LEC54: Cancer Pathways and Tumor Biology

Question 1

what are the components of the Rb pathway

Answer 1

Question 2

how are Rb pathway targets altered in cancer?

Answer 2

in a mutually exclusive manner: it’s not merely Rb that’s the target, the whole pathway is the target

i.e. deletion of p16 is mutually exclusive w/ D1 and Rb, and the same tumor won’t sustain mutations in multiple components of the same pathway unless the pathway’s inactivated

Question 3

what mutations happen to p16? result?

Answer 3

deletion, missense mutation, promoter methylation

it is deleted in sporadic melanoma, muated in many melanomas

Question 4

what mutations happen to cyclin D1 gene?

Answer 4

amplification, chromosomal translocation

Question 5

what muations occur to genes encoding Cdk4 or Cdk6? result?

Answer 5

amplification, missense mutation

prevents binding of p16

occurs in glioblastoma and other brain cancers

Question 6

mutations that occur to Rb?

Answer 6

deletion, mutation

Question 7

what does human papilloma virus (HPV) lead to?

Answer 7

expression of E7 protein

this inhibits pRb

Question 8

what is pRb? when is it deleted -> result?

Answer 8

tumor suppressor

deleted in retinoblastoma, osteosarcoma

Question 9

what happens re: cyclins in breast cancer?

Answer 9

cyclin D1 is amplified in some breast cancers

overexpression of D1 inactivates Rb

Question 10

what does p53 pathway normally cause?

Answer 10

arrest or apoptosis

Question 11

components of the p53 pathway?

Answer 11

Question 12

what are mechanisms to arrest the p53 pathway?

Answer 12

1) ARF gene deletion, missense mutation, or promoter methylation
2) Mdm2 gene amplification and Mdm2 protein overexpression
3) p53 missense mutation
4) HPV E6 protein targets p53 for degredation
* ONE OF THESE THINGS, NOT ALL, OCCUR, SHOWING MUTUAL EXCLUSIVITY AND THAT THE PATHWAY IS THE TARGET IN CANCER*

Question 13

what does cervical cancer inactivate in p53 pathway?

Answer 13

p53

Question 14

cells w/ a mutant Mdm2 have what kind of p53?

what does this demonstrate?

Answer 14

WT p53

demonstrates the PATHWAY is the target, not the actual GENE or PROTEIN

Question 15

what is the APC pathway?

Answer 15

Question 16

what is APC, what is its normal function re: beta-catenin?

Answer 16

APC: adenomatous polyposis coli protein

normally, is a scaffold that interacts w/ Beta-catenin, facilitates its degredation, by bringing GSK-3-beta and beta-catenin teogether

Question 17

what does loss of APC cause?

Answer 17

upregulation of Myc and Cyciln D, via transcriptional effects of beta-catenin

Question 18

what do mutations in APC cause?

Answer 18

expression of a truncated protein that can’t bind beta-catenin

Question 19

what do mutations in beta-catenin cause?

Answer 19

changes in its phosphorylation sites, so it cannot be degraded

if it’s not phosphorylated&degraded, doesn’t matter if APC or Axin is present

can cause regulatory issues w/ Myc, Cyclin D

Question 20

mutations in which parts of the Apc pathway are mutually exclusive in many cancers?

Answer 20

mutations in Apc, Axin, B-catenin

Question 21

what activates the Erk pathway?

Answer 21

growth factors binding to receptor on cell surface

cause pathway to go

Question 22

what are the components of the Ras/PI3K pathways?

Answer 22

Question 23

what does Ras pathway result in cellularly?

Answer 23

cell growth

Question 24

what is the result of the PI3K pathway?

Answer 24

cell survival

Question 25

what muations occur to the Erk pathway in human cancers?

Answer 25

1) **GENE AMPLIFICATION** b/c of GROWTH FACTOR expression 2) **CONSTITUITIVELY ACTIVE RTK** if GENES encoding CELL SURFACE RECEPTOR are amplified, missense mutated 3) **Ras MISSENSE MUTATION** -\> CONSTITUITIVE ACTIVITY b/c cannot hydrolyze GTP 4) **Raf can have missense mutation** causing **constituitive activity**

Question 26

what is Mek's relevance to human cancers?

Answer 26

Mek is not usually altered, however can be a good drug target b/c Mek inhibitor will deal with a hyperactive Raf or Ras growth factor receptor that's constituitively signaling or overexpressed GF

Question 27

what is the PI3K pathway?

Answer 27

Question 28

what mutations can occur in the PI3K pathway to cause human cancer?

Answer 28

1) PI3K and Akt can be muated to be constituitively active 2) PTEN, a phosphotase, prevents PI3K signaling and PTEN is often deleted in tumors

Question 29

what are the mutually exclusive changes to the PI3K pathway that can cause cancer?

Answer 29

PTEN alteration or AKT activation

Question 30

what are PI3K and Akt considered?

