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?