question

benign tumors

answer

abnormal proliferation of cells Has the potential to develop into a malignancy, a cancer - step one or two down the multistep pathway leading to cancer missing two key elements of a malignancy: Not invasive - don't have the ability to leave their specific area and infiltrate into surrounding tissues Lack ability to undergo metastasis - ability for a cancer to disciminate throughout the body - Move through site of origin to a different place, normally worse for the patient (Usually through the circulatory and lymphatic systems)

question

Two main characteristics of a malignancy

answer

invasive - has the ability to leave their specific area and infiltrate into surrounding tissues ability to undergo metastasis - ability for a cancer to disciminate throughout the body Move through site of origin to a different place, normally worse for the patient (Usually through the circulatory and lymphatic systems)

question

most cancers are adult/childhood

answer

most cancers are adult cancers childhood cancers are relatively rare

question

spectrum difference in adult vs. childhood cancers

answer

In adults, most all involve epithelial cells (~90%) Childhood cancers - completely different spectrum More leukemia, lymphoma, involve nervous system, brain tumors, etc.

question

Study of philadelphia chromosome - conclusions

answer

Philadelphia chromosome - is a signature chronic milogenis luekemia (CML) Translocation involving chromosomes 9 and 22 - Flip flop long arm of 22 with tip of 9 if sequence the breakpoint: - in same person, all cells of cancer have breakpoint at exact same location: means cells are clonal, all derived from a single population of cells - if compare cells of different patients, breakpoints in different places conclusion: cancer cells usually derive from a single cell or primary tumor (then are cloned and amplified into the malignancy)

question

Translocation

answer

exchange of nonhomologous chromosomes

question

genetic recombination

answer

exchange of homologous chromosomes

question

clonal cells

answer

means that all derived from a single cell or primary tumor then cloned and amplified ex. philadelphia chromosome experiment

question

total cell division in human per lifetime

answer

10^16 total cell divisions in human life span

question

mutation frequency per gene per cell division

answer

10^-6 (about one in a million) - small, each one of our genes somewhere in our body has been mutated about 10 billion times individually rare events, but considering how many cell divisions there are, over the life span of a human being this is a very frequent occurrence

question

why doesn't cancer occur more frequently based on number of mutations

answer

Mutations must occur in a given cell, a single cell that experiences that many mutations that causes it to become cancerous Key - that in order for a cell to be cancerous, we have to have to the right set of genes be mutated to cause that transformation Evidence - it takes multiple mutations in genes A single gene mutation is not normally enough to provoke or create a cancer Have graph that shows us the relationship of age to cancer Goes up astronomically as you get older - because the older you are the more time you have had to accumulate the wrong set of mutations - allows cell to become cancerous The older - the more chance to accumulate mutations in these genes Epidemiological evidence suggests this to be the case - plot cancer as a function of age - cancer is primarily a disease of the elderly

question

carcinogenesis

answer

the genesis (beginning) of cancer important factor: mutations occur in cancer critical genes

question

genetic instability of cancer cells

answer

One of the ways cancer cells are different from stable, normal cell Instability at a number of different levels At the level of individual nucleotides - if look at mutation frequency it is much higher in cancer cells than normal cells Thus DNA repair in cancer cells is inherently more error prone than is DNA repair in normal cells At the chromosomal level - find cancer cells are very unstable Results show Aneuploidy - incomplete sets of chromosomes

question

aneuploidy

answer

incomplete sets of chromosomes - seen in virtually all cancer cells Have extra or missing chromosomes - aneuploidy at level of chromosomes Can also act at sequence level, having multiple chromosomal rearrangements aneuploidy results from translocation events - combining non homologous chromosomes seen in painted chromosomes pic

question

euploidy

answer

in humans 2n = 46 normal number of chromosomes and pairs of chromosomes

question

epidemiology

answer

Looks at a population, try and discern patterns/cause of disease

question

most cancers in adult have strong/weak environmental components - expand

answer

Most cancers in adults have a STRONG environmental component Something in their lifestyle/exposure that will dramatically influence cancer rates This data tells us there's either something in the environment that increases their rates of cancer OR there is something in the genetic background of those individuals that cause this difference Know the cause is environmental because if transplant people from one environment to another, and they adapt to the ways of the indigenous people, they also end up adapting to their cancer frequencies Thus it is not, in most cases, the genetics...IT IS IN THE ENVIRONMENT/LIFESTYLE

question

carcinogen (basic def)

answer

agent that causes cancer

question

3 sources of carcinogens (basic description)

answer

Chemicals - certain chemical agents that will increase cancer Radiation - main mechanism is DNA damage Viruses - viral etiology (fancy word for cause), one of the causes of cancer

question

chemicals

answer

Most carcinogens are mutagens (mutate by damage of DNA and provoking a misrepair ), but some must be activated

question

mutagens

answer

mutate by damage of DNA and provoking misrepair of DNA

question

ex. Aflatoxin (produced by Fungi)

answer

it is a procarcinogen - aflatoxin by itself is not carcinogenic/mutagenic - it must be activated Activation in mammals is going to occur primarily by liver enzymes - attempting to detoxify (paradox) with chemical modification Metabolized into oaflatoxin-2,3-epoxide (don't need to know name) which is an active carcinogen Has ability to bind to guanine in DNA - form of damage that can be misrepaired into a mutation Alone noncarcinogenic, after metabolize it, become carcinogenic