Answer 30

oncogenes

Question 31

what is PTEN considered?

Answer 31

a tumor suppressor b/c it can reverse teh AKT for PI3K

Question 32

how is there redundancy in the PI3K pathway?

Answer 32

a receptor mutation means there is also a PTEN pathway mutation; not just a receptor mutation alone impacts teh PTEN pathway, and PTEN alone isn't mutated

Question 33

why is colorectal cancer so well documented and studied?

Answer 33

colon is easily accessible can detect early, middle, late lesions, and analyze them for protein expression

Question 34

what is the schematic from normal epithelium -\> metastisis?

Answer 34

Question 35

what occurs to the genetic/epigenetic characteristis of a pt as colorectal cancer progresses?

Answer 35

increasing genetic and epigenetic instability

Question 36

what is the sequence of changes from earliest to latest that occurs in colrectal cancer progression?

Answer 36

1) loss of Apc 2) activation of K-Ras 3) loss of Smad4 and other tumor suppressors 4) loss of p53 (LATE EVENT!) 5) other unknown alterations

Question 37

what is p16?

Answer 37

CDK inhibitor of the Ink class; tumor suppressor suppressor of Rb pathway

Question 38

what is ARF protein?

Answer 38

Mdm2 inhibitor, so can act as a tumor suppressor because it facilitates p53 activation suppressor of p53 pathway

Question 39

what is expressed from the CDKN2A locus? what's the structure of the locus?

Answer 39

both p16 and ARF they share exon 2 and 3 but each have their own promoter and exon 1

Question 40

how are different proteins produced from the CDKN2A locus given its structure?

Answer 40

both p16 and ARF share the CDKN2A locus but have different 1st exons; 1-beta is ARF and 1-alpha is p16-INK splicing of the locus puts the 1a-exon2 or 1b-exon2 in different reading frames, creates different RNA, different proteins

Question 41

what's relationship of transcriptional regulation of p16 and ARF?

Answer 41

completely independent because each has its own promoter

Question 42

if a mutation occurs in exon 2 or 3 of CDKN2A locus, what occurs?

Answer 42

inactivation of both Rb via p16 and p53 via ARF pathways because both are encoded at this locus

Question 43

how does upregulation of ARF occur?

Answer 43

loss of Rb -\> activation of E2F -\> ARF activation -\> Mdm2 suppression -\> p53 activation

Question 44

what upregulates Arf? result?

Answer 44

Myc and Ras upregulate Arf This inhibits Mdm2, thus activates p53 -\> cell-cycle arrest or apoptosis

Question 45

what is Arf a transcriptional target of? what does loss of Arf result in?

Answer 45

Arf is target of E2F E2F expression and inactivation of pRb upregulates p53

Question 46

how is Arf an oncogene checkpoint?

Answer 46

must both upregulated Myc and mutate p53 ?

Question 47

what mediates epithelial to mesenchymal transition during normal development?

Answer 47

Slug, Snail, Twist transcription factors can be altered to have this change in cancer situation

Question 48

what occurs to cancer cells of epithelial origin to make them behave like mesenchyme cells?

Answer 48

1) loss of cell-cell junctions due to loss of E-cadherin expression 2) loss of cell polarity 3) increased migratory behavior, more motility

Question 49

what is metastitis dependent on in order to cause cancer-associated death?

Answer 49

1) invasiveness of the tumor 2) immune response and tumor vasculature of the host

Question 50

what are the 6 key steps of metastisis?

Answer 50

1) angiogenesis 2) invasion 3) intravasation 4) metastasis 5) extravasation 6) secondary growth

Question 51

when does angiogenesis occur? what happens? what is expressed, what is reduced?

Answer 51

whe ntumor mass reaches 1-2mm angiogenesis factors are produced that induce blood vessel formation acidic FGF, basic FGF, VEGF are expressed factors inhibitors such as thrombospondin are reduced

Question 52

what occurs during invasion?

Answer 52

tumor cells become attached to sub-endothelial extracelular matrices via cell surface receptors protease-mediated degredation of the matrix follows migration via chemotaxis using the degredation products or tumor-associated autocrine motility factors occurs

Question 53

what occurs during intravasation?

Answer 53

tumor cells invade through cascular endothelial cells and sub-endothelial basement membranes and enter vasculature

Question 54

what happens during extravasation?

Answer 54

tumor cells extravasate out of vasculature, into pervascular stroma this is reverse of invasion!

Question 55

what occurs during secondary growth?

Answer 55

at distant sites, get formation and growth of secondary tumor metastasis

Question 56

what is the rational basis of targeted therapies in cancer?

Answer 56

the tumor cell behaves different from the normal cell, it is dependent on the activated oncogene for proliferation and survival, and the normal cell is not targeted therapies actually make cells w/ a mutation DIE, whereas normal cell's pathway may be inhibited, but it'll grow again