Cancer Flashcards
1
Q
overgrowth of normal tissues
A
hyperplasia (hypertrophy)
2
Q
lack of growth (lack of tissue)
A
aplasia (atrophy)
3
Q
overgrowth of dysregulated tissue
A
Transformation
4
Q
normal growth of abnormal tissues
A
dysplasia
5
Q
process by which cells take on cancer properties (immortalized/ uncontrolled growth)
A
transformation
6
Q
_________ occurs when:
- loss of control cell cycle/proliferation
- tissue invasion
- autonomous growth factor, angiogenesis
- avoidance of immune surveillance
A
malignancy/cancer
7
Q
Malignant transformation is characterized by formation of malignant/cancerous tissue from _______ tissue
A
benign
8
Q
Normal gene that acquires mutation or over expression to drive transformation
Multiple mechanisms of activation:
mutation
gene amplification/overexpression
novel gene fusion/chromosomal rearrangement
A
proto-oncogene
9
Q
ALV picks up src to be v-src to become RSV, which is _________ for chickens
A
oncogenic
10
Q
c-MYC
Ras
Her2/neu
are examples of ________
A
human proto-oncogenes
11
Q
Burkitt’s lymphoma (and other B cell lymphomas) can have ______ be ontogenically activated by specific chromosomal translocations
Can be activated by retrovirus mediated promoter insertion
Activation by rearrangement in B cell
A
c-myc
12
Q
Adenovirus (E1)
Polyomavirus (T Ag)
HPV (E6, E7)
A
DNA tumor viruses (important genes for transformation)
13
Q
E1A, T Ag, E7 inhibit Rb, which is a ________________ that normally inhibits E2F (TF)
A
tumor-suppressor gene
14
Q
E1B T Ag E6 inhibit p53, protecting a tumor cell from ________
A
apoptosis
15
Q
Retinoblastoma is often an inherited cancer. Many cancer have genetic predispositions, but are caused by _________ mutations
A
sporadic
16
Q
Rb and p53 __________ is common in retinoblastoma and many cancers
A
inactivation
17
Q
Sources of cancer heterogeneity
A
Inter and intra tumoral heterogeneity
Selection of resistance features key to cancer spread and drug resistance
18
Q
Tumors have _________ changes in genetic/genomics plus gremlin variation
A
somatic
19
Q
Recurrent mutation pattern for ___________ is “hotspot” activating mutations
A
oncogenes
20
Q
Recurrent mutation pattern for ___________ is scattered, open stop gains or insertions/deletions
A
tumor suppressor genes
21
Q
Simplest idea for personalized cancer treatment with targeted therapy is to target oncogene activation with ____________
(novel oncogenes/fusion products good targets: BCR-ABL1)
Other proto-oncogenes, toxicity is a concern (targeting normal proteins)
A
small molecule inhibitors
22
Q
Targeting of ER signaling in breast cancer
_______ block aromatase, so estrogen is not produced
A
Aromatase inhibitors
23
Q
Targeting of ER signaling in breast cancer
_______ compete with estrogen for binding to the ER
A
SERMs (selective estrogen receptor modulators)
Tamoxifen
24
Q
Upregulation of bypass pathway or ER mutations are primary ways for an ER+ breast cancer to become _______
A
resistant
25
CML is a myeloproliferative, malignant clonal disorder affecting the ____________ cell
pluripotent hematopoietic stem cell
26
Triphasic clinical course of CML
Chronic
Accelerated
Blast crisis
27
Neutrophil differentiation becomes progressively impaired and leukocytes counts are more difficult to control
Phase in CML
Accelerated phase
28
CML phase resembling acute leukemia in which myeloid or lymphoid blasts fail to differentiate
Blast crisis
29
Genetic cause of CML
Philadelphia translocation (balanced translocation between 9 and 22) that results in bcr-abl fusion
30
__________ is a disregulated tyrosine kinase protein capable of both auto- and substrate phosphorylation.
Constitutively active
Bcr-Abl
31
```
_____________ active BCR-ABL induces tyrosin P of many proteins and leads to:
Resist apoptosis
Changes in adhesion
Unstable cytogenetics
Proliferative advantage for Ph+ cells
```
Constitutively
32
Imatnib mesylate (Gleevec) occupies the ATP binding pocket of Abl kinase domain to prevents substrate P and signaling, which inhibits proliferation and survival
Selectively inhibits Bcr-Abl fusion
Treatment for:
CML
33
How is cancer an evolutionary process?
Darwinian corollary: There is tremendous selection for mutations that circumvent growth restrictions
(Nowell model)
34
How many driver mutations needed?