question

procarcinogen

answer

by itself is not carcinogenic, must be activated to become carcinogenic

question

2 different categories of chemical carcinogens (list)

answer

Initiators Promotors

question

chemical carcinogens - initiators

answer

Group of cells that are exposed to a mutagen, called an initiator (in this ex.) Mutagen/initiator will cause damage in DNA and induce a mutation Have a single cell that has been mutated

question

chemical carcinogens - promotor

answer

they are mitogens - chemicals that stimulate the cell cycle Number of compounds to which we are exposed that increase cancer frequencies not by causing mutations but by causing a proliferation of the cell type Cause a proliferation of the mutated cell type, increased the population of the precancerous region Cancer is the accumulation of a series of mutations - so the larger this mass of potentially cancerous cells - the greater the probability that one of those cells will accumulate enough mutations to become cancerous (Result of promoter carcinogen)

question

mitogens

answer

chemicals that stimulate the cell cycle

question

radiation

answer

source of carcinogen going to cause DNA damage, which causes mutations that increase the probability of cancer

question

Viruses - as carcinogen

answer

source of carcinogen used to think they were the main reason for cancer, then that they cause few if any cancers, then pendulum swing back Today, that viruses cause 15-50% of cancers, basically a significant number of cancers have viruses as part of their ediology Viruses as a singular event normally don't cause cancer in being a singular event, rather they are a contributing factor For all of these, the number of people infected is much larger than the numbers who develop cancer Predisposition - something that increases the probability of cancer, but doesn't cause cancer Do it in different ways, different molecular/cellular basis Signature of all of these viruses - cause chronic infections The chronic aspect is what really sets the stage for that cancer tissue Can be a long incubation period, cancer much later than had virus

question

signature of all viruses that act as carcinogens, result in cancer

answer

cause chronic infections The chronic aspect is what really sets the stage for that cancer tissue Can be a long incubation period, cancer much later than had virus

question

epigenetic

answer

a change that alters the gene expression but doesn't alter the DNA sequence itself, not a mutation, doesn't change the DNA sequence

question

2 epigenetic ways of turning off gene expression (list)

answer

1) change chromatin structure (euchromatin -> heterochromatin) 2) methylation of GC islands

question

epigenetic change of chromatin structure -> turn off gene expression

answer

if take euchromatin region of DNA and repackage/condense as heterochromatin effectively turned off transcription of those genes (this is the process that happens in all chromosomes during mitosis when they are condensed)

question

heterochromatin

answer

regions are not actively transcribed because chromatin structure much more tightly compressed

question

euchromatin

answer

nucleosomes are separated from each other, DNA more accessible to RNA polymerase and transcription

question

epigenetic methylation of GC islands -> turn of gene expression

answer

Methylation of cytosine nucleotides Important because cytosine is thought to be a target for methylation - specific methylases that will add a methyl group to that cytosine Methylation of GC islands turns gene transcriptionally inactive, turns gene expression off Demethylation turns gene expression back on

question

GC islands

answer

a bunch of GC nucleotides grouped together in clusters

question

methylase

answer

will add methyl group to something seen when methylating cytosine of GC islands -> turn off gene expression

question

pap smear - cancer usage

answer

allows us to see histological differences without taking full sections of tissue can see clear histological differences between normal cell and cancerous cell -> help doctor decide on diagnosis/treatment

question

adenoma

answer

benign tumor abnormal proliferation but lacks the ability to metastasize and invade surrounding tissue

question

adenocarcinoma

answer

malignant tumor much less favorable prognosis

question

2 main categories of cancer genes (list)

answer

protoncogenes -> oncogenes tumor suppressor genes

question

oncogenes (basic def)

answer

mutated protooncogene -> cause an overreactivity, sometimes referred to as a gain of function

question

protooncogenes

answer

nonmutated form, noncancerous if mutated becomes oncogene

question

Protooncogen mutation is a single event - dominant mutation

answer

dominant - means only need one allele mutated single event means that one mutation is all you need to go from pro to -> oncogene

question

gain of function mutation

answer

seen in pro to -> oncogene Mutated gene has an additional function than seen in a normal gene enable oncogenes to promote cellular transformations

question

dominant mutation event

answer

means only need one allele mutated

question

recessive mutation event

answer

need both alleles mutated

question

density dependent inhibition

answer

same as contact inhibition Normal cell, form a monolayer - a single cell layer thick across the bottom of the petri dish when bump into neighbors, will recognize this and stop dividing

question

contact inhibition

answer

same as density dependent inhibition Normal cell, form a monolayer - a single cell layer thick across the bottom of the petri dish when bump into neighbors, will recognize this and stop dividing

question

cancer cells do/don't exhibit contact inhibition

answer

DON'T exhibit contact inhibition Will continue to proliferate even when they are touched by their neighbors Their behavior in vitro is very much like their behavior in vivo

question

transfection experiment

answer

add DNA from cancer cells to normal epithelial cells Able to render normal cells to be cancerous cells In some cases, take these cells and put them in mice - show that cells cause cancer in vivo Allowed investigators to identify specific DNA sequences that are causing this

question

V-onc

answer

viral oncogenes general term for a gene that causes a cell to be cancerous very similar (in structure and sequence) to the C-onc (cellular oncogenes) that were identified by transfection experiments

question

C-onc

answer

cellular oncogenes that were identified by transfection experiments What's really happening - in most cases we have protooncogenes (indigineous, normal, nonmutated genes, normal function to help progress the cell cycle forward) When mutate, goof up the cell cycle, cause it to advance forward more than it should Mutation of protooncogenes renders it a c-onc very similar in structure to v-onc

question

Viral oncogenes have moved from virus into genome OR genome into virus? explain!

