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120 Cards in this Set

  • Front
  • Back
play a role in imortalization genes
telomeres - involved in cell senescence
Proteins athta are involved in regulating angiogenesis
cell-cell and cell-matrix adhesion
and proteolytic enzymes required for invasion are referred to as
"landscaper genes" looking outward
genes with produts that repair DNA
caretaker genes
gene that encodes a protein that mediates or stimulates cell proliferation
inappropriately activated proto-oncogene, either by mutation or aberrant expression
aberrant expression may refer to what two mechanisms of expression
ectopic expression
6 types of proteins encoded by oncogenes
growth factors
growth factor receptors
signal transduction molecules
steriod hormone receptors
transcription factors
cell cycle proteins
encodes platelet derived growth factor (PDGF).
is proto-oncogene
works via the autocrine stimulation loop

oncogene v-sis
EGF-Receptor Family are what kind of proto-oncogenes
transmembrane receptor tyrosine kinasesa

Growth Factor Receptor

this receptor has increase expression and increased sensitivity
growth factor receptor overexpressed in 80% of squamous cell carcinomas of the lung
EGF-R (c-erB1)
amplified in some breast, ovary, lung, stomach CAs

growth factor Receptor
HER2-neu (c-erbB2)

the receptor has increased expression and increased sensitivity
non-receptor protein-tyrosine kinase signal transduction molecule
cytoplasmic serine/theronine kinase signal transduction molecule
GTP binding protens serving as signal transduction molecules
single most comomon abnormality of dominant oncogenes in human tumas
ras gene

Ki-ras involved in lung, ovarian, colon and pancreatic cancers
Gain of function mutations are dominant. what is one qualitative change
changes in the structure (loss of regulatory elements) resulting in abnormal gene product (oncoprotein) with uncontrolled, aberrant function e.g ras
up-regulation or ectopic expression of a structurally normal growth-promoting protein is a dominant or recessive mutation
e.g breast cancer cells often produce excess of cyclin D and Cyclin E
Quantitiative dominant
disease which is an example where a proto-oncogene has ben placed adjacent to a powerful tissue specific promotor, resulting in an overexpression

(chromosomal translocation leads to activaiton of oncogene)
Ig genes in B-cells (t(8;14))
C-myc-IgH in Burkitt lymphoma
first chromosomal abnormality ever linked to specific cacner
Philadelphia chromosome
t(9;22) fuses the proto oncogene c-abl w/ gene called bcr

loss of regulatory domains

bcr fusion protein has incread tyrosine kinase actvity and abnormal cellular localization
amplified in 20-25% of breast carcinomas
a growth receptor which has increased expression and therefore increased sensitivity
HER2-neu, cerbB2

correlates with high grade and short survival - correlates with node positive patients
bcr-abl fusion protein has increased tyrosine kinase activity and abnormal cellular localization refers to what chromosome
philadelphia chromosome
STI571 as therapy targeting oncogene products
a phenylaminopyrimidine molecule which is a signal transduction inhibitor which occupies the kinase pocket of the BCR-ABL protein and blocks access to ATP, therby preventing phosphorylation of any substrate

inhibits constitutive RTK activity
Cell fusion experiments by Henry Harris showed that
genes derived from normal cell can inhibit (or suppress) the tumorigenic phenotype
demonstrated that "cancer is a recessisve trait"
The Two-Hit Hypothesis of Alfred Knudson explained what
the physical or functional loss of one allele is followed by the elimination or damage of the remaining normal copy
when detected LOH - if one copy of the gene is deleted, we see what on PCR
only one band by PCR
"hot spots"
prevalence of LOH differs at different positions w/in genomeand is more prevalent at certain hot spots wihch are locations of TSGs
detecting LOH by PCR is based off the idea that
DNA sequences are normally slightly different in various regions (heterozygous)
failed cell cycle checkpoints results in
either apoptosis or genomic instability
Primary regulotory protein of the G1/S phase transition
there is LOH or Rb in what kind of cancers
retinobalstomas, osteosarcomeas, adenocarcinomas, etc..
induces G1 cell cycle arrest by inhibiting CDK4 and CDK6
a cyclin-dependent kinase inhibitor
four key regulators of the cell cycle
cyclin D
one of the four is usually altered in malignancies
mutations of this guardian of the genome are inovlved in 50% of cancers
the most common target of genetic alterations in sporadic human malignancies
dominant negative mutations
e.g p53
mutation in one allele prevents function of the other (usally by physical association, such as dimerization)
why are p53 levels often up-regulated in cancer
mutations reduce/alter p53 function But ALSO increase its half-life perhaps by altered MDM2 binding
binds to and promotoes the degradation of p53 - is coded in virus genome
binds Rb and displaces E2F transcrption factors

