3.2 Carcinogenesis Flashcards
1
Q
Carcinogenesis: categories of disrupted systems (3)
A
- Oncogenes
- Tumor suppressor genes (p53, Rb, APC)
- Regulators of apoptosis (Bcl2)
2
Q
Categories of oncogenes (5). Picture sequence of cell growth signalling.
A
- Growth factors
- Growth factor receptor
- Signal transduction proteins
- Nuclear transcription factors
- Cell cycle regulators
3
Q
Oncogenes: growth factors
- example (1)
- associated tumor?
A
- PDGF, overexpression
- Astrocytoma (glial cell)
4
Q
Oncogenes: growth factor receptors
- examples (1 major + 2 others)
- associated tumor
A
- ERBB2 [HER2/neu]–Human Epidermal GF Receptor
- breast carcinoma
- blocked by Trastuzumab - RET–neural GF receptor
- MEN (multiple endocrine neoplasia) - KIT–stem cell GF receptor
- GI stromal tumor
5
Q
Oncogenes: signal transducers
- examples (1 major, 1 other)
- mech
A
- Ras.
- signal transducer through nuclear membrane
- in 25% of tumors (carcinoma, lymphoma, melanoma) have defect in this.
- activated by GTP; overactivated when GAP has defect, so increased growth signals - ABL–tyrosine kinase
- CML, some types of ALL
6
Q
Oncogenes: Nuclear transcription factors
- examples (1 major, 2 others)
- mech/etiology
- associated tumor
A
- c-Myc
- t(8:14) with IgH
- Burkitt’s lymphoma (B cells)
- “starry sky appearance” - N-Myc
- Neuroblastoma - L-Myc
- Lung carcinoma
7
Q
Oncogenes: Cell cycle regulators
- examples (1 major, 1 other)
- mech/etiology
A
- CCND1 (cyclin D1)
- controls G1 to S by making a complex (binds with CDK4–a cyclin dependent kinase) that activates Rb to release “the key” of E2F
- t(11:14) with IgH, causes overexpression of CCND1
- Mantle cell carcinoma (subtype of B Cell lymphoma) - CDK4–cyclin-dependent kinase
- see above, binds with cyclin D1 for same effect on Rb
- Melanoma
8
Q
Tumor suppressor genes:
- classic examples (2) + 1 other
- mech
A
- p53
- 2 traffic cops: “show me your DNA” before going from G1 to S
- if errors repairable, increase expression of repair enzymes
- if errors not repairable, induce apoptosis with BAX, which inhibits Bcl2, allowing Cyt C to leak. - Rb
- also regulates G1 to S
- Rb “tightly holds the key” of E2F, a TF necessary for transition to S
- E2F is released normally when Rb is phosphorylated by a complex (cyclin D1/CDK4)
- Familial retinoblastoma (in eyes) - APC
- reduces beta catenin
- familial adenomatous polyposis
9
Q
Li-Fraumeni syndrome
A
- One of the 2 p53 genes has germline mutation
- remember, p53 is the 2 traffic cops that check G1 to S
- more likely to develop a variety of tumors
10
Q
Knudson 2-hit hypothesis
A
- Both of the classic tumor suppressors contain 2 copies
- p53
- Rb
- APC
- so, both require double ‘hit’ to disable
11
Q
BAX
A
- Bcl2 Associated X protein
- released by p53 (traffic cops) when a cell needs to undergo apoptosis
- inhibits Bcl2, allowing Cytc C to leak
12
Q
PDGF
- what is it
- associated cancer
A
- oncogene, GF category
- Platelet derived growth factor
- Astrocytoma (glial cell)
13
Q
ERBB2 (HER2/neu)
- what is it, mech
- associated tumor
A
- Epidermal GF receptor, oncogene
- (Human Epidermal GF Receptor 2). overexpressed in cancer
- associated with breast carcinoma
14
Q
Ras
- what is it
- mech
A
- family of signal transducer genes (GTP-binding protein)
- oncogenes; 25% of tumors have defect in Ras
- activated by GTP. GAP converts GTP to GDP.
15
Q
c-Myc
- what is it
- mech of disorder
- associated tumor
A
- “michael burkitt, born August 14”
- oncogene, nuclear TF
- t(8:14) with IgH causes overexpression of c-Myc.