answer

Viral oncogenes have moved from genome into virus, rather than reverse At first thought it was the viral oncogenes that are getting into our genomes and have the potential to cause cancer What's really happening - in most cases we have protooncogenes (indigineous, normal, nonmutated genes, normal function to help progress the cell cycle forward) When mutate, goof up the cell cycle, cause it to advance forward more than it should Mutation of protooncogenes renders it a c-onc Dominant mutation, gain of function mutation Very similar in structure to v-onc

question

cancer critical genes

answer

Genes that when mutated result in transformation of a normal cell into a malignancy

question

protooncogenes

answer

Genes that when mutated in a dominant, gain of function fashion - meaning that a single allele mutation is enough at that locus Meaning that they take on a new function rather than losing a funciton

question

mechanisms by which a protooncogene becomes activated to become an oncogene (list and basic result)

answer

deletion or point mutation in coding sequence - hyperactive protein made in normal amounts regulatory mutation - normal protein greatly overproduced gene amplification - normal protein greatly overproduced chromosome rearrangement: - nearby regulatory DNA sequence causes normal protein to be overproduced - fusion to actively transcribed gene produces hyperactive fusion protein

question

regulatory element

answer

usually occurs upstream of gene, before gene is transcribed if mutated - Results in an overproduction of the protein Normal protein, just too much of it Typically result in overproduction of mRNA which is translated into protein

question

gene amplification (mutation)

answer

Instead of just having one copy of the gene on each chromosomes, have multiple copies of it Each gene transcribed normally - hence have more protein than we want

question

2 categories of chromosomal rearrangement (mutation, basic def)

answer

puts a regulatory element in close proximity to the gene Translocation - bringing together two nonhomologous chromosomes

question

chromosomal rearrangement that puts a regulatory element in close proximity to the gene ex./result

answer

Ex. Have translocation that puts an Enhancer (enhance rate of transcription), put close to structural component of gene -> overproduction of protein (completely normal protein, but present in excess)

question

translocation

answer

bringing together two non homologous chromosomes

question

chromosomal rearrangement - translocation (result of mutation)

answer

result: fusion protein Light blue is amino acid sequence from one gene, dark blue is amino acid sequence from another gene Hybrid gene, contains components of two different proteins Results in hyperactivity

question

automobile - protooncogenes analogous to __________. effect of mutation - analogy result

answer

protooncogenes are analogous to the accelerator In a normal cell we are able to regulate the "speed" or rate Mutations - equivalent to "flooring it", stuck accelerator -> rapidly cell cycling

question

minute

answer

very small chromosomes usually occur in pairs really extra-chromosomal pieces of DNA

question

tandem duplication

answer

had gene amplification, but all the copies have stayed contiguous to one another

question

2 mechanisms of amplification -> gene amplification (list, result)

answer

minute tandem duplication result: Rather than replicating the protooncogenes once in a cell cycle, they become replicated many times in a cell cycle -> increasing their number so that we see both or one of these two results

question

tumor suppressor genes - car analogy (mutation and result)

answer

Analogous to the brakes on the car occasionally used to slow the cell cycle down, access cell cycle status Most genes that work in cell cycle checkpoints are in fact tumor suppressor genes Access status of the cell and have ability to transiently stop or at least slow down the eukaryotic cell cycle What happens if have a defect in protooncogenes - analogous to having a defect in the brakes - unable to slow down

question

mutation in both protooncogenes and Tumor suppressor genes (car analogy, result)

answer

Bad news if have mutation in protooncogenes -> oncogenes (causing accelorator to be stuck) and in Tumor suppresor genes (take out the brakes) results in cells that are cycling out of control

question

tumor suppressor gene - mutation, result

answer

undergo mutations called "underactivity mutations" or "loss of function mutations" that cause the cells to become cancerous Oposite of gain of function for protooncogenes These loss of function mutations - any sort of mutation that reduces or eliminates the activity of that gene product Takes two hits in order to render a problem - these mutations are RECESSIVE - so we have to have both alleles inactivated in order for there to be a problem Thus, heterozygous (one wildtype, one mutated) - no problem, just not able to apply brakes with full out force of normal Some gene product still exist so able to still have some brake function Second hit - major problems, no brakes

question

under-activity mutation

answer

aka loss of function mutation cause cell to become cancerous lose a function - reduce or eliminate activity of that gene product seen in tumor suppressor genes

question

loss of function mutation

answer

aka under-activity mutation cause cell to become cancerous lose a function - reduce or eliminate activity of that gene product seen in tumor suppressor genes