is encode in Viral genome
kind of TSGs which do not promote tumorigenesis directly
caretaker genes

inactivaiton leads to increased mutation of all genes leading to accelerated tumorigenesis
disease caused by defective excission of pyrimidine dimers (defective nucleotide excision repair) (damage to a type of caretaker gene)
xeroderma pigmentosum

sensitivity to light and increased skin cancer
disease caused by mutatnt mismatch repair genes (hMSH2, hMLH1, hPMs2, etc)
Hereditary non polposis colocn cancer syndrome (HNPCC)
loss of function results in replication error (RER) which can be detected by
microsatellite instability (MSI)
macrosatellites are
tandem repeats of oneto six nucleotides scarttered throughout genome and are fixed for life and are same in every tissue
microsatellites in normal vs tumor tissue differ why
in RER (replication error), there are expansions and contractions of these repeats in tumor cells
retinoblastoma is caused by a mutation in
Li-Fraumeni syndrome is caused by a mutation in
Defective APC gene causes

APC is gatekeeper gene present in colonic epithelial cells
Famililial adenomatous polyposis
familial atypical multiple mole melanoma syndrome is caused by a mutation in
neurofibromin mutation causes
BRCA1 or BRCA2 mutation caues
which are recombination repair genes and play a role in double st breaks
Familial breast / ovarian cancer
DNA mismatch repair gene defects causes
Hereditary Non-polyposis colon cancer (HNPCC)
xeroderma pigmentosum is caued by a defect in
DNA excision repair
ataxia telangiectasia is caused by a defective
DNA repair "sensor"
Bloom syndrome is caused by a
recombination repair defect
Fanconi anemia is cuaed by
recombination repair defect
cancer treatment depends on the cells ability to
undergo apoptosis

when apoptosis pathways are mutated - there is increased risk of resistance to therapy
the most curable cancers are those in which what pathway is intact
hayflick index
after many replication cycles cell reaches hayflick index which indicates that there is to much telomeric esosion - cell arrests in Go
in germ and stem cells and lots in tumor

enables the cell to resonstruct telomeres
four triggers of apoptosis
chemo, XRT, hypoxia
genetic damage
GF or cytokine withdrawel
Loss of cohesion/adhesion
e.g of apoptosis modulator family
BCl-2/Bax family
what kind of tumors are the most curable (p53 is not mutated)
hematopeoietic and germ cell tumors
sensecence can be circumvented by disabling what two pathways
pRb and p53
progressive shortening of telomeres is attributed to
inability of DNA polymerases to completely replicate the 3' ends of chromosomal DNA during each S phase
erosion of telomeres eventuallyu causes them to lose the ability to
protect the ends of chromosomal DNA
replicative generations are counted by the loss of how many bps of telomeric DNA during each cell cycle
50-100 bp
ends of chromosomes which are not protected by telomeres can participate in what kind of fusion
end to end
after the erosion of telomeres what might lead to crises and death of affected cell
karyotipic disarray
mutation of VHL (von Hippel Landale tumor suppressor protein) gene leads to what
increased expression of VEGF
what stimulates VEGF
Folkman's lab proposed
primary tumors may secreted angiogenic inhibitors which supress metastases from differnt types of tumors
a secretable anti-angiogenic protein
thrombospondin-2 (TSP-2)
a 20kD internal fragment of collagen XVIII which is an angiogenesis inhibitor
a 38kD internal fragment of plasminogen which is an angiogenesis inhibito
how does neoangiogenesis aid in a tumor's ability to enter microcirculaiton
it is leaky and discontinous
how many circulating tumor cells survive to initiate a metastatic focus
1 in 10,000
transmembrane glycoproteins that mediate circulating cells (in lung and liver)
"soil and seed" hypothesis
tumor cells have membrane receptors for molecules present in sites of prefered metatastasis.
mediate homotypic cell-cell interactions at adherens junctions
complexed with cytoskeleton via family of cytoplasmic proteins (alpha, beta, gamma)
signalling pathways involving cadherins regulate what four things
cell proliferation
cell motility
loss of cadherins correlates with
increaed invasiveness and met
transmembrane receptors for basement membrane components and other ECM molecules
focal adhesion kinase pathways do what what three things
regulate apoptosis, proliferation, and cell motility
integrin switching causes what three things to happen
tumor cells alter integrin expressoin patterns

