cancer

Question 1

hallmarks of cancer cells

Answer 1

self-sufficiency in growth signals
insensitivity to anti-growth signals
evading apoptosis
limitless replicative potential
sustained angiogenesis
metastasis

Question 2

oncogene

Answer 2

mutated proto-oncogene
preserves function of original protein
over-expressed
hyperactive
arises from dominant mutations

Question 3

proto-oncogenes

Answer 3

genes that control cell division
encode proteins that promote cell growth (TFs, GFs, GFRs, PKs)
mutate into oncogenes

Question 4

mechanisms to convert proto-oncogene to oncogene

Answer 4

deletion (point) mutation in coding region
regulatory mutation in non-coding promoter region
gene amplification
chromosome rearrangement

Question 5

types of oncogenes

Answer 5

Her receptors
Ras protein
c-Fos and c-Myc

Question 6

neurofibromatosis

Answer 6

mutation in gene NF1 that encodes for neurofibromin
neurofibromin inactivates Ras by hydrolyzing GTP to GDP
loss of NF1 function –> no inactivation of RAS –> constitutively active Ras –> cell proliferation

Question 7

Her receptors

Answer 7

human epidermal receptors
receptor tyrosine kinases, form dimers
binding of EGF triggers receptor dimerization, activation of kinase domain, then auto-phosphorylation and MAP kinase cascade

Question 8

Ras

Answer 8

G-protein downstream of receptors for many GFs
part of MAP kinase cascade
mutations can cause Ras to become constitutively active if uncoupled from binding of GF
clinical correlate: neurofibromatosis

Question 9

c-FOS and c-MYC

Answer 9

unstable transcription factors
levels are increased by stimulation of quiescent cells
oncogenic versions may be stable, leading to inappropriate activation of downstream targets in absence of growth factors

Question 10

Burkitt’s lymphoma

Answer 10

aka non-Hodgkin’s
translocation moves c-MYC gene from chromosome 8 to chromosome 14
new location is near genes encoding antibody heavy chains, regulated by promoter elements of these genes
constitutively active c-MYC can cause B-cells to become cancerous

Question 11

tumor supressors

Answer 11

anti-growth factors
inhibit cell proliferation when cell is not ready to divide or DNA is damaged
loss of function –> loss of sensitivity to anti-growth signals –> cancer cell proliferation and tumor growth
encode proteins that inhibit cell proliferation
mutations are recessive
“two hit” model of tumorigenesis
mutations increase risk of cancer

Question 12

Rb

Answer 12

protein that inhibits cell cycle progression by binding E2F proteins
keeps E2F in inactive form, not allowing it to stimulate transcription of genes required for DNA replication in S phase
mutation in Rb –> no signal to inhibit cell cycle progression in absence of GF –> E2F is uninhibited

Question 13

retinoblastoma

Answer 13

rare childhood cancer
impacts RB1 gene that encodes Rb protein in immature cells of retina
two forms:
hereditary (one defective allele inherited, other is somatic mutation)
sporadic (two independent somatic mutations in same retinal cell, less common)

Question 14

p53

Answer 14

transcription factor
encoded by TP53 gene
regulates cell cycle progression
monitors DNA damage
unstable due to association with Mdm2–targets p53 for destruction by proteasomes
in response to DNA damage, ATM phosphorylates p53, displacing Mdm2, rendering p53 more stable
p53 activates p21, which arrests cell cycle

Question 15

Li-Fraumeni syndrome

Answer 15

hereditary cancer predisposition
caused by inherited dominant defects in TP53
disrupted function of p53 tetramer
cells with damaged DNA continue to divide, accumulating damage –> tumor development

Question 16

HPV-induced cervical cancer

Answer 16

HPV expresses two proteins E6 and E7

these proteins inhibit p53 and Rb and assist in their degradation, thereby inducing cell proliferation

Question 17

caretaker genes

Answer 17

responsible for integrity of genome
do not directly affect cell proliferation
inactivation of caretaker genes can cause rapid accumulation of DNA damage, leading to cancer

Question 18

BRCA1 and BRCA2

Answer 18

caretaker genes
regulate repair of DS DNA breaks during homologous recombination
deliver effector proteins
in their absence, homologous recombination is impeded, allowing accumulation of mutations
clinical correlation: HBOC

