Block 1 Week 5: Cancer

Front 1

first step in cancer development

Back 1

hyperplasia

Front 2

hyperplasia (3)

Back 2

1) first step in cancer development
2) increased # cells
3) reversible

Front 3

epidermis is usually how many cells thick?

Back 3

7

Front 4

dysplasia

Back 4

1) second step in cancer development
2) morphologic abnormalities
3) reversible

Front 5

anaplasia

Back 5

really extreme dysplasia...cells are looking super undifferentiated

Front 6

neoplasia

Back 6

1) point of no return = cancer
benign
malignant

Front 7

malignant

Back 7

1) invasion of basement membrane
2) (optional) metastisize

Front 8

which cancer does not metastisize?

Back 8

BCC

Front 9

tumor cell heterogeneity important because....

Back 9

treatment of primary tumor might not work on metastisis

Front 10

chemo targets

Back 10

dividing cells

Front 11

pathways of tumor spread (3)

Back 11

1) local invasion
2) direct seeding (i.e. ovaries --> peritoneum)
3) vascular (lymph or blood)

Front 12

hematogenous spread os most common for

Back 12

sarcomas

Front 13

before metastisizing, a tumor cell mus acquire which mutation?

Back 13

become resistant to apoptosis of "wandering" cells

Front 14

first step of metastasis

Back 14

detach from neighboring cells --> downregulate E-cadherin

Front 15

after detaching from neighboring cells...

Back 15

orient to basal direction = face basement membrane

epi-to-mesenchymal --> looks more like a fibroblast now

Front 16

after tumor cell faces basement membrane...

Back 16

dissolve/eat basement membrane

via MMPs and down-reg of TIMPs

Front 17

which tissues are too hard to degrade for tumor cells?

Back 17

cartilage and scars

Front 18

how to tumor cells move through ECM?

Back 18

re-align ECM fibrils into "highways"

chemotaxis
from ECM sigs
or autocrine

Front 19

after tumor cells move through ECM...

Back 19

intravasation = enter lymph or blood vessel

Front 20

which tumors usually travel through blood vs. lymph?

Back 20

epithelial --> lymph
mesenchymal --> blood

Front 21

which organs have higher rates of metastasis?

Back 21

those with leaky vessels

NOT brain, b/c bbb = super tight

Front 22

after intravasation...

Back 22

circulation --> as tumor cell emboli

Front 23

after circulation...

Back 23

attach to endothelium at a distant site

"organ specific honing"

Front 24

after attaching to endothelium at a distant site...

Back 24

extravasation

Front 25

paget's seed/soil hypothesis

Back 25

tissues in the body express different arrays --> particularly attractive to particular tumor cells

Front 26

after extravasation...

Back 26

attach to ECM at distant site

Front 27

what are some chemotactic factors that can attract tumor cells at metatstatic sites?

Back 27

IGF 1 and 2

Front 28

after attachemnt to ECM at distant site...

Back 28

growth at distant site

Front 29

after growth at distant site...

Back 29

angiogenesis

tumor cells make VEGF, other cells make TNFa

Front 30

what could be a new target for cancer therapy?

Back 30

angiogenesis

Front 31

how do some tumor cells avoid detection from body?

Back 31

hide out in immune-privileged tissues, ie. brain, testes

Front 32

clinical approaches to cancer therapy

Back 32

1) surgery
2) radiation
3) chemotherapy

Front 33

why should you always use a combinatorial approach to cancer treatment?

Back 33

tumor heterogeneity

Front 34

experiments with adding serum to a dish and seeing more cells divide showed...

Back 34

EGF = one of the proteins in serum --> EGF receptor --> kinase --> phosphorylate Rb protein --> Rb unbinds from E2F complex --> E2F complex turns on tranx --> cell divides

Front 35

do tumor cells divide faster than normal cells?

Back 35

no, they just divide more often

Front 36

dominant oncogene

Back 36

gene that can drive cell into division even in presence of a normal copy of the same gene

Front 37

tumor suppressor gene (recessive oncogene)

Back 37

genes whose loss of function = cancer

Front 38

how did we discover oncogenes?

