B2.032 Cancer Mechanisms Flashcards
what proportion of all genes have the potential to cause cancer when mutated?
small
are most mutations of cancers somatic or constitutional?
somatic (found only in neoplastic cells)
why are constitutional mutations important?
they can predispose to cancer
can be inherited
where are the two DNA damage checkpoints in the cell cycle?
1 : before S phase chromosomal duplication
2: before mitosis begins
what happens if a normal cell finds DNA damage during the checkpoints of the cell cycle?
most errors are fixed
if there are too many error, cells are left to senescence or die via apoptosis
what are some types of chromosomal changes that can lead to dysregulation of cancer-associated genes?
translocations
deletions
gene amplification
chromothrypsis
what effects can translocations have?
dysregulation of gene expression (a gene that is usually on could be turned off or vice versa if translocated into a different chromosome)
structural alteration of a gene (weird combo proteins result)
what is chromothrypsis?
extensive chromosomal breaks and rearrangements
worst type of chromosomal changes
what other changes can affect dysregulation of cancer associated genes?
point mutations
epigenetic changes
noncoding RNAs
how can point mutations have a large effect?
can interfere w a critical amino acid
can place a stop codon
in RAS, there is a lack of an inhibitor binding site so the protein can’t be silences
what is intraclonal heterogeneity?
not all clonal cancer cells are alike, there is accumulation of new mutations as clonal cells proliferate
allow neoplastic cells to escape and migrate to different sites
do all cancers have all of the “hallmarks of cancer”?
yes, not all to the same degree, but all must be present to achieve metastasis and invasion
what are the hallmarks of cancer?
avoiding immune destruction evading growth suppressors enabling replicative immortality tumor promoting inflammation activating invasion and metastasis genomic instability inducing angiogenesis resisting cell death deregulating cellular energetics sustaining proliferative signaling
what are oncogenes?
genes that promote autonomous cell growth
how many copies of an oncogene need to be affected to show an effect?
1, heterogeneous
characterize the gain of function possibilities in an oncogene
change in structure can create an abnormal gene product with aberrant function
change in regulation of gene expression can lead to aberrant expression of inappropriate production of structurally normal protein
what are the major classes of oncogenes?
growth factors growth factor receptors proteins involved in signal transduction nuclear regulatory proteins cell cycle regulators
what are tumor suppressor genes?
gatekeeper genes, put brakes on cell division
how many alleles of a tumor suppressor gene need to be mutated to be inactivated?
2
if both alleles are not mutated, how else can you evade tumor suppressor genes?
inactivate protein function
which virus is associated with inactivation of protein product of tumor suppressor genes?
HPV
how does inheritance factor into the inactivation of tumor suppressor genes?
you need both copies to be mutated
if you inherit a mutation, at least one copy is present in all of your cells
this makes it more likely (100%) for a second mutation to occur, so you would have an early onset form of the disease
what is the result of evasion of apoptosis?
allows defected cells to live with excessive DNA damage, therefore this damage persists over time
what is a mechanism of apoptosis evasion?
BCL-2 overexpression, protects from mitochondrial apoptotic pathway
what genes mediate senescence?
p53 and p16
which checkpoint is escaped in the evasion of senescence?
G1/S checkpoint
what leads to mitotic crisis?
loss of telomeres as DNA is replicated accumulates over time
sensed as DNA damage
leads to inability to divide (mitotic crisis)
how is mitotic crisis escaped?
reactivation of telomerase
how is self renewal mediated in cancers?
cancer stem cells are present in every tumor
what is tumor angiogenesis?
circulatory system forming within a tumor
why is tumor angiogenesis important?
required for growth beyond 1-2mm for any tumor (angiogenic switch)
can be targeted with drugs to stabilize tumor size (but doesn’t kill them)
what is the angiogenic switch?
altered balance between angiogenic growth factors (VEGF, FGF, others) and inhibitors
what times of enzymes are produced by a cancer cell to break through the basement membrane?
collagenase, elastase, metalloprotease
describe the process of a primary tumor metastasizing
- clonal expansion, growth, diversification, angiogenesis
- metastatic subclone
- adhesion to and invasion of basement membrane
- passage through extracellular matrix
- intravasation
- interaction with host lymphoid cells
- tumor cell embolus
- extravasation
- metastatic deposit
- angiogenesis/growth
what is the Warburg effect?
shifting balance towards aerobic glycolysis from oxidative phosphorylation
what are the effects of a shift toward aerobic glycolysis?
decreased ATP output
increased glucose uptake
provides metabolic intermediates for synthesis of cellular components (carbon moieties, “building materials”)
which mutated genes are utilized in metabolic reprogramming?
P13K/AKT
MYC
what are tumor antigens?
products of mutated genes
overexpressed or aberrantly expressed cellular proteins
cell type-specific differentiating antigens
what are some antitumor effector mechanisms?
cytotoxic T lymphocytes
natural killer cells
macrophages
how can a tumor cell escape immune response?
selective outgrowth of antigen-negative variants
loss or reduced expression of MHC molecules
activation of immunoregulatory pathways
secretion of immunosuppressive factors by cancer cells
induction of regulatory T cells
what are some sources of genomic instability that can lead to cancer?
defective mismatch repair genes
defective nucleotide excision repair
defective DNA repair by homologous recombination
what are the steps of inflammatory reaction to infiltrating cancer?
release of growth factors that promote proliferation
removal of growth suppressors
enhanced resistance to cell death
inducing angiogenesis
activating and assisting invasion and metastasis
evading immune destruction