question

recessive mutation

answer

takes two hits on loci in order to render a problem have to have both alleles inactivated in order for there to be a problem seen in tumor suppressor genes -> Thus, heterozygous (one wildtype, one mutated) - no problem, just not able to apply brakes with full out force of normal Some gene product still exist so able to still have some brake function Second hit - major problems, no brakes

question

how to identify tumor suppressor genes

answer

based solely on pedigree analysis

question

retinolblastoma - details, hereditary version

answer

first tumor suppressor gene to be molecularly identified Normal individual has 2 copies of good Rb gene Some heterozygous, but not a problem Hereditary form of retinolblastoma, basis to fact that individauls inherit one defective allele, deffective Rb gene Relatively less infrequent to have a hit in the second gene Have examples of two hits, have excessive cell proliferation -> rettinolblastoma because the tumor suppressor gene is inactive Clinically - people with the inherited mutation develop multiple tumors in both eyes, fairly early in their lifespans Half way there with inherited one mutant Rb, thus only need one hit to develop cancer

question

results of hereditary version of retinolblastoma

answer

Clinically - people with the inherited mutation develop multiple tumors in both eyes, fairly early in their lifespans Half way there with inherited one mutant Rb, thus only need one hit to develop cancer

question

nonherditary version of retinolblastoma

answer

aka SPORADIC fashion Clinically happens very infrequently (1/30,000) - rare cancer This is where an individual has one hit in a gene, then somewhere down the line has a second hit in that same gene -> cancer Occurs much later in life Normally only results in one tumor in one eye

question

number of ways to eliminate 2nd "good" allele in person with inherited mutant one Rb gene - list and short explanation

answer

Nondisjunction - have cell that's lost the second chromosome Have nondisjunction event then chromosome duplication (essentially the same thing) Mitotic recombination and gene conversion Deletion of the second allele Point mutation in the second allele All of these result in either changing or eliminating the wild type allele that is present in addition also have epigenetic changes that occur (no affect on DNA but change expression of gene) - condensation into heterochromatin - methylation of GC islands

question

microRNAs

answer

Small microRNA, only ~21 nucleotide pieces of RNA If look at the profile of microRNAs, about 70-100,000 different regions on our chromosomes that are going to be transcribed into microRNAs Those profiles are different in normal cells and cancer cells Different, and specific to that type of cancer in cancer cells One of the hallmarks of a cancer cell - has an altered display/production of these microRNAs Clearly micro-RNAs are one intrical part of the genetics of cancer

question

UTR

answer

untranslated region (5' UTR) Start codon and stop codon (3' UTR) in the UTR Thus head and tail are transcribed, but not translated into protein

question

microRNA and UTA interaction

answer

Not infrequent that microRNAs will bind to the 3' UTR and regulate translation of messengerRNAs Therefore if alter profile of these, altering the translation, affectively altering gene expression -> different profile of proteins

question

on average, there are about _____ mutations that alter amino acids in human cancers

answer

~80 mutations per human cancer this is not including the epigenetic mutations that silence genes without affecting DNA

question

"mountains and hills"

answer

Mountains - in almost all cases of a particular cancer, that gene is virtually always mutated One ex. Is p53 - frequently mutated in virtually all kinds of cancers Hills - gene has been mutated occasionally in that particular gene, but in most cases that particular gene has not been mutated

question

presence of hills - make it more challenging to "sequence" cancer because...

answer

Prior to this, most people thought there would be 80-100 genes, that if we understand their biology we can understand the biology of all cancers (MOUNTAINS) But now know there are also hundreds of hills - have ability to be mutated to cause cancer, but rarely utilized much more complicated than we thought

question

up to ___ cancers have been sequenced by whole genome sequencing

answer

up to 80 cancers sequenced allows us to asses differences at nucleotide sequence level

question

in childhood cancers there are only about ____ mutations vs. the ____ in adults that affect amino acids

answer

In childhood cancers there are only 11 mutations vs. the 80 in adults that affect amino acids in adult cancers Makes sense because children don't have as long to accumulate those mutations

question

in childhood cancers, mutation tend to affect ______ pathways

answer

In childhood cancers mutations tend to affect developmental pathways Regualtion that makes a muscle cell a muscle cell, etc.

question

role of stem cells in cancer biology

answer

cancer stem cells, cells that are actually replenishing the bulk of the cancer Thoughts previosly - all of the cells in a cancer are about the same, all equally malignant and equally proliferative People do experiments, take a particular type of leukemia cells and inject them into mice susceptible to leukemia Found, depending upon type of cancer, only about 1/million cells from this cancer were able to actually cause and sustain cancer Support idea that not all cancer cells are the same

question

only about __ / ___ cells from a cancer, when translocated into a mouse were able to sustain cancer

answer

only about 1 in a million cells from this cancer were actually able to cause and sustain cancer

question

can divide cancer cells into two main categories

answer

One - vast majority of cancer cells Two - cancer stem cells, cells that are actually replenishing the bulk of the cancer

question

stem cells (basic def)

answer

relatively undifferentiated cells, that have the ability to constantly regenerate, provide the pool of cells as we need to replenish them ex. white and red blood cells constantly turning over, stem cells that produce these new cells

