Exam 1

Question 1

describe the hallmark of cancer: self-sufficient in growth signals

Answer 1

acquired capability
- normal cells require mitogenic growth signals before they can move from a quiescent state into an active proliferative state
oncogenes
1) produce their own growth signals via autocrine signaling
2) “bug neighbors” to make more growth factor
3) make more receptors for the growth factor
4) activates downstream creating a positive feedback loop

Question 2

describe the hallmark of cancer: insensitivity to antigrowth signals

Answer 2

acquired capability
- in normal tissues, multiple anti proliferative signals operate to maintain cellular quiescence and tissue homeostasis
pRB - recognizes if the cell is dividing too much in the cell cycle
TP53 - stops cell cycle of too many mutations (induces apoptosis)
NF2 - merlin -> sucks up signals and makes the cells less sensitive to GF
oncogenes avoid all of these things

Question 3

describe the hallmark of cancer: evading apoptosis

Answer 3

acquired capability
- a cell’s apoptotic program can be triggered by an over expressed oncogene
1) disrupts pathway to avoid TP53
2) necrosis - cells explode and releases pro inflammatory signals
3) inflammatory signals recruit immune system and promotes tumor growth

Question 4

describe the hallmark of cancer: limitless replicative potential

Answer 4

acquired capability
- once a normal cell population has progressed through a certain number of doublings, they stop dividing
oncogenes: phenotype suggesting limitless replicative potential
- differentiation/cell death - exit the cell cycle

Question 5

describe the hallmark of cancer: sustained angiogenesis

Answer 5

acquired capability
- all cells must reside close to a capillary blood vessel due to supply of oxygen and nutrients
tumors: activate the angiogenic switch by changing the balance of angiogenesis inducers and countervailing inhibitors
- needs blood because metabolically active
- VEGF - vascular endothelial growth factor
- FGF - fibroblasts growth factor

Question 6

describe the hallmark of cancer: tissue invasion and metastasis

Answer 6

acquired capability
- normal cells remain in place
tumor cells spawn pioneer cells that move out, invade adjacent tissues, and travel to new sites where they form new colonies
1) cell adhesion decreases
2) EMT - epithelial mesenchymal transition
3) invades blood vessels
4) escapes the vessel
5) finds new home

Question 7

describe the hallmark of cancer: genome instability

Answer 7

enabling characteristic
a growing number of other genes involved in sensing and repairing DNA damage or in assuring correct chromosomal segregation during mitosis is lost in different cancers
- mutations, epigenetic reprogramming, physical changes to chromosome
- faulty DNA repair pathway

Question 8

describe the hallmark of cancer: tumor-promoting inflammation

Answer 8

enabling characteristic
- all tumor cell contain inflammatory immune cells
- inflammation provides growth factors and enzymes that promote angiogenesis and invasion
- inflammatory cells release oxygen mutagenic

Question 9

describe the hallmark of cancer: deregulating cellular energetics

Answer 9

emerging hallmark
- uncontrolled cell division demands increase in fuel and biosynthetic precursors that is obtained by adjusting energy metabolism
- cancer cells carry out glycolysis and normal cells do not

Question 10

describe the hallmark of cancer: avoiding immune destruction

Answer 10

emerging hallmarks
- immune system can recognize and eliminate cancer cells
- successful cancer cells do not stimulate an immune response

Question 11

differentiate between benign tumors and malignant tumors

Answer 11

benign
- not evidence of cancer
- do not spread throughout the body (metastasize)
- can be life-threatening depending on location

malignant
- do not remain encapsulated
- show features of invasion
- metastasize

Question 12

describe carcinomas

Answer 12

• occur in epithelial cells
• 85% of cancers

Question 13

describe adenocarcinoma

Answer 13

cancers of granular tissue (breast)

Question 14

describe sarcomas

Answer 14

derived from mesoderm cells (bone, muscle)

Question 15

describe leukemia

Answer 15

cancer of blood cells
differentiation of a stem or precursor cell is blocked and the cell divides

Question 16

explain why most carcinogens (though not all) are also mutagens

Answer 16

carcinogens that do not directly damage DNA include substances that accelerate cell division, leaving less opportunity for the cell to repair induced mutations or errors in replication

