Carcinogenesis - Molecular Hallmarks of Cancer Cells (21)

Question 1

Caretaker genes (TSG)

Answer 1

Maintain genetic stability by repairing damaged DNA and replication errors (control accuracy of mitosis)

Question 2

Gatekeeper genes (TSG)

Answer 2

Regulate normal growth (positively regulate apoptosis and cell differentiation, negatively regulate cell cycle and proliferation)

Question 3

Carcinogens and TSGs

Answer 3

Cause reduced/lack of protein expression/inactivation of protein > loss of function

Question 4

2nd hit inactivation of TSG

Answer 4

Both chromosomes need to be inactive to inactivate TSG (1 copy can do work of 2)

Question 5

Retinoblastoma

Answer 5

RB1/Retinoblastoma (Gatekeeper)

Question 6

Li-Fraumeni

Answer 6

p53/Sarcomas, breast (Gatekeeper/care taker)

Question 7

Familial adenomatous polyposis

Answer 7

APC/Colorectal (Gatekeeper)

Question 8

Familial breast cancer

Answer 8

BRCA1/BRCA2, Breast, ovarian (Care taker)

Question 9

Hereditary non-polyposis colorectal cancer

Answer 9

hMLH1, hMSH2, colon, endometrial (Care taker)

Question 10

Proto-oncogenes

Answer 10

Promote cell proliferation, survival, angiogenesis and inhibit of apoptosis

Question 11

Oncogenes

Answer 11

Mutations lead to activated versions of increased expression of proto-oncogenes (gain of function), only 1 copy of genes needs to be activated

Question 12

Mechanisms of oncogene activation

Answer 12

Translocation, point mutation, amplification

Question 13

Multi-step tumourigenesis

Answer 13

Activation of oncogenes/inactivation of TSGs, minimum of 3 genetic alterations needed

Question 14

Self-sufficiency in growth signals

Answer 14

Normal cells require the stimulus of positive growth factors, tumour cells acquire ability to growth in absence (RB key regulator of cell cycle prevents GI > S phase, inactivated in most tumours)

Question 15

Insensitivity to antigrowth signals

Answer 15

Normal cells have finite life span, after so many divisions they die due to loss of DNA from telomeres, tumour cells express telomerase that replaces lost material and cells become immortal

Question 16

Telomeres

Answer 16

Thousands of repeats of hexanucleotide sequence, protect end of chromosomes, everytime divides gets shorter > apoptosis

Question 17

Evading apoptosis

Answer 17

Tumour cells lose ability to apoptose (Tp53 main player in apoptosis, transcription factor induces transcription of >100 genes, induces cell cycle arrest to allow repair of DNA damage/apoptosis, inactivation > loss of apoptotic response >50% tumour)

Question 18

Sustained angiogenesis

Answer 18

Tumour grow >2mm require good blood supply, out grow blood supply (hypoxia stabilises HIF-1 transcription factor, induces VEGF, actively recruit endothelial cells, construct new capillaries and vessels, angiogenesis decrease in dysplasia, extensive in invasive tumours - metastasis)

Question 19

Tissue invasion and metastasis

Answer 19

Normal cells are unable to detach from neighbouring cells/grow into new compartments outside their own tissue, malignant tumour cells acquire ability to invade new tissues, detach and migrate, epithelial cells held tightly together by adhesion E-Cadherin - tumour cells have no E-Cadherin due to mutation/hypermethylation > epithelial-mesenchymal transition (EMT), mesenchymal cells are motile and secrete proteases (allowing them to break through basement membrane and invade underlying stroma)

Question 20

Prostate-specific antigen

Answer 20

Serum protein marker (1/3rd with raised don’t have prostate cancer)

Question 21

CA-125 serum antigen

Answer 21

Ovarian cancer - not good at detecting early stage disease

Question 22

Predictive markers for prognosis

Answer 22

Arrays, AML subtypes (t(11q23)/MLL, t(8;21), t(15;17), inv(16))
Correlate with prognosis outcome

Question 23

Predictive markers for therapeutic response

Answer 23

HER2 positive growth factor receptor, over expression found in 30% breast tumours, Herceptin antibody drug targeted to HER2 dampens effects of overactive HER2