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Path3 > Neoplasia > Flashcards

Neoplasia Flashcards

1
Q

somatic mutation hypothesis of cancer

A

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

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2
Q

3 classes of genes involved in cancer

A

growth promoters
growth suppressors
caretakers

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3
Q

Growth Promoters

A

mutations ACTIVATE encoded protein

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4
Q

growth suppressors

A

mutations INACTIVATE encoded protein

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5
Q

caretakers

A

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

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6
Q

6 phenotypic hallmarks of cancer

A

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

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7
Q

gene products involved in apoptosis or cell senescence

A
  • pro or anti-apoptotic proteins

- immortalization genes (telomerase)

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8
Q

landscaper genes

A

proteins involved in regulating angiogenesis

proteins involved in cell-cell and cell-matrix adhesion

proteolytic enzymes req for invasion

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9
Q

proto-oncogene

A

gene that encodes a protein that mediates or stimulates cell proliferation

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10
Q

oncogene

A

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

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11
Q

6 types of proteins encoded by oncogenes

A
  • growth factors
  • growth factor receptors
  • signal transduction molecules
  • steroid hormone receptors
  • transcription factors
  • cell cycle proteins
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12
Q

ex of growth factor

A

v-sis which encodes PDGF in an autocrine stimulation loop

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13
Q

ex of growth factor receptor

A

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

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14
Q

ex cell cycle proteins

A

cyclins and CDKs

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15
Q

ras

A

GTP binding protein involved in signal transduction from RTKs

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16
Q

ki ras

A

lung, ovarian, pancreatic cancer

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17
Q

N-ras

A

leukemias

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18
Q

3 ex signal transduction molecules

A
  • non-receptor protein tyrosine kinases: src
  • cytoplasmic serine/threonine kinases: raf
  • GTP-binding proteins: ras
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19
Q

dominant mutations

A

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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20
Q

ras pathway

A

growth factor receptor (tyrosine kinase)

  • ->adaptor proteins
  • ->ras GDP-GTP exchange
  • ->raf
  • ->MEK
  • -> MAP-kinase
  • ->activated transcription factor (SRF)
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21
Q

Ras mutations that diminish GTPase activity

A

increase ras signaling output (because cant break down GTP)

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22
Q

gene amplification mechanism

A

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

ex-burkit lymphoma

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23
Q

chromosome rearrangement mechanism

A

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

ex-philadelphia chromosome

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24
Q

ex of nuclear regulatory factor

A

persistant expression or overexpression of myc transcription factor in

  • neuroblastoma/glioblastoma (n-myc)
  • small cell lung cancer (l-myc)
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25
Q

philadelphia chromosome

A

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

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26
Q

why are TSG sometimes referred to as recessive oncogenes?

A

both alleles of a TSG must be “knocked out” for transformation– knocking a gene that normally inhibits tumor growth

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27
Q

loss of heterozygosity

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

one band on PCR- LOH

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28
Q

4 mechanisms of LOH

A
  • mitotic recombination
  • chromosome mis-segregation during mitosis (nondisjunction during G2/M checkpoint–>deletion of WT allele
  • epigenetic gene inact
  • random pt mutation (unlikely)
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29
Q

four key regulators in cell cycle

A

p16
cyclin D
CDK4
Rb

30
Q

regulator of G1/S phase transition

A

Rb

31
Q

Rb inhibits by

A

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

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

32
Q

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

A

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

33
Q

p53 mech

A

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
Q

MDM2

A

binds to p53 and inactivates it

35
Q

how do DNA viruses induce neoplasia

A

encode proteins that bind and inactivate TSGs

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

36
Q

how many gatekeeper gene does each cell type have

A

only one or a few

37
Q

caretaker genes

A

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
Q

three major types of DNA repair systems

A

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

39
Q

Hereditary non-polyposis colon cancer (HNPCC)

A
  • mismatch repair gene issue
  • -decreased proofreading capacity–>errors in repetitive nucleotide sequences, so they will have expansions or contractions in DNA (instability)
40
Q

xeroderma pigmentosum

A

-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
Q

BRCA1, BRCA2

A

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
Q

autosomal dominant cancer list

A 
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
Q

autosomal recessive

A

zeroderma pigmentosum- dna excision repair

ataxia-telangiectasia- defective DNA repair sensor

Bloom syndrome- recomb repair defect

fanconi anemia- recomb repair defect

44
Q

2 methods to evade apoptosis

A
  • dysregulation of anti-apoptotic signals

- loss of pro-apoptotic signals

45
Q

apoptotic signaling pathways

A

PTEN, Akt, p53, bax, bid

46
Q

Hayflick index

A

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
Q

crisis stage of cell

A

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
Q

in order for tumors to grow, they MUST

A

induce an accompanying blood supply (angiogenesis)

49
Q

formation of new blood vessels is dependent on

A

ratio of angiogenic inducers to anti-angiogenic agents

–tipping the balance during tumorgenesis–>angiogenic switch

50
Q

angiogenesis inducers

A

VEGF, bFGF

51
Q

VEGF

A

upregulated by hypoxia and often upregulated near areas of tumor necrosis

52
Q

VHL

A

inhibits VEGF

part of the ubiquitin igase complex–mediates HIF1, resulting in HIF1 degradation

53
Q

if VHL keeps HIF1 levels low..

A

prevents production of VEGG and other angiogenic factors

54
Q

angiogenesis inhibitors

A

angiostatin
endostatin
altered antithrombin III
thrombospondin-2

55
Q

what else is also angiogenesis dependent?

A

metastasis

56
Q

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

A 
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
Q

cadherins

A

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

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

58
Q

TIMPs`

A

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
Q

integrin switching

A

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

60
Q

malignant cells and integrins

A

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

basis for anchorage independent growth

61
Q

growth factors stimulate

A

tumor cell motility

IGF, FGFs, TGF-b, hepatocyte growth factor

62
Q

what helps protect tumor cells in circulation?

A

tumor cell interactions with fibrin, platelets, and clotting factors

63
Q

how do tumor cells avoid immune surveillance

A

“cloak” tumor-specific antigens and inactivate leukocytes in the vicinity

64
Q

3 targets of therapy for metastasis

A

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

65
Q

MMPIs

A

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

66
Q

taxanes

A

block microtubule cycling

67
Q

CAI

A

inhibits Ca influx through non-voltage gated Ca channels

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

68
Q

clonal progression

A

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
Q

tumor heterogeneity

A

not all cells in a tumor carry the same genetic defects

70
Q

DNA methylation

A

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

hypermeth around TSG

71
Q

molecular therapeutics

A
  • specific antagonists
  • cytotoic monoclonal antibodies (binds to specific tuors that overexpress tumor specific antigen)
  • molecualr therapy targeting oncogene products (TK inhibitors)
  • antisense oligodeoxynucleotides
72
Q

differentiation therpay

A

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

Path3 (11 decks)

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