question

importance of stem cells - demonstrated by radiation experiment

answer

If take an organism and whole body irradiate that organism - treat it with a relatively high dose of radiation, kill stem cell population That organism will be dead in a matter of months - because it needs those stem cells to replenish circulatory cells, epithelial cells, etc. Stem cells, apart from cancer, are intrigal to sustaining a multicellular organism because they are constantly replenishing a variety of cells

question

normal vs. cancer stem cell

answer

both are non differentiated and have the ability of self renewal normal - still exhibits response to normal contact inhibition cancer - doesn't display contact inhibition, no response to normal signals

question

2 important implications (stem cells based) that invoke understanding and treating cancers

answer

if treatment good at eliminating "other" cells but doesn't do anything to stem cells - not a very good therable think about using stem cells as therapeutic device quite apart from cancer - treat variety of "unrecoverable" injuries must keep in mind that stem cells could go rogue and become malignant -> cancer

question

using stem cells to treat other things, outside of cancer

answer

Ex. Treating parkinson's, alzheimers, regenerating nerves to help with spinal cord therapies Need to be increasingly mindful that as we do that, the stem cells could go rogue and become malignant and cause cancer

question

microEnvironment (basic def)

answer

the local environment of a cancer

question

solid tumor is much more than the sum of its parts..explain

answer

microEnvironment - the local environment of a cancer A solid tumor is much more than the sum of its parts In addition to the primary tumor cells, there are a variety of other cells in its micro environment that are there and serve a purpose Sometimes those cells have been brought there by the tumor cells

question

angiogenesis

answer

developing a blood supply Creating a circulatory system in a specific location Idea that there is a tumor cell, must encourage that circulatory system to grow in that environment Need nutrients and oxygen and etc. Only one ex. Of many microenvironment uses

question

mitogens

answer

stimulate the cell cycle cause mitosis and the cell cycle to move forward

question

growth factor

answer

cause the cell to get larger needed for nutrient activation and utilization

question

RAS

answer

key protein kinase that is part of signal transduction pathway RAS can mutate such that it is always on (constitutive) even in the absence of a growth factor - pathway always on cancer cells do that with mitogens and growth factors

question

warburg effect (details)

answer

1930's by scientist named Warburg If you compare a cancer cell to a non-cancer cell - you find that cancer cells utilize glycolysis a lot more than they utilize TCA cycle and electron transport Normal cell - will take glucose and run it all the way through glycolysis then to TCA cycle then to oxidative phosphorylation or the electron transport chain Warburg effect in cancer cells - things stop at glycolysis, forcing the cell to go through fermentation reaction (make lactic acid to regenerate NAD+) and generate ATP Recall: glycolysis/fermentation (2) are much less efficient in generating ATP than are running things like a normal cell (36) thus cancer cells are tremendously less efficient

question

hypothesis about why see warburg effect

answer

provides more intermediates to run those biosynthetic pathways - used for biosynthetic pathways OR ROS - reactive oxygen species When do oxidative phosphorylation, in best of all worlds, go ahead and reduce oxygen to water Doesn't always happen, at certain frequencies generate reactive oxygen species - have ability to damage variety of cellular constituencies Idea, if you shove more things into the into glycolysis, actually reduce ROS and cell would be less susceptible to stress Essentially turning down a stressful part of its machinery Basically - Reconfiguring the signalling pathways and altering cell growth

question

ROS

answer

ROS = reactive oxygen species When do oxidative phosphorylation, in best of all worlds, go ahead and reduce oxygen to water Doesn't always happen, at certain frequencies generate reactive oxygen species - have ability to damage variety of cellular constituencies Idea, if you shove more things into the into glycolysis, actually reduce ROS and cell would be less susceptible to stress Essentially turning down a stressful part of its machinery part of hypothesis of why see warburg effect in cancer cells

question

cancer cells mutate p53 -> result?

answer

Such a frequently mutated gene, so essential to so many cancers p53 is an integrated gene - such that it has the ability to sense a number of different signals of problems that lead to cancer cells Each one of those signals will activated p53 to cause: Senescence - stops cell from replicating Cell cycle arrest - p53 operates 2 checkpoints (not the metaphse-anaphase transition) - Normally transient - when cell cycle checkpoints work they normally work for a relatively short time period, fix whatever damage or problem is there, then cell cycle moves on - if becomes pervasive or too long, it could lead to apoptosis Sort of a one step two step process - one has cell cycle arrest - either damage is fixed or results in apoptosis Either problem is fixed or if problem is so overwhelming it results in apoptosis Apoptosis (usually result of above, cell cycle arrest)

question

3 results of signals activating p53

answer

Senescence - stops cell from replicating Cell cycle arrest - p53 operates 2 checkpoints (not the metaphse-anaphase transition) - Normally transient - when cell cycle checkpoints work they normally work for a relatively short time period, fix whatever damage or problem is there, then cell cycle moves on - if becomes pervasive or too long, it could lead to apoptosis Sort of a one step two step process - one has cell cycle arrest - either damage is fixed or results in apoptosis Either problem is fixed or if problem is so overwhelming it results in apoptosis Apoptosis (usually result of above, cell cycle arrest)

question

senescence

answer

stops cell cycle from replicating

question

p53 operates ____ cell cycle checkpoints

answer

operates 2 cell cycle checkpoints not including the metaphase to anaphase transition

question

cancer cells misrelate Bcl-2 family -> result?