Question 17

relate growth to cell number

Answer 17

cell growth/division results in 2 daughter cells

Question 18

relate differentiation to cell number

Answer 18

during differentiation cells enter an inactive phase of cell growth

Question 19

describe an oncogene and the type of genetic trait

Answer 19

a gene mutated so the protein product in produced in higher quantities or has increased activity and acts in a dominant manner to initiate tumor formation
- dominant - a mutation in one one allele is sufficient for an effect

Question 20

describe a tumor suppresser gene and the type of genetic trait

Answer 20

code for proteins that play a role in inhibiting both growth and tumor formation
- mainly recessive in nature because one intact allele is usually sufficient to inhibit growth
- both alleles of the gene must be mutated before the loss of function is actually seen phenotypically

Question 21

how does the environment influence your risk for cancer development

Answer 21

unprotected exposure to the sun exposes your skin to UVB radiation which can directly alter your DNA radiation which can directly alter your DNA by forming dimers and mutations

Question 22

explain how reproductive life influences our risk for cancer development

Answer 22

having children reduces the risk of breast cancer
- age of women at the time of birth and termination of menstrual cycle also influences risk
- hormonal contraception and fertility treatments also affect cancer risk by altering the ovulation schedule
- sexually transmitted human papillomaviruses can be found in the many cervical cancers

Question 23

explain how diet and exercise influences risk for cancer development

Answer 23

eating fresh fruits and vegetables, better foods decrease risk
- risk of breast cancer decrease when more physically active

Question 24

explain how alcohol influences risk of cancer development

Answer 24

alcohol is a carcinogen

Question 25

explain how smoking influences risk of cancer development

Answer 25

smoking causes lung cancer and 40% of cancer - 82 carcinogens found in cigarette smoke

Question 26

explain how age influences risk of cancer development

Answer 26

longer time allow for the cells to mutate

Question 27

explain a phase 1 trial

Answer 27

examine dose responses for assessing drug safety - using a small number of healthy volunteers for patients

Question 28

explain a phase 2 trial

Answer 28

examines efficacy in a larger group of people

Question 29

explain a phase 3 trial

Answer 29

should not be initiated prior to knowing the effective drug dosage - efficacy tested against conventional treatments

Question 30

describe kinases

Answer 30

encoded by one of the largest families of genes in eukaryotes - can be found at the cell surface as transmembrane receptors, inside the cell as intracellular transducers, or inside the nucleus - play critical role in major cell functions - cell cycle production, signal transduction, and transcription - mutational analysis of human protein tyrosine phosphates suggests several kinases act as tumor suppressors in some cancers

Question 31

describe RAS

Answer 31

a set of proteins encoded by genes which are mutated in over 50% of cancers - an intracellular transducer protein that acts downstream to the binding of a growth factor to its receptor and is involved in transmitting the signal from the receptor through a cell - reside in the intracellular side of the plasma membrane and are activated by the exchange of guanosine diphosphate for guanosine triphosphate

Question 32

describe p53

Answer 32

guard the integrity of the genome by coordinating responses of the cell (cell cycle arrest, DNA repair, apoptosis) - a tumor suppressor gene that inhibits carcinogenesis - mutated in more than half of all cancers - acts as a transcription factor and induces the expression of genes required to carry out its functions

Question 33

describe the structure of the 5' end of a eukaryotic gene

Answer 33

contains nucleotide sequences that make up the promotor region involved in regulating gene expression

Question 34

describe transition mutations

Answer 34

substitute one purine for another purine

Question 35

describe transversion mutations

Answer 35

substitute a purine for a pyrimidine or vice versa

Question 36

describe insertion/deletion mutations

Answer 36

can alter the reading frame and can also be called a frameshift mutation

Question 37

describe chromosomal translocations

Answer 37

exchange of one part of a chromosome for another part of a different chromosome and results in changes of the base sequence of DNA

Question 38

describe the carcinogen ionizing radiation and its mechanism of action

Answer 38

when high energy radiation, such as gamma rays strikes a particle in its path, electrons may be displaced from atoms within the molecule - the loss of one or more electrons converts the whole molecule from being electrically neutral to carrying an electrical charge - can damage DNA directly by causing ionization of the atoms comprising the DNA, or indirectly by the interaction with water molecules to generate dangerous intermediates called ROS

Question 39

describe the carcinogen ultraviolet radiation and its mechanism of action

Answer 39

the conjugated double bonds in the rings of the nitrogenous bases of DNA absorb UV radiation - the formation of a pyrimidine dimer causes a bend in the DNA helix and DNA polymerase cannot read the DNA template