3-8
35
Two main ways mutation rate can be increased
Exposure to metabolic or environmental mutagens
| Inactivate mutation avoidance pathway
36
The genome load of pre-mutagenic DNA lesions depends on the rate of lesion production and the efficiency of __________
lesion rectification
37
DNA damage can result from:
Exogenous factors
Endogenous factors
Mutagens, error
38
UV dimers and large, bulky lesions rectified by
NER (nucleotide excision repair)
39
______
complex (XPA-G) recognizes damage and excises portion of damaged strand spanning lesion
DNA sun using undamaged strand as template
Ligase
NER (njcelotide excision repair)
40
Example of ____
OGG1 and MutY are DNA glycosylases that cleave the bond lining the base to deoxyribose
(OGG1 removes GO when paired with C, MutY removes A when paired with GO)
Baseless site is repaired by an AP endonuclease, DNA pol b, and ligase
BER (Base excision repair)
41
____________ (error-free) initiates by transfer of broken strand into a complementary region of homology DNA helix
DNA syn using hom helix as template
BRCA1 (signaling) and BRCA2 (direct) required in human cells
Homologous recombination
42
________ corrects replication erros
Products of MSH2, MSH6, MLH1, and PMS2 genes required for initiation
MSH2-MSH6 and MLH1-PMS2 heterodimers assemble at mismatch and recruit other required proteins
System relies on secondary signals in the helix to identify new DNA strand. A portion of the new strand spanning the replication error is excised and resynthesized.
MMR (mismatch repair)
43
abnormal chromosome number
aneuploidy
44
abnormal recombination events
chromosome rearrangements
45
failure to repair chemical/photo-chemical base damage and replication errors
base substitution and small insertion/deletion mutations
46
_______ mutations are extremely common in cancer cells
Somatic
47
```
Xeroderma pigmentosum: an _____ disease
Rare, aut rec.
UV - skin cancer
XPA-G defects
UV dimers
```
NER (nucleotide excision repair)
48
```
MYH-associated polyposis colon cancer: a _____ disease
Rare rec.
Defective in removal of A-8oxG
G-C to T-A tranversion
colon polyps
```
MutY
49
```
Lynch syndrom (hereditary nonpolyposis colon cancer): a _________ disease
MSH2, MLH1, MSH6, or PMS2 defect
Inheriting only one - strong predisposition
Frequent base substitution, small insertion/deletion mutations (micro satellite instability)
```
Mismatch Repair (MMR)
50
Hereditary breast cancer: a _________ disease
BRCA1 or BRCA2
nheriting only one - strong predisposition
Chromosome breaks and rearrangements
Double-strand break repair
51
Inheritance of only one copy a defective gene for Lynch or BRCA gives strong predisposition because inactivation of the wild type allele by _____ mutation occurs
(Not really dominant)
somatic
52
___________ of both MLH1 promoters by cytosine methylation of CpG sequences leads to tc block, fail to produce MLH1, mismatch repair deft
Biallelic silencing
53
```
Steps in _________
Primary tumor
1. invasion (EMT)
2. intravasation
3. systemic dissemination
4. extravasation
5. dormancy
6. colonization (MET)
Secondary tumor
```
metastasis
54
Circulating tumor cells often use _______ as travel companions to help them survive
platelets
55
Cancer cells need to change their _______ properties, to lose their adhesion and to penetrate through potent physical barriers (basal lamina and CT)
epithelial
56
```
Certain cancer have more propensity to metastasize to a certain target organ
Depends on:
pattern of blood flow
Organ specific factors
Tumor progression
Immune system
```
Metastatic tropism
57
_________ is inefficient (in and out of circulation is hard)
Metastasis
58
Some tissues secrete _________ that simulate proliferation of cancer cells
growth factors
59
The blood can be a harsh environment because:
cells are normally anchorage-dependent (anoikis)
| shear forces tear cells apart
60
Hypoxia increases metastasis by inducing ________ which crosslinks ECM proteins and CXCR4 to bind to SDF-1
lysyl oxidase
61
During EMT, cancer cells lose ___________ which normally forms adherens junctions. Loss of this protein means it no longer binds Beta catenin, which drives Wnt gene expression (stem cell traits)
Also:
cell shape changes to round driven by Rho GTPases, MMPs
Other TFs besides b-catenin: Zeb1, Twist, Snail
E-cadherin
62
