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Flashcards in Neoplasia Deck (72):
1

somatic mutation hypothesis of cancer

cell growth, differentiation, and survival are under genetic control and malignant transformation is due to mutations in specific classes of genes

2

3 classes of genes involved in cancer

growth promoters
growth suppressors
caretakers

3

Growth Promoters

mutations ACTIVATE encoded protein

4

growth suppressors

mutations INACTIVATE encoded protein

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caretakers

doesnt inhibit or activate, but promotes stability of genome (proteins involved in DNA repair)-- when inactivated, likelihood of mutation events in either oncogenes or tumor suppressor genes increases

6

6 phenotypic hallmarks of cancer

1) dysregulation of cell proliferation (too proliferative)
2) insensitivity to growth inhibitory signals
3) evasion of apoptosis
4) limitless replicative potential
5) angiogenesis
6) invasion and metastasis

7

gene products involved in apoptosis or cell senescence

-pro or anti-apoptotic proteins
-immortalization genes (telomerase)

8

landscaper genes

proteins involved in regulating angiogenesis

proteins involved in cell-cell and cell-matrix adhesion

proteolytic enzymes req for invasion

9

proto-oncogene

gene that encodes a protein that mediates or stimulates cell proliferation

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oncogene

inappropriately activated proto-oncogene, either by mutation or changed expression

11

6 types of proteins encoded by oncogenes

-growth factors
-growth factor receptors
-signal transduction molecules
- steroid hormone receptors
-transcription factors
-cell cycle proteins

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ex of growth factor

v-sis which encodes PDGF in an autocrine stimulation loop

13

ex of growth factor receptor

transmembrane receptor tyrosine kinase
EGF-R in lung
HER-2-neu in other parts

14

ex cell cycle proteins

cyclins and CDKs

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ras

GTP binding protein involved in signal transduction from RTKs

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ki ras

lung, ovarian, pancreatic cancer

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N-ras

leukemias

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3 ex signal transduction molecules

- non-receptor protein tyrosine kinases: src
- cytoplasmic serine/threonine kinases: raf
-GTP-binding proteins: ras

19

dominant mutations

gain of function
-Qualitative: changes in structure of gene resulting in uncontrolled function
-Quantitative: up-regulation of expression of structurally normal protein

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ras pathway

growth factor receptor (tyrosine kinase)
-->adaptor proteins
-->ras GDP-GTP exchange
-->raf
-->MEK
--> MAP-kinase
-->activated transcription factor (SRF)

21

Ras mutations that diminish GTPase activity

increase ras signaling output (because cant break down GTP)

22

gene amplification mechanism

place proto-oncogene adjacent to powerful tissue-specific promoter, resulting in overexpression

ex-burkit lymphoma

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chromosome rearrangement mechanism

can create fusion genes--result in unregulated or aberrant activity and transformation

ex-philadelphia chromosome

24

ex of nuclear regulatory factor

persistant expression or overexpression of myc transcription factor in

-neuroblastoma/glioblastoma (n-myc)
-small cell lung cancer (l-myc)

25

philadelphia chromosome

fuses proto-oncogene c-abl with gene bcr, with loss of abl-regulatory domains

26

why are TSG sometimes referred to as recessive oncogenes?

both alleles of a TSG must be "knocked out" for transformation-- knocking a gene that normally inhibits tumor growth

27

loss of heterozygosity

-inheritance of one defective copy of TSG
-second hit- transformation occurs

one band on PCR- LOH

28

4 mechanisms of LOH

-mitotic recombination
- chromosome mis-segregation during mitosis (nondisjunction during G2/M checkpoint-->deletion of WT allele
-epigenetic gene inact
-random pt mutation (unlikely)

29

four key regulators in cell cycle

p16
cyclin D
CDK4
Rb

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regulator of G1/S phase transition

Rb

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Rb inhibits by

shutting down E2F-->repress transcription of a number of genes

regulated by cyclin D/CDK -->phos and inact Rb-->release E2F

32

why do people only get tumors like retinoblastomas and osteosarcomas with Rb mutation?

we don't know- in most tissue, defective E2f triggers apoptosis in p53 manner, maybe these are resistant

33

p53 mech

Dna damage--P53-->activates CDK inhibitor P21-->induces cell cycle arrest at G1 and G2 to try to repair-->if cant repair, p53 triggers apoptosis

34

MDM2

binds to p53 and inactivates it

35

how do DNA viruses induce neoplasia

encode proteins that bind and inactivate TSGs

ex) HPV E6- binds and degrades P53 and HPV E7- binds under-phosed form of RB

36

how many gatekeeper gene does each cell type have

only one or a few

37

caretaker genes

prevent mutation

mutation means that if the DNA has a damage, it cant be repaired and may lead to cancer

behave genetically like TSG

38

three major types of DNA repair systems

1) Mismatch repair genes
2) Nucleotide excision repair genes
3) recombination repair genes

39

Hereditary non-polyposis colon cancer (HNPCC)

