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Flashcards in Molecular Mechanisms of Cancer Deck (61):
1

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

10^8

2

how many cell divisions before cancer is palpable?

10^9

3

how many cell divisions before death?

10^12

4

definition of "hallmarks of cancer"

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

5

six hallmarks of cancer

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

6

what gives cancer its growth factor independence?

oncogenes

7

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

tumor suppressors

8

what gives cancer its limitless replicative potential?

telomerase

9

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

10

oncogene

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

11

what type of mutation creates oncogenes?

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

12

what type of mutation creates tumor suppressors?

loss of function

13

relationship of oncogenes to growth factor

GF independent

14

PI3K (phosphatidylinositol 3-kinase)

lipid kinase that phosphorylates membrane (PIP2 to PIP3)

15

PIP2 (phosphatidylinositol biphosphate)

substrate for PI3K

16

activator of PI3K?

receptor tyrosine kinases (RTKs)

17

PIP3

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

18

primary downstream effector of PI3K signaling?

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

19

biomechanical consequence of activated AKT in cancer cells?

increased glucose transport and glycolysis

20

warburg effect

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

21

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

22

PET positive

cancers with elevated AKT levels

23

protein that negatively controls PI3K pathway?

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

24

mutations in PTEN that lead to cancer?

loss of function mutations. leads to elevated AKT activity

25

tumor suppressor genes

genes in which loss of function mutations promote cancer

26

more common mutation in PI3K/AKT pathway?

loss of PTEN function

27

most common mutated tumor suppressor gene?

p53

28

role of p53

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

29

Li-Fraumeni syndrome

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

30

what type of TF is p53?

DNA binding TF.

31

what types of mutations render p53 nonfunctional?

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

32

what activates the p53 pathway?

stress

33

consequences of p53 activation?

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

34

p21

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

35

GADD45

DNA repair. regulated by p53

36

proapoptotic proteins turned on by p53?

Bak, Bax, Puma, Noxa

37

MDM2

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

38

at what level is p53 regulated?

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

39

auto regulation of p53

MDM2

40

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.

41

caspases

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

42

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.

43

components of apoptosome

cytochrome c, Apaf-1, procaspase 9

44

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

Bcl-2 family

45

Bcl-2

anti-apoptotic

46

pro-apoptotic proteins in mitochondrial membrane?

BH3, Bak, Bax, Puma, Noxa

47

extrinsic (death receptor) apoptotic pathway

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

48

how can cancer cells bypass apoptosis?

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

49

telomerase

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

50

where is telomerase activated?

Expressed embryonically, in stem cells, and lymphocytes

51

hayflick limit

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

52

consequence of telomere loss?

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

53

angiogenic switch

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

54

problem of angiogenesis in tumors?

vessels serve as conduit for metastatic cells

55

problem of telomerase in tumors?

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

56

when does tumor growth really kickstart?

after the angiogenic switch

57

gross morphology of tumor vasculature

disorganized and dysregulated. highly chaotic.

58

VEGF (vascular endothelial growth factor)

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

59

what does VEGF activate?

receptor tyrosine kinases on endothelial cells

60

avastin

human monoclonal antibody against VGEF. works better in mice

61

how do cancer cells metastasize

through the blood and lymph