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89 Cards in this Set
- Front
- Back
what are protooncogenes?
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they are the genes responsible for regulating cell growth
they become oncogenes only after a mutation has occured only a single gene allele mutation is required for this |
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what are the growth factors we are concerned about
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PDGF-B
FGF |
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what is PDGF-B a gene product of and what cancers arise from its mutation
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sis
glioblastoma |
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what is FGF a gene product of and what cancers arise from its mutation
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HST
gastric sarcomas Karposi's sarcoma |
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what do growth factors bind to?
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tyrosine kinase domains
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what happens to tyrosine kinase activity during oncogenesis
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they autodimerise
I.E. turn on by themselves |
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genes responsible for EDGF receptor
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ERB-1: EGFR
ERB-2: Her-2 neu |
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what does a mutation in the FLT-3 receptor gene lead to? what is the receptor
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leukemia
FMS-like TK3 |
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what gene makes the neutrotrophic growth factor receptor and what does its mutation lead to
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RET
endocrine tumors |
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mutations in KIT lead to?
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GI stromal tumors
leukemias |
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what cancers arise from mutations of ERB-1
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carcinomas of the lung, head, and neck
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what cancer therapies are directed at EGFR
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monoclonal Ab therapy
tyrosine kinase inhibitors |
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what cancers are corrilated to ERB-2 mutations
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25% of breast cancers
Poor prognosis with this mutation |
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treatment for cancers with mutated ERB-2/ Her2 neu genes
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trastuzamab
monoclonal Ab that prevents TK activity and leads to apoptosis |
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what is the most common oncogene mutation
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RAS
20% of all human tumors |
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what type of cancers arise from RAS mutations
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adenocarcinomas
hematologic malignancies |
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How does a RAS oncogene happen?
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point mutations
typically chemically induced |
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how is RAS activated and what is its cascade pathway
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growth signal
GDP to GTP binds RAF and activates MAP K pathway |
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how is RAS inactivated
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intrinsic GTPase activity
GAP (GTPase activating protein) - NF-1 is a GAP |
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what is different about a mutated RAS?
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it evades GAP (NF-1) and remains bound to GTP
I.E. remains active |
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what type of cancers develop from the mutated KRAS
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colon
Lung Pancreatic |
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what type of cancers develop from the mutated HRAS
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UT carcinomas
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what type of cancers develop from the mutated NRAS
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melanomas
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how many alleles must be inactivated for a cancer to develop via an oncogene (growth factor)? tumor suppressors?
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one for oncogenes
two for suppressors |
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what is cABL
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a non-receptor tyrosine kinase
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how does cABL become an oncogene
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when it is translocated to BCR
bcr-abl oncogene= persistant signal transduction |
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what types of metastases are associated with a bcr-abl mutation
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chronic myelogenous leukemia
some acute lymphoblastic leukemias |
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what is the effective treatment for a bcr-able mutation
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imatinib
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what is JAK2
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a nonrecepter tyrosine kinase in the JAK-STAT pathway
a point mutation in the regulatory domain leads to proliferation of myeloid cells in bone marrow |
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what is MYC
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a nuclear transcription factor that influences cell cycling and is activated early in the process
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tumors associated with MYC disregulation
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Burketts lymphoma- t(8:14)
N-MYC in neuroblastomas- poor prognosis |
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how do you detect a MYC mutation
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karyotyping- homogenous staining regions
FISH for translocations and double minutes |
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during what phase does CyclinD bind to and activate CDK4?
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G1
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what phase does CyclinE regulate
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S
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what are the cell cycle checkpoints
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G1/S- check for DNA damage
G2/M- monitors DNA repair |
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what are gate keeper genes?
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transcribe/translate tumor suppressors
key to almost all cancers |
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what is LOH
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loss of heterozygosity
born with only one gene and looses the other due to mutations |
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examples of LOH
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RB
WT1- wilms tumor VHL- von Hipple Lindau |
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what is a CpG island?