_________ converts plasminogen to the active protease plasmin, which degrades basal lamina and ECM and activates MMPs
Plasminogen activator
63
Anti-Apoptotic genes can act as __________
oncogenes
64
Pro-apoptotic genes can act as
tumor suppressors
65
Follicular lymphoma is characterized by a t(14;18) that juxtaposes the _________ gene with the immunoglobulin heavy chain gene and leads to over expression of that gene
Bcl-2
66
Bcl-2 is over expressed in follicular lymphoma. Bcl-2 is ____-apoptotic
Anti-apoptotic
67
Bcl-2 prevents _________ upon withdrawal from growth factor
prevents cell death (intrinsic)
68
Intrinsic cell death is regulated at the _________ and initiated by cyt c, Apaf1, and caspase 9 (Bcl-2 inhibits cyt c release)
mitochondria
69
Apaf1 or Capspase 9 deficiency promote cellular __________
transformation
70
p53 is a nuclear protein ____________ tumor suppressor that regulates expression and Bcl-2, Bax, Puma, Noxa (BH3 only), etc. to lead to apoptosis (also induces p21 for cell cycle arrest)
transcription factor
71
p53 activates ______ (pro-apoptotic) directly or via induction of the BH3-only protein Puma (can sequester anti-apoptotic proteins such as Bcl2, helps promote apoptosis)
Max
72
_______ Bcl-2 function to promote apoptosis
```
Through:
antisense oligonucleotide (oblimersen)
Structural mimics (of BH3)
```
Block
73
________ works as a survival mechanism for cancer cells
| Can block with chloroquine to block lysosomal degradation
Autophagy
74
Puma is _____ apoptotic, because it inhibits Bcl-2 (Bcl-2 which inhibits Bax)
pro-apoptotic
75
de novo formation of blood vessels requiring differentiation of endothelial cells from their embryonic precursors
vasculogenesis
76
the sprouting of new capillaries from pre-existing vascular structure
angiogenesis
77
_________ is important for growth and development, wound healing, menstruation, ovulation, placental development, exercise
angiogenesis
78
Excessive __________ is implicated in cancer, atherosclerosis, obesity, psoriasis, diabetic retinopathy, arthritis
angiogenesis
79
Insufficient __________ is associated with stroke, atherosclerosis, hypertension
angiogenesis
80
Multiple endothelial _____ and their ligands directly regulate angiogenesis
VEGF/VEGFR
Angiopoietin/Tie
Ephrin/Eph
RTKs (receptor tyrosine kinases)
81
VEGF is __________________, resulting in multiple variants with distinct effects
alternatively spliced
82
The prototypical angiogenic stimulus is __________ which is a polypeptide growth factor secreted by most cell types in response to hypoxia
vascular endothelial growth factor (VEGF)
83
Steps of ___________
Protease production (basement membrane breakdown)
Recruitment of leukocytes and bone marrow-derived progenitor cells
Endothelial cell migration (nascent vascular sprouts)
Endothelial cell proliferation (sprout elongation)
Capillary morphogenesis (still leaky)
Vascular maturation (NOT regulated by VEGF, regulated by Ang1, Tie2)
angiogenesis
84
VEGF is one of the most potent endothelial ___________
mitogens
85
Maturation into a fully functional vessel acts as ___________ on VEGF
negative feedback
86
____________ and VEGF regulate the transition between mature and remodeling vessels
Angiopoietins
87
VEGF and _______ regulate tip cell formation
Decrease, get more sprouts
Increase, get less sprouts (more stalk)
Notch
88
Hypoxia-inducible factor (HIF) 1 alpha protein is stabilized by _______
hypoxia
89
Turmor vessels lack normal _________ signals
| Chaotic geometry with no hierarchy
maturation
90
Theoretical advantages of anti-angiogenic drugs
| VEGF mAb - bevacizumab/avastin
avoiding or delaying drug resistance
91
Bevacizumab (VEGF mAb) causes in increase in ___________ events
(higher levels of adhesion factors)
thromboembolic events
92
VE-PTP inhibits Tie2 (TKR) signaling through dephosphorylation and blocks vascular ____________
Want Tie2 to work, want to target an inhibit VE-PTP
VE-PTP can lead to early tumor growth, established tumor growth and micrometastatsis
normalization
93
VE-PTP inhibition promotes humor vascular normalization through _____
Tie2
94
______ binds the Tie2 RTK and activation of Tie2 in this setting is important for stabilization and maintenance of the vasculature
Ang1
95
If vessel is perturbed and needs to be remodeled, ______ is expressed and competes with Ang1 to bind Tie2 and disrupt its signaling
May promotes vascular regression through endothelial cell apoptosis
Ang2
