Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
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
|
proto-oncogenes
|
|
|
inappropriately activated proto-oncogene, either by mutation or aberrant expression
|
oncogene
|
|
|
aberrant expression may refer to what two mechanisms of expression
|
over-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 |
c-cis
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 |
|
|
src
|
non-receptor protein-tyrosine kinase signal transduction molecule
|
|
|
cytoplasmic serine/theronine kinase signal transduction molecule
|
raf
|
|
|
GTP binding protens serving as signal transduction molecules
|
ras
|
|
|
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
|
Rb
|
|
|
there is LOH or Rb in what kind of cancers
|
retinobalstomas, osteosarcomeas, adenocarcinomas, etc..
|
|
|
induces G1 cell cycle arrest by inhibiting CDK4 and CDK6
|
CDKIp16
a cyclin-dependent kinase inhibitor |
|
|
four key regulators of the cell cycle
|
p16
cyclin D CDK4 Rb one of the four is usually altered in malignancies |
|
|
mutations of this guardian of the genome are inovlved in 50% of cancers
|
p53
|
|
|
the most common target of genetic alterations in sporadic human malignancies
|
p53
|
|
|
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
|
HPV E6
|
|
|
binds Rb and displaces E2F transcrption factors
is encode in Viral genome |
HPV E7
|
|
|
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
|
Rb
|
|
|
Li-Fraumeni syndrome is caused by a mutation in
|
p53
|
|
|
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
|
p16
|
|
|
neurofibromin mutation causes
|
neurofibromatosis
|
|
|
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
|
p53
|
|
|
hayflick index
|
after many replication cycles cell reaches hayflick index which indicates that there is to much telomeric esosion - cell arrests in Go
|
|
|
Telomerase
|
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
|
hypoxia
|
|
|
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
|
endostatin
|
|
|
a 38kD internal fragment of plasminogen which is an angiogenesis inhibito
|
angiostatin
|
|
|
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)
|
Cadherins
|
|
|
"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
|
cadherins
|
|
|
complexed with cytoskeleton via family of cytoplasmic proteins (alpha, beta, gamma)
|
cadherins
|
|
|
signalling pathways involving cadherins regulate what four things
|
cell proliferation
apoptosis differentiation, cell motility |
|
|
loss of cadherins correlates with
|
increaed invasiveness and met
|
|
|
transmembrane receptors for basement membrane components and other ECM molecules
|
integrins
|
|
|
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
|
integrins
|
|
|
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
|
DCC
p53 |
|
|
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
|
cytokines
|
|
|
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
|
|
|
Herceptin is used against
|
metastatic breast cancer
|
|
|
erbB2 is also called
|
Her-2/neu
|
|
|
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
|
Zevalin
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
|
