7 Molecular biology of Cancer

Question 1

What is cancer as a disease characterized by?

Answer 1

loss of regulation of the cell cycle

Question 2

Cancerous cell bypass normal cell division checkpoints and allows defective DNA replication. What does this lead to a greater frequency of?

Answer 2

aneuploidy or a the incorrect number of chromosomes

Question 3

describe in one word the division of cancerous cells

Answer 3

unregulated (NOT faster…)

Question 4

what are the three usual sources of DNA mutations?

Answer 4

ionizing radiation(UV)
chemicals
spontaneous errors during replication

Question 5

what are the two outcomes that can result if a mutation is detected by the cell?

Answer 5

corrections can be made and resume normal cell proccess

if mutation is severe or numerous enough –> apoptosis

Question 6

what are four diseases that is due to defects in DNA repair and what are their phenotypes as well as the process affected?

Answer 6

HNPCC –> mismatch repair leading to colon cancer

Ataxia telangiectasia which is a defect in the ATM gene (recognizes DNA damage) which will lead to increased x ray sensitivity and thus breast cancer

BRCA2 which is a defect in the repair by homologous recombination which can lead to breast, ovarian and prostate cancer

Xeroderma pigmentosum which results from mutation of the nucleotide excision repair which can lead to UV sensitivity and ultimately skin cancer

Question 7

what are the six characteristics of cancer cells?

Answer 7

infinite proliferation
anchorage independent
resistant to growth inhibition even with cell to cell contact
resistant to apoptosis
de-differentiation
metastatic

Question 8

what gives a mass of tumor tissue the ability to adapt and survive?

Answer 8

heterogenicity of the cells that gives the tissue traits that represents cancer are simply the make up of individual cells that may contribute to the tissue mass in an additive fashion

Question 9

cancers are based on what three factors of the tissue?

Answer 9

type, physio control mech, fxn of tissue

Question 10

give an example of the following and explain:
gain of function mutation
loss of function mutation

Answer 10

oncogenes are defined as gain of function mutations as they derive from previously inactive proto-oncogene sequences

tumor suppressor gene mutations are called loss of fxn oncogenes as their expression was what protected against cancer

Question 11

What are the 6 classes for which c-onc exists?

Answer 11

c-onc is a proto-oncogene found in cells (v-onc in virus)

1 growth factors
2 hormone/gh receptors
3 signal transduction proteins
4 GTP-binding proteins
5 nonreceptor kinases
6 transcription factors

Question 12

What activates the cell cycle? keeps it running? regulates it?

Answer 12

activated by GF and hormones

runs via cyclins and cyclin dependent kinases

regulated by cyclin-dependent kinase inhibitors

Question 13

what are the three ways by which protooncogenes can become oncogenes?

Answer 13

chem/rad mutation of gene or promotor

amplification of the proto-oncogene

gene rearrangement by binding of a strong promotor or new gene causing altered expression of the proto-oncogene

Question 14

explain the MAPK pathway

Answer 14

upon ras activation -> activate ref -> phosphorylate MEK -> phosphorylate MAPK which then can phosphorylate two things

AP-1 which activates jun/fos
transcription factors that induce myc/fos

both lead to cell proliferation

Question 15

what activates the ras pathway?

Answer 15

growth factor binding to a g-protein receptor

Question 16

define NF-1

Answer 16

it is a tumor suppressor which fxn to activate activate rasGTPase which inactivates ras from activating ref

defect in NF-1 will cause neurofibromatosis

Question 17

explain rb-1

Answer 17

rb-1 is a gene that creates rb(retinoblastoma protein) which is a tumor suppressor product
rb fxn to halt cell cycling at G1 phase via binding to E2F1 transcription factors

loss or mutation of rb-1 leads to retinoblastoma in young children/infants

Question 18

what is the fxn of E2F?

Answer 18

E2F initiates G1/S cell cycle transition period, thus rb binding will arrest cycling at the G1 checkpoint

Question 19

name the 4 key regulators of the cell cycle that are commonly dysregualted in cancers

Answer 19

p16/INK4
cyclin D
CDK4
Rb

Question 20

Explain how retinoblastoma can be de novo or inherited

Answer 20

rb-1 in sporadic retinoblastoma is initially normal and requires mutations of both sets of chromosome 13 at the long arm to cause cancer

rb-1 in familial retinoblastoma needs only one mutation of chromosome 13 due to a defective rb-1 in the other chromosome being passed down from the parent

Question 21

what is p53 and the three things it does in response to dna damage/hypoxia?

