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Cellular ParticipationIn Physiology
Jim PierceJim Pierce
Bi 145aBi 145a
Lecture 3, 2009-2010Lecture 3, 2009-2010
Cellular Physiology
There is more to cells than just performing basal There is more to cells than just performing basal functions.functions.
Cellular Physiology is the study of how cells Cellular Physiology is the study of how cells perform both basal and tissue specific functions. perform both basal and tissue specific functions.
It is the bridge between molecular biology and It is the bridge between molecular biology and tissue function.tissue function.
Cellular Physiology
General Cellular PhysiologyGeneral Cellular Physiology
The study of inputs, metabolism, and outputs.The study of inputs, metabolism, and outputs.
Our goal for this lecture is to look at examples of Our goal for this lecture is to look at examples of inputs and outputs. inputs and outputs.
Cellular Physiology
Specific Cellular PhysiologySpecific Cellular Physiology This is the study of specific aspects of cellular This is the study of specific aspects of cellular
function.function.
Our goal in this lecture is to discuss some of the Our goal in this lecture is to discuss some of the common functions: membrane function, cellular common functions: membrane function, cellular structure, cellular motors, and secretion. structure, cellular motors, and secretion.
General Cell Physiology
Homeostasis versus Active FunctionHomeostasis versus Active Function Often, we want to do more thanOften, we want to do more than
“cruise along” at status quo. “cruise along” at status quo.
This means doing stuffThis means doing stuff
Homeostasis
What is homeostasis?What is homeostasis?
It is central to understanding physiology, and makes It is central to understanding physiology, and makes metabolism much easier.metabolism much easier.
It is the property of a system to try to maintain It is the property of a system to try to maintain constancy in the face of external perturbations.constancy in the face of external perturbations.
Homeostasis
RegulationRegulation When a system maintains some variable despite When a system maintains some variable despite
internal or external perturbation.internal or external perturbation. ControlControl
When a force adjusts the output of a system over When a force adjusts the output of a system over time.time.
Refrigerator ThermostatRefrigerator Thermostat Glycogen in a MyocyteGlycogen in a Myocyte
Homeostasis
Figuring out the Refrigerator is easyFiguring out the Refrigerator is easy
The thermostat controlsThe thermostat controls The “dial” indicates the set pointThe “dial” indicates the set point
A circuit in the Refrigerator regulates.A circuit in the Refrigerator regulates. It compares the actual temperature to It compares the actual temperature to
the thermostat’s set pointthe thermostat’s set point It heats or cools accordinglyIt heats or cools accordingly
Refrigerator
Cooling
Homeostasis
Glycogen is not so easy.Glycogen is not so easy.
What controls glycogen levels?What controls glycogen levels? There is no thermostat.There is no thermostat. The myocyte does not receive a specific The myocyte does not receive a specific
“glycogen level signal.”“glycogen level signal.”
Homeostasis
What controls glycogen levels?What controls glycogen levels? There are external signals that inform the myocyte of the There are external signals that inform the myocyte of the
state of the body.state of the body.
There are internal signals that inform the myocyte of the There are internal signals that inform the myocyte of the state of the cell.state of the cell.
The cell must integrate these signals to make that The cell must integrate these signals to make that decision.decision.
Homeostasis
The way a cell integrates these signals to The way a cell integrates these signals to make that decision is calledmake that decision is called
A Control StructureA Control Structure
Homeostasis
How is glycogen level regulated?How is glycogen level regulated? Because there is no thermostat,Because there is no thermostat,
it is not a simple “compare” like the fridgeit is not a simple “compare” like the fridge
Instead the pathway “pays attention” to every Instead the pathway “pays attention” to every reaction, intermediate, and final productreaction, intermediate, and final product
This is called This is called a Regulatory Structurea Regulatory Structure
Homeostasis
How is glycogen level regulated?How is glycogen level regulated?
The Regulatory Structure is affected by The Regulatory Structure is affected by the Control Structure.the Control Structure.
