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120 Cards in this Set
- Front
- Back
play a role in imortalization genes
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telomeres - involved in cell senescence
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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
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genes with produts that repair DNA
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caretaker genes
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gene that encodes a protein that mediates or stimulates cell proliferation
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proto-oncogenes
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inappropriately activated proto-oncogene, either by mutation or aberrant expression
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oncogene
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aberrant expression may refer to what two mechanisms of expression
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over-expression
ectopic expression |
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6 types of proteins encoded by oncogenes
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growth factors
growth factor receptors signal transduction molecules steriod hormone receptors transcription factors cell cycle proteins |
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encodes platelet derived growth factor (PDGF).
is proto-oncogene works via the autocrine stimulation loop |
c-cis
oncogene v-sis |
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EGF-Receptor Family are what kind of proto-oncogenes
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transmembrane receptor tyrosine kinasesa
Growth Factor Receptor this receptor has increase expression and increased sensitivity |
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growth factor receptor overexpressed in 80% of squamous cell carcinomas of the lung
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EGF-R (c-erB1)
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amplified in some breast, ovary, lung, stomach CAs
growth factor Receptor |
HER2-neu (c-erbB2)
the receptor has increased expression and increased sensitivity |
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src
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non-receptor protein-tyrosine kinase signal transduction molecule
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cytoplasmic serine/theronine kinase signal transduction molecule
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raf
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GTP binding protens serving as signal transduction molecules
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ras
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single most comomon abnormality of dominant oncogenes in human tumas
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ras gene
Ki-ras involved in lung, ovarian, colon and pancreatic cancers |
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Gain of function mutations are dominant. what is one qualitative change
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changes in the structure (loss of regulatory elements) resulting in abnormal gene product (oncoprotein) with uncontrolled, aberrant function e.g ras
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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
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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 |
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first chromosomal abnormality ever linked to specific cacner
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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 |
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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 |
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bcr-abl fusion protein has increased tyrosine kinase activity and abnormal cellular localization refers to what chromosome
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philadelphia chromosome
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STI571 as therapy targeting oncogene products
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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 |
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Cell fusion experiments by Henry Harris showed that
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genes derived from normal cell can inhibit (or suppress) the tumorigenic phenotype
demonstrated that "cancer is a recessisve trait" |
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The Two-Hit Hypothesis of Alfred Knudson explained what
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the physical or functional loss of one allele is followed by the elimination or damage of the remaining normal copy
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when detected LOH - if one copy of the gene is deleted, we see what on PCR
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only one band by PCR
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"hot spots"
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prevalence of LOH differs at different positions w/in genomeand is more prevalent at certain hot spots wihch are locations of TSGs
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detecting LOH by PCR is based off the idea that
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DNA sequences are normally slightly different in various regions (heterozygous)
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failed cell cycle checkpoints results in
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either apoptosis or genomic instability
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Primary regulotory protein of the G1/S phase transition
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Rb
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there is LOH or Rb in what kind of cancers
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retinobalstomas, osteosarcomeas, adenocarcinomas, etc..