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inactivates 2nd X chromosome
stabilizes coding regions |
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How do CpGs contribute to neoplasias
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silencing of cell checkpoint/tumor suppressor genes
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what are the CIP/WAF family of tumor suppressor genes
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block cyclin/CDK fxn
p21- induced by p53 p27- responds to TGF-B p-57 |
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what are the INK4 family tumor suppressor genes
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p15,p18,p19- inhibit Rb
p16 inhibits cyclinD/CDK4 |
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how is p16 inactivated
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mutation/deletion in carcinomas
germ-line mutations (20% of melanomas) hypermethylation in HPV cancers |
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what is RB
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tumor suppressor gene
brake for G1/S checkpoint activated/inactivated by phosphorylation active RB (hypophosphorylated) inhibits E2F active RB (hyperphosphorylated)= E2F free to transcribe |
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What does HPV have to do with RB
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HPV E7 protein hyperphosphorylates Rb which allows the cell cycle to progress through S phase
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what are the General functions of p53
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arrest the cell cycle
(quiescence) permanant cell cycle arrest (senescence) cause apoptosis |
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what regulates the half life of p53
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MDM2
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what activates p53 during times of cell DNA damage
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ATM & Rad3
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what molecules does p53 activate
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p21- arrests cell cycle in G1
GADD45- DNA repair gene BAX- apoptosis gene mir34- inhibits translation of death and growth genes |
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what does mir34 do
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inhibits the translation of :
Bcl-2- anti BAX protein (anti-apoptosis) MYC and CDK4- growth genes |
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what other proteins are in the p53 family
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p63- epithelium
p73- apoptosis of chemo damaged cells |
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what is LiFraumeni synd
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germline heterozygous p53 mutation
25x the risk of cancer development before the age of 50 |
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what genes cause senescence and why
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p53 and RB
protective response in cells that have oncogenes |
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what does APC stand for
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adenomatous polyposis coli
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what does APC regulate
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B-catenin pathway
degrades B-catenin |
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what does B-catenin do
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binds E-cadherin and maintains cell to cell adhesion
also a nuclear transcription factor |
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what does the homozygous loss of APC lead to (familial adenomatous polyposis synd)
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colon polyps and cancers
hepatic cancers |
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what are cadherins
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glue epithelial cells together
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what does a loss of cadherin fxn lead to
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metastatic cancers
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what is the function of TGF-B
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stimulates the production of CDKI's, p21, and p15
inhibits CDKs, cyclins, and MYC |
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what do TGF-B mutations lead to
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cell proliferation and develo[pment of:
pancreatic, colon, gastric cancers |
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what does a mutation in NF-1 lead to
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familial neurofibromas
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what does a mutation in NF-2 lead to
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bilateral acoustic neuromas
schwanomas meningiomas |
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what does a mutation in the VHL gene cause
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renal cell carcinoma
pheochromocytoma hemiangioblastomas of the CNS homozygous inactivation |
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what is the function of VHL protein
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binds to and inactivates HIFa which is a gene regulator for VEGF and PDGF
inhibition of VHL promotes angiogenesis |
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what is PTEN and what pathways does it suppress
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tumor suppressor gene
PIP3/AKT pathway (cell proliferation) dephosphorylates PIP3 to PIP2, inactivating it |
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what do mutations in PTEN lead to
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cowden synd- benign hamartomas, inc risk for breast, colon, prostate, lung and brain tumors
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what chromosome is WT-1 on and what is its function
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Chromo 11
tumor suppressor |
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momozygous mutations in WT-1 lead to
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Wilms tumor
nephroblastoma pediatric renal carcinoma |
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how do cancer cells evade apoptosis
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reduced FAS on cell surface
inhibition of caspase 8 via FLIP BCL-2 overexpression p53 mutation- BAX not transcribed |
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factors that lead to autophagy
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alternative path to apoptosis
PTEN and TSC promote AKT, bcl-2 and mTOR inhibit |
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types of DNA repair systems
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mismatch repair
nucleotide excision repair recombination repair cancers evade/inactivate these systems |
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why does HNPCC lead to colon polyps and cancer
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defect in mismatch repair genes
MLH-1 MSH-2 |
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what disease is caused by an inherited mutation in nucleotide excision repair process
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xoderma pigmentosa
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what genes are involved with homologous DNA repair and what cancers are caused by these mutations
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BRCA-1
BRCA-2 ATM ataxia talangiectasia fanconi anemia |
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what do 90% of cancers do to acquire a limitless growth potential
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reactivation of telemorase
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what are the pro-angogenic factors
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VEGF
bFGF |
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what cancer therapy inhibits VEGF
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bevacizumab
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what are the antiangiogenesis factors
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thrombospondin 1
angiostatin endostatin vasculostatin |
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what causes a tumor to dissociation
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loss of E-cadherins
reduced catenin production |
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how do tumors degrade the ECM
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MMP9- type IV collagenase
cathepsin D urokinase plasminogen activator |
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how do tumors attach to the ECM
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loss of polarization of laminin and fibronectin receptors
cell contraction and attachment to fibronectin autocrine motility factor |
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how do tumors migrate through the ECM
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proteases
invadopodia |
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once malignant tumors intravasate into the blood vessel, how do they attach to a distant site
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CD44 adhesion molecule attaches to:
P-selectins, fibrin, vWF |
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where do prostate tumors migrate to
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lumbar vertebrae
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where do bronchogenic carcinomas migrate to
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brain and adrenals
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where do neuroblastomas migrate to
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liver
bone |
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where do breast cancers migrate to
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bone liver lung
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what is the Warburg effect?
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Tumors have a very high glucose demand that leads to a high aerobic glycolisis
this can be seen on a PET scan when 18-F-deoxyglucose is administered |