Question 40

describe the carcinogen polycyclic aromatic hydrocarbons and its mechanism of action

Answer 40

additional rings and or methyl groups in the bay region of the 3 aromatic rings cans covert inactive phenanthrene into an active carcinogen - metabolized further in order to give ultimate carcinogen that will form adducts with purine bases of DNA

Question 41

describe the carcinogen heterocyclic aromatic amines and its mechanism of action

Answer 41

produced by cooking meat, formed by heating amino acids and proteins - further metabolic activation by the cytochrome p450 enzyme creates products that can be converted to arylnitrenium ions that can form covalent adducts with DNA

Question 42

describe the carcinogen nitrosamines and nitrosamides and its mechanism of action

Answer 42

found in tobacco or are formed when preservative nitrites react with amines in fish and meats during smoking

Question 43

describe the carcinogen alkylating agents and its mechanism of action

Answer 43

mustard gases - bi-functional carcinogen that damages DNA by forming DNA intra- and inter-chain crossing links directly

Question 44

describe the carcinogen fibrous minerals: asbestos and erionite and its mechanism of action

Answer 44

- asbestos induced mutagenicity, chromosomal abberations, and epigenetic alterations - erionite a fibrous zeolite formed by volcanic rock - exact mechanism unclear, may include generation of ROS, physical interactions with mitotic machinery, and induction of chronic inflammatory response in addiction to genetic and epigenetic alterations

Question 45

describe the DNA repair mechanism: one step repair

Answer 45

direct reversal of DNA damage - repair enzyme alkyltransferase directly removes an alkyl group from the O6 atom of guanine after exposure of DNA to alkylating carcinogens - a methyl ground is transferred to a cysteine residue on the alkyltransferase and it becomes inactive

Question 46

describe the DNA repair mechanism: base excision repair (5 steps)

Answer 46

targets base lesions occurring from oxidation, deamination, and alkylation 1) family of DNA damage specific glycosylases scan millions of base pairs for 8-oxoguanine lesions 2) glycosylases then flip the lesion outside of the helix and cleave the base from the DNA backbone, creating an abasic (AP) site 3) AP endonuclease creates a nick in the DNA stand 5' to the AP site, resulting in a 3' - hydroxyl end and a 5' - deoxyribosephosphate end 4) DNA polymerase beta removes the 5'-dRP and replaces the nucleotide 5) Ligase 1 seals the nick and the repair is complete

Question 47

describe the DNA repair mechanism: nucleotide excision repair

Answer 47

specific for helix-distorting lesions such as pyrimidine dimers and bulky DNA adducts induced by environmental agents - removal of damage by the excision of a fragment of up to 2 nucleotides in length

Question 48

describe the DNA repair mechanism: mismatch repair

Answer 48

corrects replication errors that have escapes editing the polymerases - includes base-base mismatches as well as insertions and deletions produced as a result of slippage during the replication of repetitive sequences

Question 49

describe the DNA repair mechanism: recombination repair

Answer 49

mend double stranded DNA breaks - homologous recombination depends on the presence of sister chromatids formed during DNA synthesis as a template for recombining severed ends

Question 50

Describe the chemo/radio therapy: alkylating agents and platinum drugs

Answer 50

alkylating agents have the ability to form DNA adducts by covalent bonds via an alkyl group - bi functional alkylating agents for intra-strand and inter-strand crosslinks in DNA that alter the conformation of the double helix or prevent separation of the DNA strand and interfere with DNA replication platinum based drugs form covalent bonds via the platinum atom - the resulting DNA damage induces apoptosis

Question 51

describe the DNA repair mechanism: antimetabolites

Answer 51

can mimic the role of endogenous molecules and inhibit nucleic acid synthesis

Question 52

describe the DNA repair mechanism: organic drugs: doxorubicin

Answer 52

a microbial anthracycline antibiotics that inhibits topoisomerase II, an enzyme that releases torsional stress during DNA replication by trapping single-strand and double-strand DNA intermediates - can also form DNA adducts and intercalate into DNA - diffuses across cell membranes and accumulates in most cell types

Question 53

describe the DNA repair mechanism: radiation therapy

Answer 53

reacts with water inside cells to generate ROS that damage DNA - apoptosis will be induced in cells that contain large amounts of DNA damage

Question 54

what are PARPs?