It is through those interactions thatIt is through those interactions thatthe Regulatory Structure obeys thethe Regulatory Structure obeys theControl StructureControl Structure
Homeostasis
What makes up these structures?What makes up these structures?
Cells Do Chemistry.Cells Do Chemistry. (they do physics, too, but I don’t like physics so I won’t (they do physics, too, but I don’t like physics so I won’t
talk about it)talk about it)
Chemical Compounds (stuff)Chemical Compounds (stuff) Processes Involving Chemical Compounds (a way Processes Involving Chemical Compounds (a way
to change stuff)to change stuff)
Homeostasis
Structures are composed of reactionsStructures are composed of reactions
A B
C D
E F
Metabolism
(in a nutshell)
supply demand
Xsource --> M --> Xsink
Regulatory Network
(in a nutshell)
supply demand
Xsource --> M --> Xsink
Control Network
(in a nutshell)
supply demand
Xsource --> M --> Xsink
Why is this confusing?
The final product has the greatest effect on The final product has the greatest effect on the flux through metabolismthe flux through metabolism
So the USE of the final product So the USE of the final product exerts CONTROLexerts CONTROL
Regulation versus Control
So certain Regulatory structures giveSo certain Regulatory structures give“Control” to the end product“Control” to the end product
This is probably why biologists use This is probably why biologists use “regulate” and “control” interchangeably“regulate” and “control” interchangeably
Just remember, like precision and accuracy, Just remember, like precision and accuracy, control and regulation are different!control and regulation are different!
Metabolism and its Control
So how do we describe these things?So how do we describe these things?
We start with a Model of the systemWe start with a Model of the system
Metabolic Pathway
A B C D
A set of metabolites and reactions involving those metabolites.
(note that a metabolic pathway can be described by graph theory)
Generalized Linear Metabolic Pathway
A B C D
Generalized Branched Metabolic Pathway
Generalized Substrate Cycle
Metabolic Network
Control and Regulation
We can then describe how any given thing We can then describe how any given thing (enzyme, molecule, extrinsic parameter) (enzyme, molecule, extrinsic parameter) affects any other given thingaffects any other given thing
This gives a bunch of variablesThis gives a bunch of variables
This allows a mathematical modelThis allows a mathematical model
Control in Dynamical Systems
Models That Exist:Models That Exist:
Linear SystemsLinear Systems Linear ModelsLinear Models
Non-Linear SystemsNon-Linear Systems Non-Linear ModelsNon-Linear Models Linear ModelsLinear Models
If you want to
learn m
ore
Take CDS 101, 1
10
Metabolism
There is more to metabolism than just the graph of There is more to metabolism than just the graph of the reactionsthe reactions
Location of the reactionsLocation of the reactions Cytosolic, Membrane Bound, NuclearCytosolic, Membrane Bound, Nuclear
Job in “the bigger picture”Job in “the bigger picture” Anabolism versus CatabolismAnabolism versus Catabolism
Control by Supply
Feedforward Control:Feedforward Control:
1) Can achieve high control of flux1) Can achieve high control of flux
2) High control of flux forces us to have low 2) High control of flux forces us to have low control of metabolites!control of metabolites! (That means AMPLIFICATION)(That means AMPLIFICATION)
Control By Demand
Feedback ControlFeedback Control
1) Can achieve high control of flux1) Can achieve high control of flux
2) High control of flux forces us to have high 2) High control of flux forces us to have high control of metabolites!control of metabolites!
Metabolic Control Analysis
We can We can proveprove that: that:
1) Feedback is the way we get control of both 1) Feedback is the way we get control of both flux and concentration.flux and concentration.
2) Feedforward is the way we get control of flux 2) Feedforward is the way we get control of flux and amplification.and amplification.
