Carcinogenesis - Molecular Hallmarks of Cancer Cells (21) Flashcards Preview

EMS - Mechanisms of Disease > Carcinogenesis - Molecular Hallmarks of Cancer Cells (21) > Flashcards

Flashcards in Carcinogenesis - Molecular Hallmarks of Cancer Cells (21) Deck (23):
1

Caretaker genes (TSG)

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

2

Gatekeeper genes (TSG)

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

3

Carcinogens and TSGs

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

4

2nd hit inactivation of TSG

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

5

Retinoblastoma

RB1/Retinoblastoma (Gatekeeper)

6

Li-Fraumeni

p53/Sarcomas, breast (Gatekeeper/care taker)

7

Familial adenomatous polyposis

APC/Colorectal (Gatekeeper)

8

Familial breast cancer

BRCA1/BRCA2, Breast, ovarian (Care taker)

9

Hereditary non-polyposis colorectal cancer

hMLH1, hMSH2, colon, endometrial (Care taker)

10

Proto-oncogenes

Promote cell proliferation, survival, angiogenesis and inhibit of apoptosis

11

Oncogenes

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

12

Mechanisms of oncogene activation

Translocation, point mutation, amplification

13

Multi-step tumourigenesis

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

14

Self-sufficiency in growth signals

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)

15

Insensitivity to antigrowth signals

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

16

Telomeres

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

17

Evading apoptosis

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)

18

Sustained angiogenesis

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)

19

Tissue invasion and metastasis

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)

20

Prostate-specific antigen

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

21

CA-125 serum antigen

Ovarian cancer - not good at detecting early stage disease

22

Predictive markers for prognosis

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

23

Predictive markers for therapeutic response

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