answer

Bcl2 family - members that are either pro- or anti- apoptotic Cancer cells usually have ways of reducing apoptosis by over/under expressing the members of this family that would lead to reduced apoptosis

question

cancer cells misregulate IAPs and anti-IAPs

answer

IAP - inhibitor of apoptosis Can modulate apoptosis by blocking the caspases If a cancer cell overproduced IAPs, that would reduce the probability of apoptosis

question

3 ways cancer cells can make apoptosis more difficult to do

answer

mutation to p53 misregulation of Bcl-2 family misregulate IAPs and anti-IAPs

question

cancer cells must gain the ability to become metastic

answer

one of the barriers cancer cells must overcome Not infrequently, the primary tumor, although problematic, is not as problematic as these metastases Not just a local invasiveness but the ability to move throughout the entirety of the body Mediated through transport through circulatory or lymphatic Usually transported through the circulatory or lymphatic system Rare events When travelling through the bloodstream, fewer than 1 in 1000 cells will survive to form metastasis, probably much lower 1/mil

question

metastasis is a challenge, divided into two main activities

answer

Travel through circulatory system, not getting stuck, exiting Challenging, but near as much as colonization Colonization of remote size - set up shop in foreign tissue Exiting circulatory system and setting up the microenvironment - difficult hurdle cancer cells must hop

question

cancer cells must get oxygen - another barrier they must overcome

answer

There is a complex set of signalling that occurs to enable that angiogenesis process to occur Much of the signalling, at least one important element is through the gene Hif Hif (hypoxia inducible factor) Master protein that senses low oxygen tension - works to turn on expression a variety of other genes Orchestrates the process that will result in the tumor sending out growth factors that will attract the circulatory system (endothelial cells) to manufacture and extend into tumor region Whole series of genes that are associated with accomplishing that

question

angiogenesis

answer

process of creating a circulatory system used to bring oxygen and nutrients to the tumor

question

Hif

answer

hypoxia inducible factor Master protein that senses low oxygen tension - works to turn on expression a variety of other genes Orchestrates the process that will result in the tumor sending out growth factors that will attract the circulatory system (endothelial cells) to manufacture and extend into tumor region Whole series of genes that are associated with ac

question

cancer cell must escape immune surveillance

answer

Best evidence for this is a correlation between increased cancer rates in immuno-compromised individuals Immuno-compromised - people who for some reason have a weaker immune system or compromised system that's not operating at peak efficiency First of all susceptible to a variety of infections Also susceptible to a variety of cancers That basic observation points to the role the immune system plays in recognizing and removing these cancers In order to be a cancer - must escape immune surveillance

question

cancer cells have certain aspects that make them almost non-self

answer

Express tumor specific antigens Antigen - foreign entity, usually a protein, that our immune system recognizes If tumors express tumor specific antigens - would be recognized as foreign - and our immune system would recognize them and attack and irradicate them Process is "immune surveillance" At a very frequent occasion we are having cells that are doing other things to escape and become cancers, but are then recognized by our immune system and eliminated

question

antigen

answer

foreign entity, usually a protein, that our immune system recognizes

question

name 5 barriers cancer cells must overcome to become full fledged malignancy - hart man's list

answer

misrelate the cell cycle and growth misregulate apoptosis gain the ability to become metastatic get oxygen (through angiogenesis, signals through Hif) escape immune surveillance

question

list 10 things cancers must do to become cancerous - from old book figure overview

answer

evading growth suppressors avoiding immune destruction enabling replicative immortality tumor-promoting inflammation activating invasion and metastasis inducing angiogenesis genome instability and mutation resisting cell death deregulating cellular energetics sustaining proliferative signaling

question

sustained proliferative signaling (basic def)

answer

Cell cycle continue to go forward when we would normally not want the cell cycle to go forward

question

evading growth suppressors (basic def)

answer

Figure out how to not respond to signals that would normally tell a cell to stop proliferating

question

avoiding immune destruction

answer

Escaping immune surveillance (previous slide) mechanism

question

enabling replicative immortality

answer

On the ends of chromosomes - telomeres - repeat sequences on the ends of chromosomes activate telomerase to continue rebuilding telomeres on ends of chromosomes -> basically cells are immortal

question

tumor-promoting inflammation

answer

Find cells of the immune system - lymphocytes - provoking an inflammatory response by sending out chemical signals (integral part of tumors) that result in inflammation Evidence that this inflammatory response is helpful to cancer cells because it enables them to spread Tumors encourage the inflammatory responses by allowing the cells from our immune system to be present and stimmulate the process of inflammation

question

genome instability and metastasis

answer

cancer cells inheritantly unstable and have high mutation frequencies

question

deregulating cellular energetics

answer

Warburg affect Cancer cells fundamentally change their basic metabolism such that they are much more reliant on glycolysis than they are on Kreb's cycle and TCA cycle

question

epidemiology

answer

survival rates of populations in terms of cancer

question

4 main reasons we are "getting better at cancer"

answer

prevention (lifestyle) early detection more aggressive treatment combination therapy (largely empirical to date)