Back 38

experiments with animal RNA tumor viruses

Front 39

what did animal RNA tumor viruses tell us?

Back 39

oncogenes are derived form normal cellular genes.... so there is a subset of genes, that, when altered lead to tumor formation

Front 40

what can oncogenes mess up?

Back 40

1) growth factors
2) receptors
3) signaling pathways
4) transcription factors

Front 41

how can oncogenes mess up growth factors?

Back 41

autocrine loop = "cellular masturbation"

cell makes it's own PDGF and responds to it

Front 42

what signaling pathway do oncogenes frequently mess up?

Back 42

Ras/MAPK

MAPK gets phosphorylated --> phorphorylates tranx factors --> "locked on"

Front 43

what is a common mutation in melanomas?

Back 43

BRAF

Front 44

how does burkitt's lymphoma occur?

Back 44

chromosomal translocation

c-myc gets moved into Ig promoter region --> inappropriate expression

Front 45

how can chromosomal translocations cause cancer?

Back 45

1) same protein, different expression
2) new fusion protein

Front 46

how does CML occur?

Back 46

philadelphia chromosome --> BCR amd ABL genes combine from chromosomes 9 and 22

Front 47

what can create an oncogene besides point mutations and chromosomal translocations?

Back 47

gene amplification

Front 48

what causes many lymphomas?

Back 48

c-myc amplification

Front 49

which type of tumor led to the discovery of the first tumor suppressor gene?

Back 49

retinoblastoma

Front 50

loss of heterozygosity

Back 50

if parent is heterozygous for mutation, child might get a spontaneous mutation in it's only good allele --> cancer

Front 51

loss of Rb protein =

Back 51

loss of Rb growth control

Front 52

what is the most commonly mutated human cancer gene?

Back 52

p53 --> usually turns on tranx of CKI

p53 mutation --> lack of CKIs --> cyclin not regulated --> cell cycle not regulated

Front 53

BRCA1 and BRCA2

Back 53

tumor suppressor oncogenes --> breast and ovarian cancer

Front 54

PTEN

Back 54

tumor suppressor --> frequently mutated in prostate, glioblastomas, etc

normally is lipid phosphatase

PTEN mutation elevates PI3kinase/AKT/TOR pathways

Front 55

because the frequency of cancer is not linear with age, we know that...

Back 55

cancer is multigenic

Front 56

3 stages of cancer

Back 56

1) initiation
2) promotion
3) progression

Front 57

complete carcinogen

Back 57

can cause cancer all by itself...doesn't need promotor/initiator

Front 58

it's not just the stage of cancer that matters...

Back 58

it's the character of the tumor. same stage of disease an have different treatment outcomes

Front 59

what technology is being used to understand individual tumor character better?

Back 59

microarrays

Front 60

monoclonal

Back 60

group of cells all derived from one ancestral cell

Front 61

most cancers are

Back 61

monoclonal...so it all starts with 1 cell becoming abnormal

Front 62

80-90% of human cancers have

Back 62

environmental causation

Front 63

what are some good examples of environmental causation of cancer?

Back 63

1) lung cancer/smoking epi
2) stomach cancer/cured food epi
3) uterine cancer/ pap smear epi
4) migration studies

Front 64

as you follow generations, migrants acquire...

Back 64

the same spectrum of cancer as inhabitants of the host country

Front 65

what are the 2 biggest env. causes to US cancers?

Back 65

tobacco
diet

Front 66

initiators

Back 66

apply once
will not produce tumors
have memory
genotoxic

Front 67

promoters

Back 67

has to be given a bunch of times
AFTER the initiator
non-genotoxic

Front 68

procarginogens

Back 68

not carcinogenic as is, but are when metabolized

Front 69

genotoxic

Back 69

mutates DNA

Front 70

max concentration of a carcinogenic agent permitted in the environment should be set based on

Back 70

the most sensitive individuals

Front 71

short-term tests for genotoxic carcinogens

Back 71

Ames test --> count # of histidine-mutated colonies in dis

useful but not definitive