Internal State
The first consideration in “doing stuff”The first consideration in “doing stuff”is the Internal State of the Cellis the Internal State of the Cell
The set of DNA, RNA, and protein (especially The set of DNA, RNA, and protein (especially “transcription factors”)“transcription factors”)
Organelles and CompartmentalizationOrganelles and Compartmentalization Membrane and its PotentialMembrane and its Potential Secondary messengersSecondary messengers
Internal State
Sometimes, the decision to ActivateSometimes, the decision to Activateis the Internal Stateis the Internal State
The best studied example is Cell CycleThe best studied example is Cell Cycle There is an internal clockThere is an internal clock
(multiple, actually)(multiple, actually) In many cases, the ticking of the clock alone is In many cases, the ticking of the clock alone is
the largest stimulus for cell divisionthe largest stimulus for cell division
Internal State
A closely related (and more interesting) example is A closely related (and more interesting) example is Early DevelopmentEarly Development
Much of the earliest patterning results from internal Much of the earliest patterning results from internal statestate Distribution of Bicoid mRNA (Drosophila)Distribution of Bicoid mRNA (Drosophila) Distribution of Vg-1 protein (Xenopus)Distribution of Vg-1 protein (Xenopus) Random Genetic and Positional NoiseRandom Genetic and Positional Noise
(Chick rotates with gravity, (Chick rotates with gravity, Mouse random based on position in ICM)Mouse random based on position in ICM)
(Bi 182 for more info!)
Internal State
Other basal functions include:Other basal functions include:
Basal secretion in glandsBasal secretion in glands Basal membrane potential patternsBasal membrane potential patterns Anabolism and Catabolism Anabolism and Catabolism
for Housekeepingfor Housekeeping
Internal State
In the case of cell cycle,In the case of cell cycle,the output includes:the output includes: Replicating DNA and organellesReplicating DNA and organelles Nuclear DivisionNuclear Division Cytosol DivisionCytosol Division
A huge number of checkpointsA huge number of checkpoints Lots of error correctingLots of error correcting
Internal State
In the case of early developmentIn the case of early developmentthe output consists of:the output consists of:
Spacial and Temporal PatterningSpacial and Temporal Patterningof space (intra and extracellular)of space (intra and extracellular)
Interpreting “Internal state” intoInterpreting “Internal state” intoCellular PhenotypeCellular Phenotype
General Cell Physiology
Obviously, though, internal state cannot be Obviously, though, internal state cannot be the only cue!the only cue!
In a complex organism, even making ATP In a complex organism, even making ATP depends on the state of the organism!depends on the state of the organism! (a fat cell should never steal glucose (a fat cell should never steal glucose
from a starving brain cell)from a starving brain cell)
General Cell Physiology
Types of Inputs:Types of Inputs:
Small MoleculesSmall Molecules Neurotransmitters, Steroids, PeptidesNeurotransmitters, Steroids, Peptides Non steroid, non peptide hormonesNon steroid, non peptide hormones
General Cell Physiology
Types of Inputs:Types of Inputs:
Large MoleculesLarge Molecules ICAMs, Selectins, IntegrinsICAMs, Selectins, Integrins LipoproteinsLipoproteins Other ImmunoglobulinsOther Immunoglobulins Other GlycoproteinsOther Glycoproteins
Small Molecules
Why Small Molecules?Why Small Molecules? They are very versatileThey are very versatile
They can carry information (in both They can carry information (in both concentration and concentration gradient)concentration and concentration gradient)
They can diffuse or be transported.They can diffuse or be transported.
Small Molecules
Why Small Molecules?Why Small Molecules? They are very They are very efficientefficient
The earliest “computation” on small molecules The earliest “computation” on small molecules was probably bacterial chemotaxiswas probably bacterial chemotaxis
Food (i.e. reduced molecules) was transduced Food (i.e. reduced molecules) was transduced into swimming behaviorinto swimming behavior
Small Molecules
Why Small Molecules?Why Small Molecules? They are very They are very efficientefficient
This system can be harnessed by using specific This system can be harnessed by using specific small molecules as a signalsmall molecules as a signal
Ever notice that many neurotransmitters are Ever notice that many neurotransmitters are decarboxylated amino acids?decarboxylated amino acids?
