Regulating normal growth
• Positive regulators of apoptosis
• -Positive regulators of cell differentiation
• Negative regulators of cell cycle and proliferation

Question 4

What is the function of caretakers?

Answer 4

• Maintain genetic stability
• DNA repair genes
• Controlling accuracy of mitosis

Question 5

How do carcinogens affect tumour suppressor genes?

Answer 5

-Induce molecular abnormalities that cause reduced/lack of protein expression or inactivation of protein

Question 6

How are TSGs inactivated?

Answer 6

• First hit normally a point mutation
• Remaining normal copy of the TSG capable of doing the job itself
• Second hit required for complete loss of function

Question 7

What are the genes affected , types of tumour suppressor and principal tumours produced by these cancer syndromes?

• Retinoblastoma
• Li-Fraumeni
• Familial adenomatous polyposis
• Famililal breast cancer
• Hereditary non-polyposis colorectal cancer

Answer 7

• Retinoblastoma= RB1 gene= principal tumour: retinoblastoma and gatekeeper
• Li-fraumeni=p53 gene= principal tumour: sarcomas, breast, gatekeeper & caretaker
• F.A.P= APC= colorectal and gatekeeper
• F.B.C= BRCA1, BRCA2, breast and ovarian and caretaker
• H.N.C.C= hMLH1, hMSH2 and colon and endometrial and caretaker

Question 8

What is the function of proto-oncogens?

Answer 8

• Promote cell proliferation -Survival
• Angiogenesis
• Negative regulation of apoptosis

Question 9

What can mutations in oncogenes lead to?

Answer 9

• Activated versions
• Increased expression of proto-oncogenes
• Gain of function

Question 10

What can oncogenes cause?

Answer 10

-Increased levels of cell proliferation, survival, angiogenesis, inhibition of apoptosis

Question 11

What are the mechanisms of oncogene activation?

Answer 11

• Translocation (from a low transcriptionally active site to an active site) aberrant expression
• Point mutation (substitution of a single base pair can alter an amino acid in the protein leading to hyperactive)
• Amplification (insertion of multiple copies of an oncogene= increased expression)

Question 12

What are the stages that turn normal epithelium into invasion & metastasis

Answer 12

1) Loss of APC
2) Hyperplastic epithelium
3) DNA hypomethylation
4) Activation of K-ras (early)
5) Loss of 18q TSG (late)
6) Loss of p53
7) Carcinomas
8) invasion & metastasis

Question 13

What are the hallmarks of cancer cells?

Answer 13

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

Question 14

How does insensitivity to antigrowth signals occur?

Answer 14

When required level of cell division has occurred normal cells will respond to negative growth factors and leave the cell cycle tumour cells do not respond

Question 15

What is the function of RB protein?

Answer 15

Key regulator of cell cycle by preventing progression from G1 to S phase

Question 16

What is the role of negative GFs?

Answer 16

Inhibit progression of cell cycle by activating Rb protein.

Question 17

What does inactivation of the RB gene result in?

Answer 17

Resistance to negative growth regulation- common event in tumours

Question 18

How is immortality achieved in tumour cells?

Answer 18

Rapid proliferation can overexposes the telomerase enzyme to maintain normal telomere length

Question 19

Why do normal cells have a finite replicative lifespan?

Answer 19

Due to shortening of chromosome ends (telomeres) after each cell division

Question 20

How are tumour cells resistance to apoptosis?

Answer 20

• TP53 key player in apoptosis
• -TP53 codes for transcription factor inducing transcription of >100 genes
• P53 induced cell cycle arrest allowing DNA repair or apoptosis if too much repair needed
• TP53 inactivation leading to loss of apoptotic response
• Inherited mutations= Li-Fraumeni syndrome

Question 21

What is angiogenesis key for?

Answer 21

Metastatic spread of malignant tumours

Question 22

How does hypoxia cause angiogenesis?

Answer 22

• Stabalises HIF-1 transcription factor inducing vascular endothelial growth factor (VEGF)
• This actively recruits endothelial cells which construct new capillaries and vessels

Question 23

How are epithelial cells held together?

Answer 23

Adhesion molecule E-Cadherin

Question 24

What do mesenchymal cells secrete? What does this allow?

Answer 24

• Motile secreting proteases

- Allows them to break through basement membrane & invade underlying stroma

Question 25

In terms of invasion/metastasis what do tumours show a loss of?

Answer 25

E-Cadherin through mutation/hypermethylation of the gene

Question 26

What is Herceptin?

Answer 26

Antibody drug targeted to HER2 and dampens the effect of an overactive HER2 receptor- prone to breast tumours