Molecular Mechanisms of Cancer

Question 1

how many cell divisions before cancer can be seen on X-ray?

Answer 1

10^8

Question 2

how many cell divisions before cancer is palpable?

Answer 2

10^9

Question 3

how many cell divisions before death?

Answer 3

10^12

Question 4

definition of “hallmarks of cancer”

Answer 4

the homeostatic cellular processes most commonly disrupted in cancers, and which are dysregulated through mutation of critical regulatory genes

Question 5

six hallmarks of cancer

Answer 5

1. growth factor independence
2. loss of response to antigrowth signals and differentiated state
3. resistance to apoptosis
4. limitless replicative potential
5. recruitment of blood/lymph
6. invasion and metastasis

Question 6

what gives cancer its growth factor independence?

Answer 6

oncogenes

Question 7

what gives cancer its loss of response to anti-growth and differentiated state?

Answer 7

tumor suppressors

Question 8

what gives cancer its limitless replicative potential?

Answer 8

telomerase

Question 9

proto-oncogene

Answer 9

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

Question 10

oncogene

Answer 10

mutant counterparts of proto-oncogenes. characterized by unregulated activity.

Question 11

what type of mutation creates oncogenes?

Answer 11

gain of function (over expression, amplification, constitutive activity)

Question 12

what type of mutation creates tumor suppressors?

Answer 12

loss of function

Question 13

relationship of oncogenes to growth factor

Answer 13

GF independent

Question 14

PI3K (phosphatidylinositol 3-kinase)

Answer 14

lipid kinase that phosphorylates membrane (PIP2 to PIP3)

Question 15

PIP2 (phosphatidylinositol biphosphate)

Answer 15

substrate for PI3K

Question 16

activator of PI3K?

Answer 16

receptor tyrosine kinases (RTKs)

Question 17

PIP3

Answer 17

organization hub for cytoplasmic signaling. docking site for important signaling proteins containing pleckstrin homology (PH) domains.

Question 18

primary downstream effector of PI3K signaling?

Answer 18

AKT (aka PKB). can be oncogenic if over expressed!! promotes cellular metabolism, cell growth, survival, motility, etc

Question 19

biomechanical consequence of activated AKT in cancer cells?

Answer 19

increased glucose transport and glycolysis

Question 20

warburg effect

Answer 20

high glycolytic rate in many human cancer cells. allows for increased ATP and intermediates for cell growth.

Question 21

positron emission tomograpgy (PET)

Answer 21

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

Question 22

PET positive

Answer 22

cancers with elevated AKT levels

Question 23

protein that negatively controls PI3K pathway?

Answer 23

PTEN (phosphatase and tensin homolog). de-phosphorylates PIP3

Question 24

mutations in PTEN that lead to cancer?

Answer 24

loss of function mutations. leads to elevated AKT activity

Question 25

tumor suppressor genes

Answer 25

genes in which loss of function mutations promote cancer

Question 26

more common mutation in PI3K/AKT pathway?

Answer 26

loss of PTEN function

Question 27

most common mutated tumor suppressor gene?

Answer 27

p53

Question 28

role of p53

Answer 28

activates cell cycle arrest or apoptosis in cells exposed to stress (DNA damage or oncogene activation)

Question 29

Li-Fraumeni syndrome

Answer 29

one germ-line mutant p53 inherited. more prone to cancers associated with loss of functional p53 allele (loss of heterozygosity)

Question 30

what type of TF is p53?

Answer 30

DNA binding TF.

Question 31

what types of mutations render p53 nonfunctional?

Answer 31

loss of function and missense mutations decrease p53's ability to bind DNA

Question 32

what activates the p53 pathway?

Answer 32

stress

Question 33

consequences of p53 activation?

Answer 33

cell cycle arrest & apoptosis (but also DNA repair and block of angiogenesis)

Question 34

p21

Answer 34

cyclin/CDK inhibitor that leads to cell cycle arrest. regulated by p53.

Question 35

GADD45

Answer 35

DNA repair. regulated by p53

Question 36

proapoptotic proteins turned on by p53?

Answer 36

Bak, Bax, Puma, Noxa

Question 37

MDM2

Answer 37

ubiquitylates p53, targeting it for proteasomal degradation. negative feedback since it is activated by p53

Question 38

at what level is p53 regulated?

Answer 38

post translational stabilization. phosphorylated on different residues by different tumor suppressors in times of stress, which stabilizes it.

Question 39

auto regulation of p53

Answer 39

MDM2

Question 40

level of p53 in tumors?

Answer 40

high accumulation. nonfunctional p53 can't bind DNA to activate genes and therefore MDM2 can't target it for degradation.

Question 41

caspases

Answer 41

proteases that use conserved cysteine residue in active site to cleave proteins after aspartate residue. initiators and executioners. effect cellular destruction.

Question 42

intrinsic apoptotic pathway

Answer 42

cytochrome c released from mitochondria and binds to Apaf-1, forming apoptosome and activating procaspase 9 to caspase 9, which activates executioner caspases.

Question 43

components of apoptosome

Answer 43

cytochrome c, Apaf-1, procaspase 9

Question 44

which protein family regulates the mitochondrial membrane permeability to cytochrome c?

Answer 44

Bcl-2 family

Question 45

Bcl-2

Answer 45

anti-apoptotic

Question 46

pro-apoptotic proteins in mitochondrial membrane?

Answer 46

BH3, Bak, Bax, Puma, Noxa

Question 47

extrinsic (death receptor) apoptotic pathway

Answer 47

Fas/FasL binding and executioner caspase activation. Not a stress response like intrinsic pathway**

Question 48

how can cancer cells bypass apoptosis?

Answer 48

over expression of Bcl2, down regulation of Bax/Bak, loss of p53, down regulating Fas/FasL

Question 49

telomerase

Answer 49

enzyme that adds telomere sequence to chromosome ends, but is not typically expressed in adult somatic cells. cancers acquire it somehow.

Question 50

where is telomerase activated?

Answer 50

Expressed embryonically, in stem cells, and lymphocytes

Question 51

hayflick limit

Answer 51

the number of times cells divide before losing enough telomeric sequences to reach replicative senescence (permanent cell cycle arrest)

Question 52

consequence of telomere loss?

Answer 52

breakage fusion bridge during anaphase (inappropriate fusion) that leads to ds strand breaks --> amplifications and deletions.

Question 53

angiogenic switch

Answer 53

the ability to recruit functional blood vessels from surrounding tissue. occurs after solid tissues grow beyond 2mm

Question 54

problem of angiogenesis in tumors?

Answer 54

vessels serve as conduit for metastatic cells

Question 55

problem of telomerase in tumors?

Answer 55

if telomeres are stabilized after a fusion event, stabilized chromosomes are aberrant

Question 56

when does tumor growth really kickstart?

Answer 56

after the angiogenic switch

Question 57

gross morphology of tumor vasculature

Answer 57

disorganized and dysregulated. highly chaotic.

Question 58

VEGF (vascular endothelial growth factor)

Answer 58

stimulates EC division, survival, differentiation, etc. master regulator of angiogenesis. increased in tumors

Question 59

what does VEGF activate?

Answer 59

receptor tyrosine kinases on endothelial cells

Question 60

avastin

Answer 60

human monoclonal antibody against VGEF. works better in mice

Question 61

how do cancer cells metastasize

Answer 61

through the blood and lymph