Small Molecules
Examples of Small MoleculesExamples of Small Molecules
Addition / IntegrationAddition / Integration Two inhibitory cells both release GABA onto the Two inhibitory cells both release GABA onto the
same dendrite, increasing hyperpolarizationsame dendrite, increasing hyperpolarization Each parathyroid cell releases hormone into the Each parathyroid cell releases hormone into the
blood, and response is a function of “total blood, and response is a function of “total hormone” levels.hormone” levels.
Small Molecules
RetentionRetention Insulin binds to its receptor and is internalized, Insulin binds to its receptor and is internalized,
providing continued signaling.providing continued signaling.
DegredationDegredation Serum Catecholamine-O-Methyl-Transferase has Serum Catecholamine-O-Methyl-Transferase has
different rates of catecholamine removal than different rates of catecholamine removal than neuronal reuptake machineryneuronal reuptake machinery
Small Molecules
GradientGradient Retinoic Acid (vitamin A) and HOX genesRetinoic Acid (vitamin A) and HOX genes DPP in certain non-mammal animalsDPP in certain non-mammal animals
TargetTarget Autocrine – stimulates selfAutocrine – stimulates self Paracrine – stimulates neighborParacrine – stimulates neighbor Neurocrine – neural synapseNeurocrine – neural synapse Endocrine – stimulates distant cell via bloodEndocrine – stimulates distant cell via blood Neuroendocrine – neural secretion into bloodNeuroendocrine – neural secretion into blood
Large Molecules
Why Large Molecules?Why Large Molecules? They can “mark” an area of extracellular space. They can “mark” an area of extracellular space.
(i.e. they stay put)(i.e. they stay put) They convey information about tissue structure They convey information about tissue structure
(both cell-cell and cell-ECM).(both cell-cell and cell-ECM).
Large Molecules
Consider Neural Crest CellsConsider Neural Crest Cells
Early development “encodes” space with a set of Early development “encodes” space with a set of small molecules, gradients, and large molecules. small molecules, gradients, and large molecules.
Neural crest cells migrate through this space, using Neural crest cells migrate through this space, using the cellular computer to respond to spacial the cellular computer to respond to spacial differencesdifferences
Large Molecules
Consider a skin injury…Consider a skin injury…
The cells at the edge of the injury lose the The cells at the edge of the injury lose the suppressing signal from cell-cell adhesion suppressing signal from cell-cell adhesion receptors. receptors.
……But they cannot grow without the stimulating But they cannot grow without the stimulating signal from the basement membrane.signal from the basement membrane.
Large Molecules
Thus, these large signals are key to tissue Thus, these large signals are key to tissue functioning.functioning.
We spend so much time thinking about the We spend so much time thinking about the small signals (Bi/CNS 150) that we small signals (Bi/CNS 150) that we sometimes forget how much information is sometimes forget how much information is encoded in these large molecules.encoded in these large molecules.
Large Molecules
Every time two cells stick together, they are Every time two cells stick together, they are communicatingcommunicating
Every time a cell sits in the extracellular Every time a cell sits in the extracellular matrix, it is listening to its surroundingsmatrix, it is listening to its surroundings
General Cell Physiology
Also remember: a huge portion of the signals Also remember: a huge portion of the signals are suppressive.are suppressive.
In the brain… In the brain… On the basement membrane…On the basement membrane… In the glands...In the glands...
General Cell Physiology
Secondary MessengersSecondary Messengers
yuk.yuk.
Secondary Messengers
Words of advice about these guys:Words of advice about these guys:
Anything can function as a secondary Anything can function as a secondary messenger if it can convey information, such messenger if it can convey information, such as small molecules, assembled structures, as small molecules, assembled structures, and even the membrane itself.and even the membrane itself.
Secondary Messengers
Always think about the cellular compartment where Always think about the cellular compartment where the secondary messenger is located; different the secondary messenger is located; different compartments have different properties.compartments have different properties.
The surface of the membrane is two dimensional, and The surface of the membrane is two dimensional, and therefore is better for diffusion. therefore is better for diffusion.
Cytosolic messengers can overcome three dimension Cytosolic messengers can overcome three dimension diffusion by assembly. diffusion by assembly.