- mismatch repair gene issue
--decreased proofreading capacity-->errors in repetitive nucleotide sequences, so they will have expansions or contractions in DNA (instability)

40

xeroderma pigmentosum

-nucleotide excision repair issue

normal skin fibroblasts repair UV radiation dmage to DNA by inserting new pases after ecision of pyrmidine dimers, but if you have this disease you can't do that and can develop skin cancer

41

BRCA1, BRCA2

recombination repair genes issue

women have mutations in these have lifetime risks of breast and ovarian cancer

- genes are thought to play a role in repair of doble strand DNA breaks, recombination, etc

42

autosomal dominant cancer list

retinoblastoma-rb
Li-fraumeni syndrome- p53
familial adenomatous polyposis- apc gene
familial atypical multiple mole melanoma- p16
neurofibromatosis- neurofibromin
breast/ovarian- brca1, brca2
HNPCC- dna mismatch

43

autosomal recessive

zeroderma pigmentosum- dna excision repair

ataxia-telangiectasia- defective DNA repair sensor

Bloom syndrome- recomb repair defect

fanconi anemia- recomb repair defect

44

2 methods to evade apoptosis

-dysregulation of anti-apoptotic signals
-loss of pro-apoptotic signals

45

apoptotic signaling pathways

PTEN, Akt, p53, bax, bid

46

Hayflick index

normal cells can divide 50-60 times before telomeric erosion

cells that have been transformed go well beyond this and eventualy reach a second phase termed "crisis"

47

crisis stage of cell

a cell in crisis usually dies, but can sometimes escape and reach crisis and become immortalized

often will have resumed expression of telomerase, or found another way to avoid senescence

48

in order for tumors to grow, they MUST

induce an accompanying blood supply (angiogenesis)

49

formation of new blood vessels is dependent on

ratio of angiogenic inducers to anti-angiogenic agents
--tipping the balance during tumorgenesis-->angiogenic switch

50

angiogenesis inducers

VEGF, bFGF

51

VEGF

upregulated by hypoxia and often upregulated near areas of tumor necrosis

52

VHL

inhibits VEGF
part of the ubiquitin igase complex--mediates HIF1, resulting in HIF1 degradation

53

if VHL keeps HIF1 levels low..

prevents production of VEGG and other angiogenic factors

54

angiogenesis inhibitors

angiostatin
endostatin
altered antithrombin III
thrombospondin-2

55

what else is also angiogenesis dependent?

metastasis

56

in order to metastasize, tumor cells must have the following properties (8)

1- detachment
2- matrix degradation
3- cell-matrix attachments
4- angiogenesis
5- motility and migration
6- vascular extravasation
7- avoiding immune survellinace
8- survive and proliferate in new foreign microenvironment

57

cadherins

transmembrane glycoprotiens that mediate homotypic cell-cell interactions at adherens junctions

loss of cadherin gene-->metastatsis therefore, function at tumor/metastasis suppressor

58

TIMPs`

tissue inhibitors of metalloproteinases--

tumor cells destroy local basement membrane and invade stroma -->enter lymphatic or blood vessels

if they decrease expression of these it helps

59

integrin switching

tumor cells often show altered integrin expression patterns--> results in decreased adhesion to BM and increased adhesiveness and migrration over alternative ECM components

60

malignant cells and integrins

indifferent to loss of integrin-mediated signaling and resist apoptotic signals generated by detachment from matrix components

basis for anchorage independent growth

61

growth factors stimulate

tumor cell motility

IGF, FGFs, TGF-b, hepatocyte growth factor

62

what helps protect tumor cells in circulation?

tumor cell interactions with fibrin, platelets, and clotting factors

63

how do tumor cells avoid immune surveillance

"cloak" tumor-specific antigens and inactivate leukocytes in the vicinity

64

3 targets of therapy for metastasis

1) anti-adhesive agents
2) matrix metalloproteinase inhibitors (MMPIs)
3) Anti-motility agents

65

MMPIs

block degradaton of matrix, activation of proteases, and release of matrix-bound growth factors

66

taxanes

block microtubule cycling

67

CAI

inhibits Ca influx through non-voltage gated Ca channels

therefore inhibits proliferation, production of MMP2, motility, and signaling of endothelial cells

68

clonal progression

involves successive rounds of mutation adn natural selection

repeated rounds of mutation and selection for cells with increasing capacity for proliferation--how they get stronger with time

69

tumor heterogeneity

not all cells in a tumor carry the same genetic defects

70

DNA methylation

methylation of C in Cpg islands--> down regulates gene expression

hypermeth around TSG

71

molecular therapeutics

-specific antagonists
-cytotoic monoclonal antibodies (binds to specific tuors that overexpress tumor specific antigen)
-molecualr therapy targeting oncogene products (TK inhibitors)
-antisense oligodeoxynucleotides

72

differentiation therpay

tumor cells are often unable to differnetiate

forcible induction of differentiation

most effective-ATRA- rearrangement between PML and RAR a genes- activates RARa ligand complexes-->myeloid differentation