Molecular Onco 1 Flashcards
cancer growth strategies
- signal activation
- deactivation of growth signal controls
- process promotion
- escaping death
- immortalization
genes that have a main role to initiate cellular growth in response to certain scenarios
oncogenes
important characteristics of oncogenes
- dominant expression (need to activate only one gene)
- highly conservative (always off = protooncogene)
- two types: viral and cellular
classification of oncogenes
*secreted growth factors
*cell surface receptors
*intracellular transducers
*dna-binding nuclear proteins
regulators of the cell cycle
- = components of signal transduction pathways
mutations where there is a change in one single dna nucleotide
point mutations
ex. bladder ca hrasa gene point mutation changes glycine to valine
types of point mutations
- transition
- transversion
- nonsense
- silent
- missense: conservative or non conservative
mutation where there is a loss or gain of nucleotide in a given gene
frameshift mutation
- loss or insertion
mutations that occur during the process of extracting the coding portion of genetic code
splice site mutation
- intron not excised
- exon that is removed
mutations that occur as chromosomes start to deteriorate with age
breakage-fusion-bridge cycle
- fraying of the ends of chromosomes = exposure of nucleotides to the environment
attempts of chromosomes to cover breakage-fusion-bridge cycle mutations
- homologous fusion: both chromosomes of a distinct pair
- nonhomologous fusion: occur between chromosomes that are part of a different pair (translocations)
effects of fusion in b-f-b c mutations
- fused chromosomes are under pressure
- bridge will break
- unequal distribution of genetic material
- –> one chromosome will have multiple copies = amplification
- –> lose important genetic material = deletion
t/f in gene amplification, a chromosome acquires multiple copes of a particular gene
true, results in multiple copies of the protein
example of gene amplification
her2 oncogene = increased egfr2 on breast ca
- increased egfr2 = increased proliferation even in physiologic levels of growth factors
- more aggressive disease, poorer prognosis
mutation caused by fusion between nonhomologous pairs of chromosomes
translocation, results in coupling of genes that are normally far apart
- can result to activation of oncogenes
example of translocations
bcr-abl fusion gene
- chromosome 9 and 22 fusion
- coupling generates a proliferative signal = malignancy
- philadelphia chromosome
- hallmark of chronic myelogenous leukemia
what happens in viral activated oncogenes
- virus incorporates genetic profile into nucleus of cell
- viral genome is an oncogene that stimulates proliferation
- oncogene remains incorporated in genome
control signals (genes) that prevent the onset of uncontrolled proliferation, preventing growth of tumors
tumor suppressor genes
characteristics of tumor suppressor gene
- inhibit growth and multiplication of mutated cells
- prevent neoplastic transformation
- recessive and highly conserved (always on)
ex. rb1 and tp53
t/f only one tumor suppressor gene needs to lose activity to initiate malignancy
false! two hit hypothesis
knudson’s two hit hypothesis: two wild type tumor suppressor genes
first hit: mutation in one pair, but the other is still functioning
second hit: mutation in second pair, FUNCTION HAS BEEN LOST
knudson’s two hit hypothesis: one wild type, one inherited mutated gene
first hit: inherited mutated gene, other still intact
second hit: mutation in second gene, FUNCTION HAS BEEN LOST
will acquire disease younger
individuals who have inherited a mutated tumor suppressor gene from their parents are termed ___
heterozygous
when does loss of heterozygosity happen
- when they lose the function of the remaining wild type
- they become homozygous
what is contact inhibition
- body’s way of ensuring that its microscopic architecture remains intact
- normal: cells are side by side, no cell invades neighbors
genes that maintain contact inhibition
nf2 gene -> merlin
- adhesive molecule keeping tight cell junctions intact
lkb1 gene -> epithelial polarity protein
- organizes cells into functioning epithelial structures by maintaining the integrity of entire tissue