On the flip side, cytosolic messengers can also change On the flip side, cytosolic messengers can also change compartments and locations in the cell. compartments and locations in the cell.
Secondary Messengers
Do not fall into the trap of thinking of certain Do not fall into the trap of thinking of certain messengers as “activating” or “suppressing.”messengers as “activating” or “suppressing.” cAMPcAMP cGMPcGMP Ca++Ca++
Secondary Messengers
““Secondary messengers” only get their name Secondary messengers” only get their name because they're supposedly restricted to the because they're supposedly restricted to the cell itself. cell itself. Some hormones (steroids) compute like Some hormones (steroids) compute like
secondary messengerssecondary messengers Some secondary messengers (nitric oxide) can Some secondary messengers (nitric oxide) can
change cells like hormones. change cells like hormones.
General Cell Physiology
Concept Questions?Concept Questions?
Cancer
We talked about:We talked about: HomeostasisHomeostasis Regulation versus ControlRegulation versus Control How one could actually study itHow one could actually study it
Now:Now: CancerCancer
Cancer
TumorTumor Tumere – “swelling”Tumere – “swelling” What can cause swelling?What can cause swelling?
Too Many CellsToo Many Cells Too Much Extracellular MatrixToo Much Extracellular Matrix Too Much FluidToo Much Fluid
NeoplasmNeoplasm Neo – “new”Neo – “new” Plasm – “growth”Plasm – “growth” Too Many CellsToo Many Cells
Cancer
NeoplasmNeoplasm Benign – Cells stay where they areBenign – Cells stay where they are Malignant – Cells invade somewhere newMalignant – Cells invade somewhere new Often benign ends in –oma (lipoma)Often benign ends in –oma (lipoma) Often malignant ends inOften malignant ends in
-carcinoma-carcinoma = malignant from epithelium= malignant from epithelium-sarcoma-sarcoma = malignant from = malignant from
meso/endotheliummeso/endothelium
Cancer
Is benign “benign?”Is benign “benign?” A benign fatty growth that squishes the trachea A benign fatty growth that squishes the trachea
and suffocates the patientand suffocates the patient
Is malignant “malignant?”Is malignant “malignant?” A slow growing skin cancer that never causes A slow growing skin cancer that never causes
any symptoms and the patientany symptoms and the patientdies 20 years later of a heart attackdies 20 years later of a heart attack
Cancer
Cancer
Multi-Hit Theory
Cancer doesn’t develop overnightCancer doesn’t develop overnight
After “watching” many different tumors, one After “watching” many different tumors, one begins to notice a progression.begins to notice a progression.
Over time, the tumor gets uglier, bigger, Over time, the tumor gets uglier, bigger, grows faster, and grows in new places.grows faster, and grows in new places.
Multi Hit Theory
The multi-hit theory was proposed simply by The multi-hit theory was proposed simply by watching the DNAwatching the DNA
The older or more severe the tumor…The older or more severe the tumor…
… … the more DNA mutations that the more DNA mutations that could be found.could be found.