Question 19

angiogenesis

Answer 19

formation of new blood vessels from pre-existing vessels to supply nutrients and O2 to tumors
allows transition from benign to malignant state
hypoxia = pro-angiogenic
triggers stabilization of Hif1α (not hydroxylated form), which escapes degradation
Hif1α pairs with Hif1β activating transcription of genes that promote angiogenesis (including VEGF)

Question 20

MMPs

Answer 20

matrix metalloproteases
involved in metastasis
secreted by tumor cells
break down basement membrane (collagen, laminin)
generates signals to cell surface receptors on tumor cells, stimulating migration

Question 21

FAP

Answer 21

familial adenomatous polyposis
nonmalignant polyps, but prone to develop into carcinomas
mutations in APC gene, which encodes tumor suppressor APC protein
APC negatively regulates growth promoting signals via Wnt signaling pathway

Question 22

HNPCC

Answer 22

hereditary nonpolyposis colorectal cancer
mutation in MSH2 or MLH1, involved in pathway of DNA mismatch repair
MSH2 involved in identifying DNA mismatch error
MLH1 involved in repairing error
in absence of functional mismatch repair, mutations accumulate –> microsatellite instability –> reduction in BAX –> survival of cells that should die

Question 23

Philadelphia chromosome translocation

Answer 23

fusion of BCR and ABL
ABL gene is tyrosine kinase
fusion generates hybrid BCR-ABL tyrosine kinase
constitutively active –> cell proliferation
when fusion occurs in bone marrow, results in increase in WBCs –> CML

Question 24

imatinib mesylate

Answer 24

Gleevec
used in treatment of CML
tyrosine kinase inhibitor, inhibits BCR-ABL fusion complex
reduces proliferation of CML cells
patients can become resistant

Question 25

trastuzumab (Herceptin)

Answer 25

used in treatment of Her2 breast cancer
monoclonal antibody that binds extracellular domain of Her2
potent anti-tumor effects, unclear mechanism

Question 26

ipilimumab

Answer 26

used in treatment of melanoma
monoclonal antibody that binds CTLA4, an inhibitory receptor on surface of T cells
blocking this allows T cells to remain reactive and fight tumor cells

Question 27

tamoxifen

Answer 27

used in treatment of breast cancer
antagonist of estrogen
estrogen can stimulate cell proliferation by binding ER (estrogen receptor)
prevents estrogen from binding to receptor, blocking cancer cell growth

Question 28

two hit model of tumorigenesis

Answer 28

individuals born with germline mutation (one mutated allele) require an independent mutation (somatic mutation) in second allele of same gene to allow for tumor progression

Question 29

HBOC

Answer 29

hereditary breast and ovarian cancer
autosomal dominant disorder
if one copy of BRCA1/2 is mutated in germline, person is at increased risk for breast, ovarian, and other cancers
loss of second allele results in cancer

Question 30

TP53 mutation

Answer 30

most common genetic alterations found in human cancers

results in nonfunctional p53 tetramer, leading to cancer

Question 31

PARP

Answer 31

polyADP-ribose polymerase
protein involved in repair of SS DNA breaks
inhibition of PARP can destroy BRCA1 and BRCA2-deficient breast cancer cells
if PARP is inhibited, cancer cells cannot survive DNA damage
currently developing PARP inhibitors for treatment

Question 32

E6 and E7

Answer 32

proteins expressed by HPV that inhibit and degrade p53 and Rb, leading to cervical cancer

Question 33

Mdm2

Answer 33

responsible for instability of p53
functions as E3 ubiquitin ligase, targeting p53 for destruction by proteasome
displaced when ATM is activated

Question 34

VEGF

Answer 34

vascular endothelial growth factor
gene that promotes angiogenesis
results in development of angiogenic gradient, stimulating growth of new vessels

Question 35

steps of tumor invasion and metastasis

Answer 35

a

Question 36

APC

Answer 36

tumor suppressor
inhibits Wnt signaling pathway, thereby leading to destruction of β catenin and inhibiting cell proliferation
when mutated in FAP, β catenin is free to enter nucleus and stimulate cell proliferation

Question 37

Wnt signaling pathway

Answer 37

promotes cell proliferation
via activation of β catenin, which translocates to nucleus and activates transcription of genes including c-MYC and cyclins
inhibited by APC