THE ORIGINAL CELLULAR PHONE: HOW A NATION OF

COMMUNICATING CELLS KEEPS YOU HEALTHY!

James E. Trosko, Ph.D.

246 Natl. Food Safety Toxicology Center

Dept. Pediatrics and Human Development

Michigan State University

East Lansing, Michigan 48824

and

Randall J. Ruch, Ph.D.

Dept. of Pathology

Medical College of Ohio

Toledo, Ohio 43614

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The Healthy Body as a Nation of Communicating Cells:

The United States is a nation of almost 300 million individuals, of different sexes, ages,

ethnicity, religious beliefs, and political views. Our nation and its individuals are at their

best when they can freely exchange information with themselves, other nations and

individuals across various levels of organization. We communicate with others by oral

and written words (language), sounds, facial expressions, body language, touch, and

smell. Communication leads to understanding, and if the two parties share similar views,

to trust and cooperation whether at the national or the individual level. Communication

makes us more "healthy" nationally and individually. We become "unhealthy” when

there is either no communication or miscommunication, because these lead to

misunderstanding, mistrust, hatred, and violence. Whether it's two nations, such as the

U.S. and Iraq on the verge of war or a husband and wife on the verge of divorce,

miscommunication can result in misunderstanding and potentially disastrous

consequences.

Like a nation comprised of millions of people, our bodies are composed of many cells; in

fact, there are approximately 100 trillion cells in the adult human body. Each cell starts

out genetically identical, yet ends up unique and organized into subgroups of similar cells

(tissues) that perform the necessary functions for the maintenance of the whole body.

Like a nation of individuals, communication between cells is necessary for the body to

function properly and remain healthy.

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The fertilized egg contains the genetic material from our mother and father via the sperm

and egg and gives rise to all of the cells in the adult body. Each of these cells contains a

unique set of approximately 30,000 genes that make up the human genome. The set of

genes each of us inherited from our parents is the foundation on which our cells respond

to various environmental factors and pyscho-social experiences (diet, medications,

pollutants, temperature, stress, etc.). The normal process of human development and

aging occurs when the fertilized egg develops in the uterus into a healthy embryo that

further develops into a viable fetus that is born and matures into a healthy child, adult,

and elderly geriatric. Throughout this process, the cells of the developing and maturing

individual, each with the unique set of inherited genes, must respond and adapt to its

environment, multiply, repair damage, sometimes die, and specialize (differentiate) into

all the cells needed for all the tasks of the body. This process is highly organized and

absolutely dependent upon cell-cell communication. Similar to a nation of individuals, in

the absence of cell-cell communication, "unhealthiness" or disease occurs (birth defects,

cancer, diabetes, deafness, infertility, nerve damage, etc.).

Within the embryo, however, some cells are set aside to provide more cells later in life

when other cells wear out, are injured, or are altered by disease. These cells are known as

“stem” cells and have the capacity for limitless regeneration. One excellent example is

the stem cells of the blood forming system. These cells replace old and damaged blood

cells on a continual basis or respond to stimuli (e.g., infections) by producing more cells.

But there are a variety of other types of stem cells in our body. Scientists are discovering

that these cells may replace old and damaged cells in all of the organs of our body such as

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the brain, heart, pancreas, and liver. When stem cells divide, one of the new daughter

cells becomes highly specialized or "differentiated" to perform the necessary functions of

the organ (for example, neurons in the brain and insulin-producing cells in the pancreas)

whereas the other daughter cell remains undifferentiated and continues as a stem cell.

Try to picture what is happening after the egg is fertilized and implanted in the uterus.

The fertilized egg divides to make two, four, eight, sixteen cells, etc. These cells form a

ball of cells that have the same genes and do pretty much the same thing. Then

something triggers these undifferentiated cells to specialize and develop into an embryo.