Answer 54

enzymes that are key in BER, a pathway that repairs DNA single-strand breaks - synthesize poly(ADP-ribose) polymers that rapidly bind to DNA strand breaks to amplify DNA damage signal and recruit DNA repair proteins

Question 55

what happens when there is an inhibition of PARP?

Answer 55

causes BER to be impaired and the accumulation of single-strand breaks can lead to double-strand breaks, normally repaired by homologous recombination pathways

Question 56

what are BCRAs?

Answer 56

BCRA1 and BCRA2 are tumor suppressor genes and patients that lack these functions that are treated with PARP inhibitors have impaired homologous recombination DNA repair pathways

Question 57

what are promotors and what is their role in gene expression?

Answer 57

a region of DNA where transcription of a gene in initiated - control the binding of RNA polymerase to DNA - mutations in this region can interfere with transcription factor binding and alter the regulation of gene expression leading to carcinogenesis

Question 58

what are promotor proximal elements and their role in regulating gene expression?

Answer 58

any regulatory sequence in eukaryotic DNA that is located close to a promotor and binds a specific protein thereby modulating transcription of the associated protein coding gene

Question 59

what are promotor distal elements and their role in regulating gene expression?

Answer 59

regulatory DNA sequences that can be many kilobases distant from the gene that they regulate - can be enhancers (inducing expression) or silencers (decreasing expression) - bind to activators and interact with mediator proteins and transcription factors

Question 60

describe the roles of HDACs in regulating histone/DNA interactions

Answer 60

remove acetyl groups - restore a positive charge to lysine residues of the histone tails which stabilize chromatin compaction and higher-level packaging - limits the accessibility of transcription factors and results in repression of transcription

Question 61

describe the roles of HATs in regulating histone/DNA interactions

Answer 61

add acetylene groups - acetylate specific histone-tail lysine and other non-histone proteins including transcription factors - neutralizes the positive charge on lysine residues and relaxes chromatin folding (looser chromatin allows for easier DNA transcription)

Question 62

describe the role of DNMT in regulating gene expression

Answer 62

enzymes that mediate the covalent addition of a methyl group from the methyl carrier, S-adenosyl-methionine - DNMT1 involved in conversion of semi-methylated DNA to fully methylated DNA during replication - addition of methyl groups may act to SILENCE genes through 3 processes 1) physically block transcription factor access to DNA 2) recruit other chromatin-modifying enzymes to alter chromatin structure 3) directly induce mutations via deamination

Question 63

describe the role of CpG islands in regulating gene expression

Answer 63

located in the promotor region of 50% of human genes - those found in gene promoter regions are not methylated in normal tissues and transcription may occur (active gene expression) - methylation is a heritable signal that is associated with a compacted chromatin structure and maintains gene silencing - methylated CpGs recruit methyl binding domain proteins and interact with HDACs and chromatin remodeling enzymes

Question 64

describe nucleoside DNMT inhibitors and how they attack cancer cells

Answer 64

nucleoside analogues that form irreversible covalent adducts with the DNA and trap the enzymes - blocks access of DNMTs to DNA, which reduces their ability to methylated DNA during replication, can lead to inappropriate silencing of tumor suppressors or expression of oncogenes - inhibits growth of tumor cells and induces apoptosis

Question 65

describe the role of telomeres on senescence

Answer 65

telomeres: repetitive DNA sequences and specialized proteins at the ends of chromosomes that function as a molecular counter of the cell's replicative potential - protects the ends of the chromosomes from digestion by nuclear enzymes and also prevent induction of mechanisms that repair DNA double-stranded breaks - directs the cell into the dividing pathway when it reaches critical length - cells with short telomeres escape senescence and become immortal

Question 66

describe the role of telomerase on senescence

Answer 66

telomerase: a ribonucleoprotein containing human telomerase reverse transcriptase and a human telomerase RNA - maintains telomere length in certain cell types - regulates senescence of cells through limiting ROS production which prevents telomere shortening and dysfunction

Question 67

how does telomerase work?

Answer 67

binds to a special RNA molecule that contains a sequence complementary to the telomeric repeat - extends (adds nucleotides to) the overhanging strand of telomere DNA using the complementary RNA as a template - prevents cell cycle arrest and senescence