decreased adhesion to BM
increased adhesion to ECM
increased migration over ECM
Matrix metalloproteinases (MMPs) and collagenases screted by tumor cells due what
destroy BM
how does a tumor influence tissue inhibitors of Metalloproteinases (TIMPs)
down regulated by tumor
two benefits to tumor cell interactions with fibrin, platelets, and clotting factors
1. protect tumor cells in circulation from immune and non-immune destruction
2. facilitation of attachment to endothelial cells
probably responsible for adhesion to vascular basement membrane
most frequent locaiton of distant metastases will usually be based on
first capillary bed encountered by tumor cells
most frequent location of distant metastases is usually what two organs
lung and liver - extensive vascular beds; slow flow
antagonists of avB3 induce
vascular cell apoptosis and inhibit angiogenesis by blocking endothelial cell-matrix interactions
Matrix Metalloproteinase inhibitors used in therapy do what
block degradation of matrix, blocks activation of proteases, growth factos
anti-invasive properties in vitro and anti-angiogenic properties in vivo
taxanes block
microtubule cycling and therefore cell motility
the anti-motility agent carboxyamido-triazole inhibits motility by
inhibiting calcium influx
what does the adenoma-carcinoma sequence in colorectal cancers tell us
illustrates the stepwise accumulation of mutations that occur in each of the pre-malignant morphological phases
the concept of tumor heterogeniety
not all cells in a tumor carry the same genetic defect
loss of the tumor-supressor gene APC occurs early in the process of transformation in colorectal cancer when does hypomethylation of DNA occur?
what about activation of Ki-ras
ealry adenomoa stage

activaiton of oncogene Ki-ras occurs in carcinoma in situ
in late disease of colonrectal cancer, what two things are lost
epigentic change means
heritable modification of the genome that does not involve a change in the DNA sequence
are epigentic mechanisms reversible
yes and act over large distances and usually result in gene silencing
DNA methylation has what effect on gene expression
shuts it down
in malignant cells - what might you see in terms of methylation state
hypomethylation w/ foci of hypermethylation around TSGS
reversion of the malignant phenotype can be achieved by
reprogramming epigenetic changes induced by differentiation
abnormal development in myeloid leukemia cells can be reprogrammed by appropriate differentiation inducing
microarray-based assays detects?

this correlates with (re tumor)
reproducible patterns of methylated CpG dinulceotides in tumor DNA
correlates to tumor type and stage!!

Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumour suppressor genes). Conversely, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells.
reversal of epigenetic changes has enormous potential for cancer therapy - this would involve inhibiting
methylation of DNA - it has been shown to induce terminal differentiation and inhibit growth of several types of tumor in the laboratory
humanized form of murine antibody directed against extracellular domain of the oncogene c-erbB2
Herceptin is used against
metastatic breast cancer
erbB2 is also called
Herceptin only works in tumors that over express
erbB2 (Her2)
side effect of Herceptin
cardiotoxicity - especially when used with adriamycin
how does mylotarg work
chimeric antibody which binds CD33 on acute myeloid leukemia cells and is internalized

its a type of cytotoxic monoclonal Ab treatment
an anti CD20 Ab that is complexed with radionuclide yttrium-90

first radioimmuno-therapeutic agent to be tested in clinical trials. treatment for non-hodgkins lymphoma
two mechanisms by which inflammation may cause cancer
generation of promutagenic reactive oxygen species

increased cell turnover
HPV proteins (E7 and E6) bind
7 - Rb
6 - p53

rapidly degraded so mimics mutation or deletion of Rb and p53
Hep C is an RNA virus which does not have reverse transcriptase - how does it cause cancer
proteins transcribed from viral genome interact with and inactivate protein products of cellular tumor suppressor genes thus deregulating control of cell division
PanIN grades
dysplasia index

PanIN-1 is mild
to PanIN-3 (severe)
laser capture microdissection (LCM)
method for isolating pure cells of interets from specific microscopic region of tissue
siRNAs (genetically engineered antisense expression vectors) are used to
block transcription or translation of oncoproteins. disapointing results due to systemic toxicity