They do so by following a highly complicated set of "rules" that depend upon cell-cell

interactions and communication. As the embryo further develops into a fetus, groups of

cells form "micro-environments" or clusters of communicating cells that further develop

into the various organs. This involves highly scripted proliferation, death, and

differentiation of the cells and is carried out by the activation of new genes and the

inactivation of others. These processes - cell birth, death, and differentiation - occur over

and over on a grand scale during embryonic development with the result being, if all goes

well, a healthy fetus ready to be born. The development of any organism from a single

cell into a multi-cellular one, whether it is a primitive form such as a sponge, or a highly

evolved one such as a human being, is poorly understood. How is this delicate

orchestration of cell proliferation, differentiation, and death brought about?

Biological Cellular Communication: Humans today use much more sophisticated

means to communicate than did their ancestors. It was only a few centuries ago that the

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only means of communication was by the spoken and written word, body language,

drumbeats, smoke signals, and occasionally an accurately thrown rock or blow from a

club. Today we have much more sophisticated ways to exchange information with

people all over the planet and in outer space, and take these technologies for granted.

Wired and wireless phones, radios and walkie-talkies, television and video, paper and

electronic mail, and pagers and instant messaging enable us to "stay in touch" with others

and to exchange information and ideas in a rapid and sometimes seamless (or sometimes

senseless) manner.

But within our bodies, the 100 trillion cells are much better at communication. Our cells

are constantly sending and receiving information of all sorts using methods that make the

most sophisticated super-computer look like an abacus. As you read this, your eyes are

seeing the words, converting and sending the information via nerves to your brain,

processing and storing it there, and evoking a (hopefully positive) emotional response. In

the background, your muscles are telling you to get up and stretch, your heart is beating

smoothly, your temperature is tightly regulated, your breathing is neither too fast nor too

slow, and your digestive track has sensed your last meal and is breaking it down. All the

100 trillion cells of your body are receiving chemical and ionic messages, nutrients, and

oxygen and releasing useful molecules and waste products. They are quietly doing the

jobs their unique pattern of expressed genes has programmed them to do.

The number of cells in our healthy bodies is also tightly controlled because cell births and

deaths are in balance. This occurs with such precision that a Mercedes Benz engineer

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would be astounded. As you turn the page, dead skin cells are sloughed off on the paper

and are replaced by new cells that are the offspring of stem cells lining the base of the

skin. These new cells are pushed out to the surface of the skin by the continuous division

of the stem cells. As the cells move upward, they differentiate into layers of flat, tough,

waterproofing cells that provides a protective covering over our bodies that keeps

moisture in and bad things out.

These elegant processes are highly dependent upon complex cell-cell communication

systems that have evolved over millions of years. Cell-cell communication can be

subdivided into three types, extra-, intra-, and gap junctional intercellular

communication. Our cells are constantly releasing ions and molecules (growth factors,

neurotransmitters, hormones, etc.) that are "sensed" by close-by or neighboring cells or

that are released and carried by the blood to cells farther away. This is known as

extracellular communication. Usually "antennas" or receptors on the outside of a cell

detect these chemical signals, although some molecules can be detected without a

receptor. In either case, the detection of these molecular signals activates a cascade of

informative signals inside the cell (intracellular communication) that cause the cell to

modify its activity (adapt), change its function (differentiate), divide, or die.

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Many Forms of Cell-Cell “Communication” Regulate Tissue Function and Phenotype

ProgenitorCells

Substrate

Terminally-differentiated cell

Gap Junctions

Stem cell

Figure 1. This cartoon illustrates how three different kinds of cells within a tissue, the

stem cell, progenitor cells coupled by gap junction channels and the terminally-

differentiated cell communicate with each other. The stem cell communicates through the

extra-cellular substrate which triggers intra-cellular signals inside the cell. It is touching

its progenitor daughter cell via cell adhesion molecules. The progenitor cell receives

communication signals from both the cell adhesion molecules and the extra-cellular

substrate. All progenitor cells also communicate intra-cellular signals to their sister

progenitor cells via the gap junction intercellular channels. As a result, the progenitor

cells secrete extra-cellular communication molecules that can enter the blood stream to

communicate with distal cells that have receptors for those specific communication

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molecules (e.g., hormones, growth factor)( ) The progenitor cell can also

communicate with its terminally differentiated daughter cell via gap junctions Lastly, the

terminally differentiated cell, by also receiving signals from the extra-cellular substrate,

together with the gap junctional-intercellular communication signal, can secrete a

negative communicating signal back to the original stem cell ( ).