what are anti-proliferative cytokines
substances produced in the cell microenvironment that keep proliferation activities subdued
example of anti proliferative cytokines
tgf-b
- can be used by cancer to help develop malignant phenotype
what are dna repair genes
- ensures fidelity of replication
- checks and correct nucleotide pairing
- deactivated = mismatches are unnoticed
areas of nucleotide mismatches are also known as ___
microsatellite instabilities or min+
two types of dna repair gene function processes
mismatch: detected by msh2 and msh6, replaced by mlh1 and pms2
insertion or deletion: detected by msh2 and msh3, excised or reinserted by mlh1 and ml3
in order for an individual to develop malignancy, there must be ___
- gain of function of protooncogene
- loss of function of tumor suppressor gene
- loss of function of mutator gene
acquisition of growth signaling
- production of growth factor ligands
- autocrine stimulation
- paracrine stimulation of normal cells (to produce substances)
- altered receptor expression
example of cell suicide
p53 in embryonic development
- webbed fingers and tails are removed through programmed cell death
cyclin regulators
effector gene p21 (inhibits cell cycle progression and permits dna repair) and tumor suppression gene p53
what is p53
- detects presence of dna damage before s phase
- damage -> halts cell cycle progression through p21 and recruits repair genes
- after repair, p53 deactivates p21
- severe damage -> p53 activates apoptotic pathway
extrinsic component of bcl2
proteins: bh3 components
receptors: nbk/bik, bmf, bid, bim, puma, noxa, bad
(detect signals from environment)
signals are strongly pro-apoptotic
signals from environment that trigger extrinsic component of bcl2
genetic stress p53 activation loss of nutrients protein synthesis damage cytotoxic agents' effects
intrinsic component of bcl2
proteins: bcl2, bclxl, bclw, mcl1, e1b19k
anti-apoptotic function
how is apoptosis avoided by intrinsic component
- prevent fusion of bax-bak
- bax from cytoplasm, bak from mitochondria
fusion = apoptosis
component of the mitochrondria released in response to apoptotic signal which activates a set of proteases
cytochrome c
cysteine containing aspartate specific proteases activated by cytochrome c
caspases
- initiator: activated in response to cell death signal
- executioner or effector: activates cascade resulting in dna fragmentation and cell death
ways to evade death signal
- mutate p53 (ts gene)
- mutate intrinsic component = always antiapoptotic even if bh3 is signaling
what is autophagy
- triggered when there is nutrient deficiency
- exhibits cross signaling with apoptotic pathway
- protective for cancer cells
how does necrosis cause cancer
- release proinflammatory antigens to recruit more cells to become cancer cells
- stimulates neighbors to become neoplastic
hayflick limit or cellular senesence
there are only finite number of replications available
functions of telomeres
- cap that protects dna strands
- prevents recombination and shortening of lagging strand
- biological clock
what is telomerase
mediates ability to add additional dna (6 nucleotide repeats to 3’-oh end)
how does telomerase promote cancer
- maintains telomere length, overcoming senesence
- low levels in premalignancy, but promotes mutations leading to telomerase expression
- overt carcinomas have high telomerase
most active receptor in angiogenesis
vegfr2
events that induce angiogenesis
- hypoxia in tumor bed!!!
- sex hormones
- growth factors
- genetic events (p53 mutations, vhl gene expression, pten mutation, oncogene activation)
clinical implications of angiogenesis
- more blood vessels = more risk for metastasis
- grow faster and more aggressive
characteristics of new blood vessels
- dilated
- tortuous with multiple branches
- bms with varied thickness = leakage = icn oncotic pressure = barrier to cytotoxic drugs
- chaotic blood flow
drivers of angiogenesis
pericytes and bone marrow derevied cells
other mechanisms of vascularization
- vascular co-option
- intussusceptive vascular growth (splitting angiogenesis)
- vasculogenic mimicry (stem cell like)
metabolic adjustments to angiogenesis
warburg cells
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