Answer 21

p53 is a transcription factor

• halts DNA synthesis to prevent replication of damaged DNA
• activates DNA repair mechanisms
• initiates apoptosis if damage is too severe via BAX gene or if DNA repair fails

Question 22

what can damage p53 or p27 genes lead to?

Answer 22

defective p53 can cause Li Fraumeni syndrome in which >25 fold incidence of cancer

p27 defect will lead to a loss of cyclin/cdk inhibition which served to block entry into S phase –> low p27 levels in breast cancer leads to poor outcomes

Question 23

explain the fxn of HH, patched and smoothened interaction and it’s dysfunction

Answer 23

HH is hedgehog ligand that binds to patched receptor(tumor suppressor) which inhibits its suppression of smoothened (oncogene) which will activate GL-1 complex that activates proliferation

defect in patched -> smooth cannot be inhibited even w/o HH

defect in smooth -> GL-1 activation even w/ normal patched and w/o HH

Question 24

Explain cadherin structure and cancers resulting from defects

Answer 24

cadherins anchor –> supported by catenin/actin intracellularly

cadherin CDH1 defect -> diffuse gastri cancer

Question 25

what are secondary roles of catenins other than as support for cadherins?

Answer 25

they are TF that can activate myc and cyclin D1

APC or adenomatous polyposis coli inhibits beta catenin which can result in sporadic colon cancer

also inherited -> FAP/familial adenomatous polyposis

Question 26

What are the extracellular and intracellular pathways of apoptosis?

Answer 26

removal of GF or binding of TNF extracellularly will activate caspase 8 and 10 which will activate caspase 3, 6 and 7

damage to mito will release cytochrome c that complexes with APAF-1 which will then activate caspase 9 which will then activate caspase 3 and 6

Question 27

Describe three subsets of BCL-2 and their fxn

Answer 27

anti-apoptotic -> Bcl-2 binds to proapoptotic and APAF-1 to inhibit apoptosis

channel forming proapop -> Bax -> already on mito membrane and forms pores so Cyto C can be released -> inhibited by Bcl-2

BH3 proapop -> Bid/Bim/Bad -> binds to Bax to activate and binds to Bcl-2 to inactivate as well as unbind APAF-1

Question 28

describe the conditions and result of the philadelphia chromosome

Answer 28

it is a 9:22 rearrangement where the abl gene from 9 fuses with bcr gene on 22 and makes the 22 chromosome into a phila chromosome

abl is a protooncogene for tyrosine kinase and bcr is for b cells

results in chronic myelogenous leukemia due to constant expression of bcr (CML)

Question 29

What causes burkitts lymphoma?

Answer 29

8:14 rearrangement where c-myc is promoted by a Ig heavy promotor thus leading to high c-myc -> high amounts of WBC

Question 30

what causes neuroblastoma?

Answer 30

N-myc which are amplified and cut out into double minutes or elongated the chromosome with a homogenous staining region (HSR) –> both cause cell survival in certain environments

Question 31

what are the four methods to targeting DNA replication in Cancer?

Answer 31

antifolates ie. methotrexate -> inhibs thymidilate synthase -> blocks purine synth

base analogues ie. 5-FU -> inhibs T creation from U

alkylating agents ie. cyclophosphamide/cisplastin -> heavily damages DNA -> trigger apoptosis

ionizing radiation -> heavily damage DNA -> trigger apoptosis

side note for the last two if cancer p53 is inactive, the treatment will not work

Question 32

what are the two methods that interfere with the mitotic apparatus

one way chokes off blood supply

two ways target oncogenic proteins

Answer 32

vinblastine depolymerizes microtubs
taxol polymerizes microtubs together the wrong way

Avastine inhibs VEGF which blocks angiogenesis

Herceptin is a monoclonal Ab that blocks Her2 protein found in many breast tumors
Gleevec/imatinib 1st rational drug design to bind bcr-abl tyro kinase and inactivate it

Question 33

What is the protooncogene that codes for the hedgehog receptor?

Answer 33

SMO