neoplasia 2 Flashcards
carcinogenesis - define
initiation of cancer formation
pinciples of carcinogensis
non-lethal damage
tumor formed by clonal expansion of single precursor that incurred damage
4 classes of regulatory genes must be mutated
carcinogenesis is mutli-step
non-lethal damage is key
tumor cell acquires mutations. if lethal = wont replicate. cell survival in altered form.
what causes mutations?
enviornmental agents - teratogen, virus, bacteria.
back luck - spontaneous mutation
inherited in germ line.
tumor formed by clonal expansion of single precursor cell that has incurred damage
monoclonal.
one cell, multiple mutations.all cells within neoplasm will have same mutations that caused neoplasm to form
4 classes of normal genes
oncogenes tumor suppressor genes apoptotic gene DNA repair genes * first cell to mutate all 4 = neoplasia
carcinogenesis is mutli-step
cancers result from accumulation of mutliple mutations.
tumor pregression. - cells can acquire own mutations different from onw another.
6 characteristic btw normal cell vs malignant
- response to growth signal
- respons to growth inhibitory signal
- response to apoptotic singal
- ablility to repair DNA
- angiogenesis
- invade and spread
N M controlled .. self-sufficient y N Y N y n limited .. induced n y
failure of DNA repair
inherited mutations in genes affecting DNA repair, cell growth or apoptosis.
- oncogene function
what signalling pathway??
gene promotes autonomous growth of cancer cells.
cant be inherited - incompatible with life.
RAS - RAF pathway. too many growth factors = replication without control or no growth factor needed to activate.
- proto-oncogene & oncoprotein
proto-onco = un-mutated cellular counterpart. drives normal cell thru cell cylce
oncoprotein: product of oncogene = lack regulatory elements of proto-oncogene.
- cell cycle
- two proteins complex
important protein at G1/G2
cyclin d1 and cdk 4 complex to drive cell protein to activations.
RB protein - when hyperphosphorylated = active.
- growth inhibitory signals
tumor suppressor genes = stop cel proliferation
two-hit hypothesis: need two mutations, loss of heterozygosity ( or haploinsuffiency) to lack inhibitory process.
- RB tumor suppressor gene
doing its job = hypophosphorylated - quiescent cell. inhibit DNA transcription.
hyperphosphorylated = activates transcription.
* normally inhibits transcription of genes for G1/S checkpoint.
* mutates = cell cycle not under this control
- retinoblastoma
why does RB protein mutation only produce retinoblastoma?
-familial= heterozygous for mutated allele, only need one mutation for LOH.
two hits = lethal. cant support life.
- Rb protein only regulatory protein in eye. other body parts have more. easily susceptible to retinoblastoma
- apoptosis
tumors and apoptosis. inactivation of?
programmed cell death.
tumors resistant. bc inactivate p53
- action of p53 in normal cells
temporary, permanent cell cycle arrest activates and signals for apoptosis, when cell in stressed. can revert back to normal state if stress is repaired.
Li-Fraumeni syndrome= mutation of p53. incompatble with life.
- DNA repair
usually enzymes repair damaged DNA. sometimes DNA repair genes damaged/mutated - allow mutations in other genes, not oncogenic on its own.
- germline mutations in DNA repair genes = high risk of malignancy. when born with one mutated gene easier to lose heterozygosity.
HNPCC, BRCA
- important characteristic for malignant cell * replicative potential
limitless replicative potential via telomerase.
normal cells, telomerase shorten. mutant p53 doesnt stop cell. 4 short chromosomes add together = dicentric chromosomes. telomerase can act on them and they replicate.
senescence
mitotic catastrophe
cell cyle arrest due to shortened telomeres
mitotic catastrophe: 4 short chromosomes come together. usually massive cell death. mutant p53 allows telomerase to continue functioning
- angiogenesis
tumors cant grow without blood supply.
angiogenesis = growth of new vessels from existing capillaries
- invasion and metastasis
malignant cells invade extracellular matric. vascular dissemination. extravasation and metastatic growth. metastatic growth thru basement membrane.
carcinogenic agents
chemical, microbial, radiation
chemical carcinogen - steps
initiation: exposure of cells to sufficient dose to cause permanent and irreversible alteration
promoter: induce tumor in initiated cell. - push to malignant
direct-acting: no metabolic conversion to be carcinogenic
indirect-acting: require metabolic conversion to be carcinogenic (smoking)
microbial carcinogenesis
virus can cause cancer.
bacteria can mutate cells and cause cancer
radiation - 3 types
sunshine
iatrogenic (medical exposure)
ionizing (electromagnetic)
host defense against tumors
- immune surveillance
- -ttumor antigens
- antitumor effector mechanisms
- immunodeficient patients
immune surveillance = body on look out for development of malignancy.
- tumor products elicit immune response
- antitumor effector mechanisms (cell mediated immunity, Ab produced but not protective.
- immunodeficient patients: some malignancies more common in these patients
late recurrence
unclear which tumors have late recurrence and why
tumor dormancy = proposed theory - prolonged survival of micrometasteses without progression. remain dormant until metastases are habitable.
