Molecular Mechanisms of Cancer Flashcards
how many cell divisions before cancer can be seen on X-ray?
10^8
how many cell divisions before cancer is palpable?
10^9
how many cell divisions before death?
10^12
definition of “hallmarks of cancer”
the homeostatic cellular processes most commonly disrupted in cancers, and which are dysregulated through mutation of critical regulatory genes
six hallmarks of cancer
- growth factor independence
- loss of response to antigrowth signals and differentiated state
- resistance to apoptosis
- limitless replicative potential
- recruitment of blood/lymph
- invasion and metastasis
what gives cancer its growth factor independence?
oncogenes
what gives cancer its loss of response to anti-growth and differentiated state?
tumor suppressors
what gives cancer its limitless replicative potential?
telomerase
proto-oncogene
normal genes with important roles in complex signaling pathways (regulating division, differentiation, survival, and movement)
any gene that can promote tumor formation or growth through mutation
oncogene
mutant counterparts of proto-oncogenes. characterized by unregulated activity.
what type of mutation creates oncogenes?
gain of function (over expression, amplification, constitutive activity)
what type of mutation creates tumor suppressors?
loss of function
relationship of oncogenes to growth factor
GF independent
PI3K (phosphatidylinositol 3-kinase)
lipid kinase that phosphorylates membrane (PIP2 to PIP3)
PIP2 (phosphatidylinositol biphosphate)
substrate for PI3K
activator of PI3K?
receptor tyrosine kinases (RTKs)
PIP3
organization hub for cytoplasmic signaling. docking site for important signaling proteins containing pleckstrin homology (PH) domains.
primary downstream effector of PI3K signaling?
AKT (aka PKB). can be oncogenic if over expressed!! promotes cellular metabolism, cell growth, survival, motility, etc
biomechanical consequence of activated AKT in cancer cells?
increased glucose transport and glycolysis
warburg effect
high glycolytic rate in many human cancer cells. allows for increased ATP and intermediates for cell growth.
positron emission tomograpgy (PET)
visualizes the uptake of 18-F labeled deoxyglucose to identify tumors. Can’t be metabolized and cancer cells with their high glucose transport light up like crazy
PET positive
cancers with elevated AKT levels
protein that negatively controls PI3K pathway?
PTEN (phosphatase and tensin homolog). de-phosphorylates PIP3
mutations in PTEN that lead to cancer?
loss of function mutations. leads to elevated AKT activity
tumor suppressor genes
genes in which loss of function mutations promote cancer
more common mutation in PI3K/AKT pathway?
loss of PTEN function
most common mutated tumor suppressor gene?
p53
role of p53
activates cell cycle arrest or apoptosis in cells exposed to stress (DNA damage or oncogene activation)
Li-Fraumeni syndrome
one germ-line mutant p53 inherited. more prone to cancers associated with loss of functional p53 allele (loss of heterozygosity)
what type of TF is p53?
DNA binding TF.
what types of mutations render p53 nonfunctional?
loss of function and missense mutations decrease p53’s ability to bind DNA
what activates the p53 pathway?
stress
consequences of p53 activation?
cell cycle arrest & apoptosis (but also DNA repair and block of angiogenesis)
p21
cyclin/CDK inhibitor that leads to cell cycle arrest. regulated by p53.
GADD45
DNA repair. regulated by p53
proapoptotic proteins turned on by p53?
Bak, Bax, Puma, Noxa
MDM2
ubiquitylates p53, targeting it for proteasomal degradation. negative feedback since it is activated by p53
at what level is p53 regulated?
post translational stabilization. phosphorylated on different residues by different tumor suppressors in times of stress, which stabilizes it.
auto regulation of p53
MDM2
level of p53 in tumors?
high accumulation. nonfunctional p53 can’t bind DNA to activate genes and therefore MDM2 can’t target it for degradation.
caspases
proteases that use conserved cysteine residue in active site to cleave proteins after aspartate residue. initiators and executioners. effect cellular destruction.
intrinsic apoptotic pathway
cytochrome c released from mitochondria and binds to Apaf-1, forming apoptosome and activating procaspase 9 to caspase 9, which activates executioner caspases.
components of apoptosome
cytochrome c, Apaf-1, procaspase 9
which protein family regulates the mitochondrial membrane permeability to cytochrome c?
Bcl-2 family
Bcl-2
anti-apoptotic
pro-apoptotic proteins in mitochondrial membrane?
BH3, Bak, Bax, Puma, Noxa
extrinsic (death receptor) apoptotic pathway
Fas/FasL binding and executioner caspase activation. Not a stress response like intrinsic pathway**
how can cancer cells bypass apoptosis?
over expression of Bcl2, down regulation of Bax/Bak, loss of p53, down regulating Fas/FasL
telomerase
enzyme that adds telomere sequence to chromosome ends, but is not typically expressed in adult somatic cells. cancers acquire it somehow.
where is telomerase activated?
Expressed embryonically, in stem cells, and lymphocytes
hayflick limit
the number of times cells divide before losing enough telomeric sequences to reach replicative senescence (permanent cell cycle arrest)
consequence of telomere loss?
breakage fusion bridge during anaphase (inappropriate fusion) that leads to ds strand breaks –> amplifications and deletions.
angiogenic switch
the ability to recruit functional blood vessels from surrounding tissue. occurs after solid tissues grow beyond 2mm
problem of angiogenesis in tumors?
vessels serve as conduit for metastatic cells
problem of telomerase in tumors?
if telomeres are stabilized after a fusion event, stabilized chromosomes are aberrant
when does tumor growth really kickstart?
after the angiogenic switch
gross morphology of tumor vasculature
disorganized and dysregulated. highly chaotic.
VEGF (vascular endothelial growth factor)
stimulates EC division, survival, differentiation, etc. master regulator of angiogenesis. increased in tumors
what does VEGF activate?
receptor tyrosine kinases on endothelial cells
avastin
human monoclonal antibody against VGEF. works better in mice
how do cancer cells metastasize
through the blood and lymph