question

why does more aggressive treatment help us fight cancer

answer

Recognition that for many cancers we need to be very aggressive in our treatment of cancers Many times when we would knock down the cancer to below noticeable levels - say individual in remission (cancer not detectable) Found that unless the treatment was more aggressive, we would just knock the cancer into remission but when relapsed, cancer came back - it was much more difficult to treat that cancer Find that relapse cancer was much worse, relapse rates were much much higher unless treatment was much more aggressive Much of the treatment now is designed not only with knocking down the original cancer, but also looking at relapse rates When cancer relapses - often comes back in a more aggressive state Reason - the relapsed cancer has accumulated additional mutations that make it even more difficult to treat than the original cancer

question

combination theory

answer

Treating cancer with a number of different agents that operate in different points or different ways of acting to fight cancer Most cancer treatments have been largely empirical Have a treatment, find that works and we try something based upon the results of that initial treatment... Empirical - means looking at data that we have acquired from treatment of cancers Try to design treatments that perhaps will be better than that

question

empirical theory

answer

means looking at data that we have acquired from treatment of cancers then try to design treatments that perhaps will be better than that

question

rational therapy

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based on pure biology, pure science Knowing the molecular details of what makes a cancer different from another cancer Use radiation a lot

question

radiation therapy (empirical vs. rational)

answer

radiation discovered by accident in WWII empirically - try many different forms of that, don't know exactly how/why it worked rational - knowing something very specific about a cancer and then designing a chemical or therapy specifically for treatment of that cancer

question

basis of radiation - treatment of cancerous cell

answer

Tumor cells lacking p53, lacking cell cycle checkpoint Because lack cell cycle checkpoint - there is no cell cycle arrest Continue through cell cycle, undergo cell division with damaged DNA/chromosomes Greatly increases their susceptibility because they don't have enough time to repair DNA Continue forward through cell cycle with damage - much more sensative Result -> GRAPH: survival vs. dose Normal cell would be gradually decreasing Cancer cell would dramatically, almost straight down, decreases

question

three main ways we treat cancer (list)

answer

surgery radiation chemicals (chemotherapy)

question

if treat normal cell with ionizing radiation

answer

Going to induce p53 and cause cell cycle arrest Either result in apoptosis OR allow time for damage to be repaired and get normal cell division

question

graph of survival vs. dose of radiation

answer

Normal cell would be gradually decreasing Cancer cell would dramatically, almost straight down, decreases

question

problem with radiation

answer

Although do have slight difference that allows them to have some degree of selective toxicity But still damaging normal cells -> all sorts of problems/side effects by exposing them to radiation we are also exposing them to a carcinogen Increase mutation frequencies - have continued mutation selection and tumor evolution

question

basically, why does radiation work on cancerous cells

answer

the difference in cell cycle checkpoints is fundamentally the basis of how radiation works

question

list 4 chemotherapeutic drugs

answer

antimetabolites - many inhibit DNA synthesis topoisomerase inhibitors - cause strand breakage alkylating agents - DNA damage plant alkaloids (ex. Taxol-microtubule assembly/disassembly

question

antimetabolites

answer

may inhibit DNA synthesis include a series of drugs that inhibit DNA synthesis makes sense because cancer cells going to undergo more rounds of DNA synthesis than our normal cells explains common side affects of these drugs - nausea, hair loss, etc. (because any other cell in the body that is undergoing rapid cell cycle becomes more susceptible to these same drugs that we are using to treat cancer cells) type of chemotherapeutic drug

question

Topoisomerase inhibitors

answer

cause strand breakage act in front of replication forks to keep DNA in its normal tortional configuration inhibitors - act by mechanisms to cause DNA strand breakage because Topoisomerases are more important in replicating cells - so again targeting cells that are undergoing rapid cell cycle replication type of chemotherapeutic drug

question

alkylating agents

answer

cause DNA damage if cause DNA damage, should induce checkpoints - but checkpoints absent in cancer cells -> die type of chemotherapeutic drug

question

plant alkaloids

answer

ex. Taxol-microtubule assembly/dissasembly recall: microtubules are a part of the mitotic apparatus - inhibiting mitosis using these chemicals type of chemotherapeutic drug

question

explanation of side affects of chemotherapy

answer

Hair falls out, Upset stomach, nausea - effect epithelial cells and other cells in the body that are undergoing rapid cell cycling Any other cell in the body that is undergoing rapid cell cycle becomes more susceptible to these same drugs that we are using to treat cancer cells

question

gyrase

answer

type of topoisomerase goes ahead of the replication fork and unwinds the double helix to take up those turns that would build up

question

taxol

answer

ex. of a plant alkaloid compound that affects the microtubule assembly and disassembly Microtubules are apart of mitotic apparatus - inhibiting mitosis by using these chemicals

question

all chemotherapeutic drugs - common goal, way derived

answer

All of these agents, chemotheraputic drugs, are looking at and attacking certain parts of the cell cycle - that are moving forward more rapidly in cancer cells than in normal cells All of these were empirically derived Use of these were derived from people who did experiments- tried them, saw that they worked - might not know how they work in specific sense But they worked, lets try and modify the dose, way we treat them, combination, etc.

question

rational therapy

answer

designed to target specific cancers - based upon specific molecular knowledge trying to design agents that work very specifically based on specific molecular knowledge we have of that

