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CarcinogenesisCarcinogenesis
1. Basic principles2. 6 hallmark features3. Abnormal cell
proliferation: mechanisms4. Carcinogens: examples
CarcinogenesisCarcinogenesisMajor Principles:Major Principles:
1. Nonlethal genetic damage is central tocarcinogenesis
2. Tumor mass arises from CLONAL expansion of a single progenitor cellthat has incurred genetic damage
3. X-linked markers can be used toassess clonality
Neoplasms
Clonality of tumors: assess in women heterozygous forpolymorphic X-linked isoenzyme/molecular markers(e.g. glucose-6-phosphate dehydrogenase)
Major Principles (contMajor Principles (cont’’d)d)
4. Principle targets of genetic damage:4 classes of normal regulatory genes:
-growth promoting proto-oncogenes-growth-inhibiting tumor suppressor
genes-genes regulating programmed cell
death (apoptosis)-genes involved in DNA repair
5.Mutant alleles of proto-oncogenes = oncogenes—DOMINANT (mutation
of single allele cell transformation)
Major principles (contMajor principles (cont’’d)d)
6. Disabled DNA repair genes (caretakergenes) predispose cells to genomemutations—”mutator phenotype”
7. CARCINOGENESIS is a MULTISTEP PROCESS--both phenotypically & genotypically
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Tumor progression andgeneration of heterogeneity
GF (Growth factor)GFR (GF receptor)
kinasepathway
2nd
messengers
signal transducingproteins
cell membrane
nuclear regulatory factors
G1-S-G2-MCell cycle
Steps innormalphysiologiccell proliferation
nucleus
DNAtranscription
cascade ofsignaltransductionmolecules
GF (Growth factor)GFR (GF receptor)
kinasepathway
2nd
messengers
signal transducingproteins
cell membrane
nuclear regulatory factors
G1-S-G2-MCell cycle
nucleus
DNAtranscription
cascade ofsignaltransductionmolecules
GROWTH FACTORS
-glioblastomasPDGF &
express itsreceptor
-sarcomas:TGF-α andits receptor
GF (Growth factor)GFR (GF receptor)
kinasepathway
2nd
messengers
signal transducingproteins
cell membrane
nuclear regulatory factors
G1-S-G2-MCell cycle
nucleus
DNAtranscription
cascade ofsignaltransductionmolecules
GFR’s
-overexpression(e.g., amplification)
cancer cells hyperrepondto levels of GF’s
-ERBB1 (EGF receptor)overexpressed in 80%sq. cell Ca’s lung
-HER2/NEU (ERBB2)amplified in 25%-30%breast Ca’s
bad prognosis
(Rx: role of anti-HER2/NEUantibodies)
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GF (Growth factor)GFR (GF receptor)
kinasepathway
2nd
messengers
signal transducingproteins
cell membrane
nuclear regulatory factors
G1-S-G2-MCell cycle
nucleus
DNAtranscription
cascade ofsignaltransductionmolecules
SignalTransducingProteins
RAS: the most commonlymutated proto-oncogene in human tumors
ABL: in chronicmyelogenousleukemia
Freidrichvon Recklinghausen
1882“neurofibromatosis”
1889“hemochromatosis”
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Schwann cellsAxonsFibroblastsCollagen
Neurofibroma
Neurofibroma in T2/T3intervertebral foramen
neurofibrominIs a GAP prot.
NF1 gene17q11.2
Neurofibromin(GAP prot.)
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Neurofibromatosis 1 (NF1)Neurofibromatosis 1 (NF1)
1. Inherited as autosomal dominant2. Incidence of NF1: 1 in 2500-30003.NF1 gene localized to chromosome 174.Gene product = neurofibromin, a GAP (GTPase-
activating protein)—inhibits cell prolif.5. Mutation in NF1 neurofibromatosis6. Neurofibromatosis phenotype:
Neurofibromas: -cutaneous-peripheral nerves
Café-au-lait spots (hyperpigmentation)
GF (Growth factor)GFR (GF receptor)
kinasepathway
2nd
messengers
signal transducingproteins
cell membrane
nuclear regulatory factors
G1-S-G2-MCell cycle
Steps innormalphysiologiccell proliferation
nucleus
DNAtranscription
cascade ofsignaltransductionmolecules
Carcinogenic agentsCarcinogenic agents
•Chemicals•Radiation•Oncogenic RNA viruses•Oncogenic DNA viruses
Sir Percival Pott, London surgeon> 200 yrs. ago: scrotal skin cancer in
chimney sweeps
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Thorotrast (X-rays: used until 1956)
Thorotrast: ThO2: alpha particles, half-life 30 yrs.
OncogenicOncogenic VirusesViruses
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HPV(Human Papillomavirus)
High Risk HPV’s:HPV 16 and 18
Oncogenic properties:Products of 2 early viralgenes: E6 & E7
E7: binds to Rb proteindisplaces E2F transcrip-tion factors that arenormally sequestered byRb progression thru
cell cycle
HHV8
Kaposisarcoma
EBV (Epstein-Barr Virus)
LMP-1gene
-acts as oncogene-activates signaling-activates cyclin D-t (8;14) translocation
activates MYC (nucleartranscription factorregulating growth promo-ting genes such as cyclins)
BurkittLymphoma(B cell)
“Starry Sky”lymph nodeappearance(Van Goghpainting)
Hepatitis C Virus(HCV)
(RNA virus, butdefinite risk forhepatocellularcarcinoma)
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Hepatitis B Virus (HBV)
HBxAg
activatetranscriptionfactors & signaltransduction
Viral integration causes secondary chromos. rearrangements deletions
HCC
Acute hepatitis Chronic hepatitis Cirrhosis Carcinoma
Ongoing inflammation, cell injury,cell division prone to mutations/viral actions
Pathogenetic sequence of HCC inchronic HBV and HCV infections