Multi Hit Theory
So it was hypothesized that cancer develops So it was hypothesized that cancer develops by sequential epigenetic mutationsby sequential epigenetic mutations
In that case, a predisposition to cancer occurs In that case, a predisposition to cancer occurs from germ line mutations, which is how from germ line mutations, which is how many important genes were found many important genes were found
Multi Hit Theory
Further Support arrived with the Further Support arrived with the identification of viruses that induce canceridentification of viruses that induce cancer
These viruses contained mutated genesThese viruses contained mutated genes v-myc (v-genes in general) = Viral mycv-myc (v-genes in general) = Viral myc c-myc (c-genes) = Cellular mycc-myc (c-genes) = Cellular myc
Multi Hit Theory
These viral genes were calledThese viral genes were calledOncogenes – (onko (greek) – mass )Oncogenes – (onko (greek) – mass )
Their corresponding cellular genes were called Their corresponding cellular genes were called “proto-oncogenes” (proto – first)“proto-oncogenes” (proto – first)
They behave (generally) asThey behave (generally) asgain-of-function phenotypegain-of-function phenotype
Multi Hit Theory
Another class of genes were described that Another class of genes were described that provided “resistance” to carcinogenesis provided “resistance” to carcinogenesis from virusesfrom viruses
These genes were calledThese genes were calledTumor Suppressor FactorsTumor Suppressor Factors
They behaved (generally) likeThey behaved (generally) likeloss of function phenotypeloss of function phenotype
Multi Hit Theory
So the multi-hit theory is the idea that cancer So the multi-hit theory is the idea that cancer arises through a series of stepsarises through a series of steps
Each one corresponds to a “gain of function” or Each one corresponds to a “gain of function” or “loss of function” mutation“loss of function” mutationin a specific genein a specific gene
Thus explaining what surgeons had been Thus explaining what surgeons had been observing since Brahman period medicine in early observing since Brahman period medicine in early IndiaIndia
Multi Hit Theory
But that implies that cancer is But that implies that cancer is “Growth out of control”“Growth out of control”
Uncontrolled Cell Cycle, which accelerates Uncontrolled Cell Cycle, which accelerates and accelerates.and accelerates.
Cancer
So why is it so difficult to grow So why is it so difficult to grow cancer cells in a dish?cancer cells in a dish?
Cancer
Primary CulturesPrimary Cultures Died if they weren’t attached to a surfaceDied if they weren’t attached to a surface Died if there were too manyDied if there were too many Died if there were too fewDied if there were too few Died without serum or growth factorsDied without serum or growth factors Died with too much serum or growth factorsDied with too much serum or growth factors ……And often just died anywayAnd often just died anyway
Cancer
HeLa cellsHeLa cells 1951 – Johns Hopkins Medical School1951 – Johns Hopkins Medical School HeHenrietta nrietta LaLacks, mother of fourcks, mother of four Cervical Cancer cells were cultured by George Cervical Cancer cells were cultured by George
Gay, MD without permission.Gay, MD without permission.
They grew “horrifically”They grew “horrifically”
Cancer
Prior to HeLa cells, primary culturesPrior to HeLa cells, primary culturesof human cells had a “finite” lifespanof human cells had a “finite” lifespan
Just to keep them alive for a week took the Just to keep them alive for a week took the addition of “serum” with its panoply of addition of “serum” with its panoply of unknown factors. unknown factors.
Cancer
So how could cancer be so awful,So how could cancer be so awful,if it won’t even grown in a dish?if it won’t even grown in a dish?
The answer lies in “phenotypes”The answer lies in “phenotypes”
Cancer is better thought of as aCancer is better thought of as a“Disease of Gain-of-Phenotype”“Disease of Gain-of-Phenotype”
Cancer
There are many different phenotypes:There are many different phenotypes: NeedsNeeds
basement membranebasement membrane neighboring cellsneighboring cells growth factorsgrowth factors
AbilitiesAbilities Secretion, AbsorptionSecretion, Absorption MetabolismMetabolism Cell CycleCell Cycle ComputationComputation
Cancer
These include “new” or “unusual”These include “new” or “unusual”phenotypes:phenotypes: Invasion through basement membraneInvasion through basement membrane Ability to migrateAbility to migrate Ability to live in a new milieu Ability to live in a new milieu
BloodBlood Lymph NodesLymph Nodes Other Tissues Other Tissues
Cancer
Evasion of Immune SystemEvasion of Immune System Resistance to killing (similar to viruses)Resistance to killing (similar to viruses)
Resistance to AgingResistance to Aging TelomeresTelomeres DNA DamageDNA Damage
Cancer
Secretion of HormonesSecretion of Hormones Autocrine StimulationAutocrine Stimulation Growth FactorsGrowth Factors Recruitment of “support” (angiogenesis)Recruitment of “support” (angiogenesis)
Cancer
So every tumor is a different combination of So every tumor is a different combination of “phenotypes”“phenotypes”
Disease progression is sequential addition of Disease progression is sequential addition of new phenotypes, each which result from new phenotypes, each which result from mutationsmutations
Cancer
External / Internal signals for survivalExternal / Internal signals for survival
Gaining proliferative phenotypeGaining proliferative phenotype
Losing apoptotic / senescent phenotypeLosing apoptotic / senescent phenotype
Gaining metastatic phenotypesGaining metastatic phenotypes
Avoiding immune responeAvoiding immune respone
Angiogenesis and other novel phenotypesAngiogenesis and other novel phenotypes
Cancer
These mutations often make the cell appear These mutations often make the cell appear less differentiated and more multipotent.less differentiated and more multipotent.