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induces G1 cell cycle arrest by inhibiting CDK4 and CDK6
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CDKIp16
a cyclin-dependent kinase inhibitor |
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four key regulators of the cell cycle
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p16
cyclin D CDK4 Rb one of the four is usually altered in malignancies |
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mutations of this guardian of the genome are inovlved in 50% of cancers
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p53
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the most common target of genetic alterations in sporadic human malignancies
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p53
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dominant negative mutations
e.g p53 |
mutation in one allele prevents function of the other (usally by physical association, such as dimerization)
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why are p53 levels often up-regulated in cancer
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mutations reduce/alter p53 function But ALSO increase its half-life perhaps by altered MDM2 binding
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binds to and promotoes the degradation of p53 - is coded in virus genome
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HPV E6
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binds Rb and displaces E2F transcrption factors
is encode in Viral genome |
HPV E7
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kind of TSGs which do not promote tumorigenesis directly
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caretaker genes
inactivaiton leads to increased mutation of all genes leading to accelerated tumorigenesis |
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disease caused by defective excission of pyrimidine dimers (defective nucleotide excision repair) (damage to a type of caretaker gene)
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xeroderma pigmentosum
sensitivity to light and increased skin cancer |
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disease caused by mutatnt mismatch repair genes (hMSH2, hMLH1, hPMs2, etc)
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Hereditary non polposis colocn cancer syndrome (HNPCC)
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loss of function results in replication error (RER) which can be detected by
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microsatellite instability (MSI)
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macrosatellites are
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tandem repeats of oneto six nucleotides scarttered throughout genome and are fixed for life and are same in every tissue
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microsatellites in normal vs tumor tissue differ why
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in RER (replication error), there are expansions and contractions of these repeats in tumor cells
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retinoblastoma is caused by a mutation in
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Rb
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Li-Fraumeni syndrome is caused by a mutation in
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p53
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Defective APC gene causes
APC is gatekeeper gene present in colonic epithelial cells |
Famililial adenomatous polyposis
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familial atypical multiple mole melanoma syndrome is caused by a mutation in
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p16
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neurofibromin mutation causes
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neurofibromatosis
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BRCA1 or BRCA2 mutation caues
which are recombination repair genes and play a role in double st breaks |
Familial breast / ovarian cancer
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DNA mismatch repair gene defects causes
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Hereditary Non-polyposis colon cancer (HNPCC)
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xeroderma pigmentosum is caued by a defect in
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DNA excision repair
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ataxia telangiectasia is caused by a defective
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DNA repair "sensor"
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Bloom syndrome is caused by a
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recombination repair defect
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Fanconi anemia is cuaed by
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recombination repair defect
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cancer treatment depends on the cells ability to
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undergo apoptosis
when apoptosis pathways are mutated - there is increased risk of resistance to therapy |
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the most curable cancers are those in which what pathway is intact
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p53
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hayflick index
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after many replication cycles cell reaches hayflick index which indicates that there is to much telomeric esosion - cell arrests in Go
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Telomerase
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in germ and stem cells and lots in tumor
enables the cell to resonstruct telomeres |
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four triggers of apoptosis
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chemo, XRT, hypoxia
genetic damage GF or cytokine withdrawel Loss of cohesion/adhesion |
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e.g of apoptosis modulator family
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BCl-2/Bax family
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what kind of tumors are the most curable (p53 is not mutated)
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hematopeoietic and germ cell tumors
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sensecence can be circumvented by disabling what two pathways
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pRb and p53
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progressive shortening of telomeres is attributed to
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inability of DNA polymerases to completely replicate the 3' ends of chromosomal DNA during each S phase
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erosion of telomeres eventuallyu causes them to lose the ability to
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protect the ends of chromosomal DNA
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replicative generations are counted by the loss of how many bps of telomeric DNA during each cell cycle
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50-100 bp
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ends of chromosomes which are not protected by telomeres can participate in what kind of fusion
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end to end
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after the erosion of telomeres what might lead to crises and death of affected cell
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karyotipic disarray
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mutation of VHL (von Hippel Landale tumor suppressor protein) gene leads to what
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increased expression of VEGF
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what stimulates VEGF
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hypoxia
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Folkman's lab proposed
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primary tumors may secreted angiogenic inhibitors which supress metastases from differnt types of tumors
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a secretable anti-angiogenic protein
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thrombospondin-2 (TSP-2)
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a 20kD internal fragment of collagen XVIII which is an angiogenesis inhibitor
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endostatin
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a 38kD internal fragment of plasminogen which is an angiogenesis inhibito
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angiostatin
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how does neoangiogenesis aid in a tumor's ability to enter microcirculaiton
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it is leaky and discontinous
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how many circulating tumor cells survive to initiate a metastatic focus
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1 in 10,000
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transmembrane glycoproteins that mediate circulating cells (in lung and liver)
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Cadherins
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"soil and seed" hypothesis
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tumor cells have membrane receptors for molecules present in sites of prefered metatastasis.