- Burkitt’s lymphoma (also associated with EBV)
16
Q
Cyclin D1 (CCND1)
- what is it
- mech of disorder
- associated cancer
A
- ‘November 14: division 1 cyclist bikes through the earth’s mantle’
- oncogene, cell cycle regulator
- complexes with CDK4 to activate Rb, making it release its “key” of E2F, allowing cells to undergo G1 to S
- Mantle cell lymphoma, 11:14
17
Q
Familial retinoblastoma
A
- One of the 2 Rb tumor suppressor genes has germline mutation
- retina cells develop tumors if the remaining copy of Rb becomes defective
- remember, Rb holds on to the “key” of E2F that controls G1 to S
18
Q
E2F
A
- the “key” protein held tightly by the 2 Rb tumor suppressor proteins
- E2F allows cells to undergo G1 to S
19
Q
Bcl2
- mech
- what inactivates it
- associated cancer
A
- Controller of apoptosis
- keeps Cyt C in mito from leaking out to cause apoptosis
- BAX (Bcl2 activating X factor) released from p53 inactivates Bcl2, leading to apoptosis
- Bcl2 is overexpressed in follicular lymphoma–t(14:18)–B cells destined to die accumulate in lymph node follicle
20
Q
Angiogenesis factors
A
- FGF (fibroblast GF)
2. VEGF
21
Q
ABL
- what is it
- mech of disorder
- associated tumor
- Tx
A
- ‘Able company was sent to fight the camels of the 9-22 terrorist attack on Philadelphia’
- signal transducer gene (tyrosine kinase)
- t(9:22)– 22 is Philadelphia chromosome
- CML, some types of ALL
- Tx with imatinib mesylate (Gleevec)
22
Q
KIT
- what is it
- mech of disorder
- associated tumor
- tx
A
- ‘kit kat bar in the stomach’
- stem cell GF receptor gene
- point mutation
- overexpression leads to Gastrointestinal stromal tumor (GIST)
- Tx with Imatinib mesylate (Gleevec)–tyrosine kinase inhibitor
23
Q
APC
- mech
- associated cancer
A
- ‘2 APCs attacking a fapping beta cat’
- tumor suppressor gene
- 2 genes, 2 ‘hits’
- down-regulates beta-catenin, which is a TF and mediates cell-cell adhesion
- Familial Adenomatous polyposis (FAP) from loss of APC
24
Q
HPV
- role in oncogenesis
- identify the low and high risk types
A
-cervical cancer
-E6, E7
E6: inhibits p53
E7: inhibitis Rb and p53
low risk: 6, 11 (A6, F1111)
high risk: 16, 18, 31, 33 (F16, F18, Su33, Mig31)
25
EBV
| -role in oncogenesis
- infects B cells.
- can cause Burkitt's lymphoma if 8:14 c-myc overexpression also occurs.
- also cause other B cell problems
26
Hep B, C
| -role in oncogenesis (2 mechs)
- liver cancer, 2 mechs:
1. chronic regeneration, aka regenerative nodular hyperplasia (B, C)
2. HBx protein inhibits p53, activates growth genes (B only)
27
H. Pylori
| -role in oncogenesis
2 tumors:
1. gastric adenocarcinoma
2. MALToma
-host inflamm response leads to carcinogenesis--metaplasia
28
Microorganisms associated with oncogenesis
| -list them and ex of associated cancer
1. EBV--Burkitt's lymphoma
2. HHV-8--Kaposi's sarcoma
3. Hep B, Hep C--hepatocellular carcinoma
4. HTLV-1: Adult T-cell leukemia/lymphoma
5. HPV--cerical carcinoma
29
HTLV-1
| -associated with what?
- oncogenic virus (human T lympotropic virus)
| - associated with Adult T-Cell leukemia/lymphoma
30
HHV-8
| -associated with what?
- Onocogenic virus (human herpes virus 8)
| - associated with Kaposi sarcoma
31
proto-onconegenes vs oncogenes: difference?
Oncogenes are mutated proto-oncogenes
32
Trastuzumab
- monoclonal Ab, blocks ERBB2 (HER2) receptor, a GF receptor in breast cancer
- tx in breast cancer
33
Imatinib mesylate (Gleevec)
-tyrosine kinase inhibitor
34
Burkitt's lymphoma
| -etiology: factors
- increased expression of c-MYC
| - associated with EBV
35
N-MYC
| -associated tumor
- nuclear TF, onocogene
| - Neuroblastoma when N-MYC is overexpressed
36
Mantle cell lymphoma
- on november 14, a Division 1 cyclist bikes through the earth's mantle.
- cyclin D1, 11;14
37
Familial adenomatous polyposis (FAP)
- 2 APCs attack the fapping beta cat
| - loss of APC leads to high levels of beta catenin, activating growth TFs
38
beta-catenin
- think :'fapping beta cat attacked by 2 APCs'
- 2 functions: TF and mediates cell-cell adhesion
- accumulation causes cancer
- accumulation occurs when both APC genes are mutated.
39
polycyclic aromatic hydrocarbons
- what are they
- how metabolized and detoxified?
-carcinogen in smoke
- CYP1A1--metabolizes polycyclic aromatic hydrocarbons into toxic form
- 10% of caucasians have highly-inducible form
- glutathione S-transferase--detoxifies it
- 50% of caucasians have deletions
40
initiator vs promoter in carcinogens
- initiator: directly causes permanent mutation
| - promotor: allows proliferation of mutated cells