So in many ways, understanding Cancer is So in many ways, understanding Cancer is very similar to understanding Stem Cells very similar to understanding Stem Cells (and their differentiation phenotypes)(and their differentiation phenotypes)
Cancer
For more on Clinical Aspects of CancerFor more on Clinical Aspects of Cancer
Try out my brand new Bi 23, Winter 09-10Try out my brand new Bi 23, Winter 09-10
Cancer Examples
Esophageal AdenocarcinomaEsophageal Adenocarcinoma Fastest Rising Western Cancer Fastest Rising Western Cancer
(~500% in the last 30 years)(~500% in the last 30 years)
Normal Esophageal Mucosa Normal Layers
Esophageal Cancer
Chronic gastroesophageal refluxChronic gastroesophageal reflux Leads to Acid and Bile ExposureLeads to Acid and Bile Exposure
The cellsThe cellswill try towill try toprotectprotectthemselvesthemselves
Barrett’s EsophagusWith Esophagitis
Esophageal Cancer
To defend itself, the cell “gains” the To defend itself, the cell “gains” the phenotype of “mucous secretion”phenotype of “mucous secretion”
Normal Barrett’s
Esophageal Cancer
This is called “metaplasia”This is called “metaplasia”- Metaplasia is when one tissue type changes to - Metaplasia is when one tissue type changes to
another tissue type that “naturally” occurs in the another tissue type that “naturally” occurs in the body in a different locationbody in a different location
Metaplasia requires that the cell respond to Metaplasia requires that the cell respond to stimuli and change phenotypestimuli and change phenotype
Esophageal Cancer
The mechanisms of metaplasia depend on The mechanisms of metaplasia depend on the tissue and stimulus, but often involve the tissue and stimulus, but often involve DNA damageDNA damage
In the case of Esophageal Cancer, bile acids In the case of Esophageal Cancer, bile acids are carcinogenicare carcinogenic Skin Cancer – UV lightSkin Cancer – UV light Lung Cancer – SmokingLung Cancer – Smoking Cervical Cancer – HPVCervical Cancer – HPV
Esophageal Cancer
Not surprisingly, continued acid exposure Not surprisingly, continued acid exposure allows progressive accumulation of DNA allows progressive accumulation of DNA damagedamage
It becomes carcinoma when:It becomes carcinoma when: It grows without regard to neighborsIt grows without regard to neighbors It is able to cross the basement membraneIt is able to cross the basement membrane
Esophageal Cancer
Adenocarcinoma
Barrett’s Adenocarcinoma
Cancer Progression
What we see is:What we see is: Primary Injury (bile)Primary Injury (bile) Progressive DNA damageProgressive DNA damage Gain of PhenotypesGain of Phenotypes
““Pre-Cancer” – not yet across thePre-Cancer” – not yet across theBasement MembraneBasement Membrane
““Cancer” – crossed overCancer” – crossed over Metastasis – gone somewhere else Metastasis – gone somewhere else
Good Cancer / Bad Cancer
Why focus on cell cycle and apoptosis?Why focus on cell cycle and apoptosis?
Removing checkpoints and error correcting Removing checkpoints and error correcting facilitates gain-of-phenotypefacilitates gain-of-phenotype
Apoptosis is the solution for excessive DNA Apoptosis is the solution for excessive DNA damage, broken apoptosis leads to proliferation damage, broken apoptosis leads to proliferation despite severe damage.despite severe damage.
Questions?