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mediate homotypic cell-cell interactions at adherens junctions
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cadherins
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complexed with cytoskeleton via family of cytoplasmic proteins (alpha, beta, gamma)
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cadherins
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signalling pathways involving cadherins regulate what four things
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cell proliferation
apoptosis differentiation, cell motility |
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loss of cadherins correlates with
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increaed invasiveness and met
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transmembrane receptors for basement membrane components and other ECM molecules
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integrins
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focal adhesion kinase pathways do what what three things
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regulate apoptosis, proliferation, and cell motility
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integrin switching causes what three things to happen
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tumor cells alter integrin expressoin patterns
decreased adhesion to BM increased adhesion to ECM increased migration over ECM |
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Matrix metalloproteinases (MMPs) and collagenases screted by tumor cells due what
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destroy BM
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how does a tumor influence tissue inhibitors of Metalloproteinases (TIMPs)
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down regulated by tumor
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two benefits to tumor cell interactions with fibrin, platelets, and clotting factors
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1. protect tumor cells in circulation from immune and non-immune destruction
2. facilitation of attachment to endothelial cells |
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probably responsible for adhesion to vascular basement membrane
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integrins
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most frequent locaiton of distant metastases will usually be based on
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first capillary bed encountered by tumor cells
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most frequent location of distant metastases is usually what two organs
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lung and liver - extensive vascular beds; slow flow
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antagonists of avB3 induce
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vascular cell apoptosis and inhibit angiogenesis by blocking endothelial cell-matrix interactions
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Matrix Metalloproteinase inhibitors used in therapy do what
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block degradation of matrix, blocks activation of proteases, growth factos
anti-invasive properties in vitro and anti-angiogenic properties in vivo |
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taxanes block
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microtubule cycling and therefore cell motility
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the anti-motility agent carboxyamido-triazole inhibits motility by
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inhibiting calcium influx
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what does the adenoma-carcinoma sequence in colorectal cancers tell us
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illustrates the stepwise accumulation of mutations that occur in each of the pre-malignant morphological phases
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the concept of tumor heterogeniety
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not all cells in a tumor carry the same genetic defect
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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 |
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in late disease of colonrectal cancer, what two things are lost
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DCC
p53 |
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epigentic change means
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heritable modification of the genome that does not involve a change in the DNA sequence
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are epigentic mechanisms reversible
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yes and act over large distances and usually result in gene silencing
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DNA methylation has what effect on gene expression
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shuts it down
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in malignant cells - what might you see in terms of methylation state
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hypomethylation w/ foci of hypermethylation around TSGS
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reversion of the malignant phenotype can be achieved by
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reprogramming epigenetic changes induced by differentiation
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abnormal development in myeloid leukemia cells can be reprogrammed by appropriate differentiation inducing
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cytokines
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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. |
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reversal of epigenetic changes has enormous potential for cancer therapy - this would involve inhibiting
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methylation of DNA - it has been shown to induce terminal differentiation and inhibit growth of several types of tumor in the laboratory
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humanized form of murine antibody directed against extracellular domain of the oncogene c-erbB2
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Herceptin
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Herceptin is used against
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metastatic breast cancer
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erbB2 is also called
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Her-2/neu
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Herceptin only works in tumors that over express
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erbB2 (Her2)
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side effect of Herceptin
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cardiotoxicity - especially when used with adriamycin
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how does mylotarg work
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chimeric antibody which binds CD33 on acute myeloid leukemia cells and is internalized
its a type of cytotoxic monoclonal Ab treatment |
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an anti CD20 Ab that is complexed with radionuclide yttrium-90
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Zevalin
first radioimmuno-therapeutic agent to be tested in clinical trials. treatment for non-hodgkins lymphoma |
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two mechanisms by which inflammation may cause cancer
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generation of promutagenic reactive oxygen species
increased cell turnover |
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HPV proteins (E7 and E6) bind
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7 - Rb
6 - p53 rapidly degraded so mimics mutation or deletion of Rb and p53 |
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Hep C is an RNA virus which does not have reverse transcriptase - how does it cause cancer
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proteins transcribed from viral genome interact with and inactivate protein products of cellular tumor suppressor genes thus deregulating control of cell division
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PanIN grades
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dysplasia index
PanIN-1 is mild to PanIN-3 (severe) |
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laser capture microdissection (LCM)
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method for isolating pure cells of interets from specific microscopic region of tissue
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siRNAs (genetically engineered antisense expression vectors) are used to
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block transcription or translation of oncoproteins. disapointing results due to systemic toxicity
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