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fusion protein result of philidelphia chromosome - genes

answer

break point includes parts of genes Bcr and Abl result - fused Bcr/Abl gene - characteristic of translocated philadelphia chromosome result in transcription of fusion mRNA and translation into fusion protein

question

novel protein

answer

protein that does not exist in normal cells

question

funcitoning Bcr/Abl protein

answer

binds atp (substrate) bind to active site - act as kinase to add a phosphate group important in this particular type of leukemia in sustaining the cell cycle

question

Gleevec

answer

scientists engineered this small molecule Has ability to bind to a site on Bcr/Abl fusion protein and inhibit the activity of the fusion protein Magic bullet because it is very specific to the particular protein Not going to attack any other proteins/enzymes that exist in our body first generation inhibitor

question

Problem with gleevec

answer

Cancer cells can mutate the fusion protein and become resistant to Gleevec Important in cases of relapse - because in most relapses we cant treat with the same chemical because the cancer cells that have relapsed have become resistant to it

question

First generation inhibitor

answer

ex. Gleevec - almost perfect fit for ATP binding site, it really fit very well into the active site of the fusion protein Great in terms of inhibiting it Bad such that mutations can arise easily that confer gleevec resistance

question

Second-generation inhibitors

answer

people created them, thinking beyond first generation inhibitors Designed such that it doesn't fit very well into the ATP binding site On one hand say that second generation not as good as first generation - true only in biochemical aspect, because doesn't fit as well in atp binding site Truth is it is better - it is more difficult to make mutations to resistance to this second generation inhibitor This compound doesn't bind as well - but by doing this it is more difficult to find a mutation that confers resistance to it - in fact makes it better than the first generation compounds

question

which is better..first or second generation inhibitors

answer

On one hand say that second generation not as good as first generation - true only in biochemical aspect, because doesn't fit as well in atp binding site Truth is it is better - it is more difficult to make mutations to resistance to this second generation inhibitor This compound doesn't bind as well - but by doing this it is more difficult to find a mutation that confers resistance to it - in fact makes it better than the first generation compounds

question

normal cell vs. cancer cell ability to fix DNA defects (DNA repair system)

answer

in normal cell: have some sort of problem during normal DNA replication (ex. Break) - have multiple repair pathways normally Repair pathways 1 and 2 - equally capable of repairing the damage - redundancy in terms of DNA repair capacity If take a normal cell and treat it with an inhibitor of pathway 1 - ok because can still utilize pathway 2 and fix DNA cancer cells - leading to their hypermutability - frequently defective in their DNA repair pathways Ex. Here is a cancer cell that has a functional pathway 1, but pathway 2 has been mutated such that it is no longer affective Can then treat this cancer with an inhibitor of pathway 1 - basically out of luck because doesn't have the redundancy seen in normal cells Capitalizing on the event that cancer cells have in making them mutationally active - reducing their DNA repair repertiore - making them more dependent on more limited DNA repair paths

question

pair of genes that are important to breast cancer

answer

Brca 1 and Brca 2 Often mutations in them result in increased levels of breast and ovarian cancer Genes that have associations with DNA repair pathways Mutations in either of these genes are more susceptible to these sorts of approaches

question

telomerase inhibitors

answer

Telomeres are the repetitive sequences on the ends of chromosomes Telomerase is the enzyme that is responsible for resulting in telomeres If can somehow inhibit telomerase - have a magic bullet that will attack the cancer cells and leave somatic cells alone, because most somatic normal cells don't have active telomerase There are a variety of telomerase inhibitor strategies that are under development

question

p53-based approaches to treating cancer (from figure)

answer

FOUR SIGNALS: Hyperproliferative signals DNA damage Telomere shortening Hypoxia RESULTS: Cell cycle arrest senescence apoptosis APPROACHES: reactivate mutant p53 by helping to fold better inhibit mdm

question

normal p53 (basic def)

answer

integrates a variety of signals - results in a series of things that we want to happen

question

approach - develop chemical that will help p53 fold better

answer

In other words, p53 has sustained a mutation such that it folds very poorly under certain conditions and thus is inactive If add chemical that specifically binds to p53 you can reactivate it

question

approach - inhibit mdm

answer

Mdm holds p53 levels in check Mdm binds to p53 and targets it for Ubquinilation and send it for proteolytic degradation If can somehow inhibit Mdm can treat that

question

immunotherapy - variety of different approaches

answer

vaccination approach Vaccinations that are developed against some specific viral cancers Ex. Human papaloma virus -> cervical cancer Other ways of using our immune system Use an antibody that would be coupled to a toxin - acts as sort of a magic bullet to be attracted to a cancer cell - has the ability to inactivate that cancer cell Number of different approaches Simple vaccination Use antibodies as carrier molecules to transport a toxin to the source of a tumor

question

vaccinations approach

answer

Vaccinations that are developed against some specific viral cancers Ex. Human papaloma virus -> cervical cancer

question

use immune system to treat cancer

answer

Use an antibody that would be coupled to a toxin - acts as sort of a magic bullet to be attracted to a cancer cell - has the ability to inactivate that cancer cell Number of different approaches Simple vaccination Use antibodies as carrier molecules to transport a toxin to the source of a tumor

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