Overlying both extracellular and intracellular communication is a third form of cell-cell

communication, known as gap junctional intercellular communication. This type of

communication enables cells to exchange molecular and ionic signals directly through

tiny tunnels or passageways known as gap junctions that connect the interiors of

neighboring cells and, as we shall see, integrate a cell's response with other cells. (Figures

1 and 2).

Gap Junctions in Cellular Homeostasis

ToxicChemicals

receptorTranslational Regulators

Transcriptional RegulatorsPost translational Regulators

Biological End Points

Cellproliferation

CellDifferentiation

ApoptosisAdaptive responses ofdifferentiated cells

ExtracellularCommunication

IntracellularCommunication

Intercellular Communication

8

8

8 88

Growthfactor

Distal cell

is

= intercellular signal

Senescence

8

8

8 88

is

8

FIGURE 2. This cartoon tries to depict a general picture of how 100 trillion cells of the

body communicate with each other. The three cells illustrate two gap junctionally-

coupled cells in a tissue communicating with a cell from a distant tissue communicating

via an extra-cellular secreted molecule (e.g., hormones, growth factors). The extra-cellar

signaling molecules can trigger various intra-cellular signals in the target cell. These

intra-cellular signals can then be transferred to the neighboring cell via gap junctions.

Depending on the extra-cellular communicating molecule, the intra-cellular

communicating molecules can either increase or decrease the cells ability to transfer the

signals via gap junctions to its neighboring cell. As a result of either increased or

decreased gap junctional intercellular communication, the cell will either proliferate,

senesce, terminally differentiate or die of a programmed cell death ( “apoptosis”).

What is a Gap Junction and What Good is it?

Our bodies are not simply “skin-covered bags” filled with 100 trillion cells all sloshing

around like a water balloon. Our bodies have structure and the cells are held together and

organized into tissues; in turn, groups of tissues make-up organs. For example, the brain

contains many different kinds of neural cells, supportive (glial) cells, blood vessel cells,

and other cells. The liver contains hepatocytes, bile ductal cells, Kupffer cells, blood

cells, and others. The lungs are made up of over thirty different types of cells. Our

bodies have a structure or shape because the cells are attached to each other and to our

skeletons by several kinds of connections or cell-cell junctions. These junctions hold

cells together, form barriers to other cells and molecules, and in some cases, act as

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sensors that detect things outside the cell including other cells. Gap junctions are also a

type of cell-cell junction, but they are unique because they have pores or channels that

connect the insides of neighboring cells; other junctions do not have channels. (Figure 3).

FIGURE 3. This cartoon illustrates a gap junction. “Hemi-channels” or connexons,

consisting of six proteins called connexins that are coded by an evolutionarily-conserved

family of genes. When two hemichannels or connexons unite across the extra-cellular

space between two neighboring cells, they form a complete channel that allows ions and

small molecules from one cell to be transferred directly to the neighboring cell without

having to enter extra-cellular space.

The diameters of gap junction channels are very, very small - approximately 1.5-2

nanometers which is about 1/250,000 the width of the period at the end of this sentence.

Each channel is made from two hemi-channels or connexons. Proteins known as

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connexins form the connexons; each one contains six connexins so there are twelve

connexins in one complete channel. The human genome contains genes for

approximately twenty different kinds of connexins, so there are many potential building

blocks and combinations of connexins that cells can use to make gap junction channels.

But our cells usually express no more than three kinds of connexins. As will be

discussed below, however, this diversity enables cells to make a variety of channels with

unique properties.

Gap junction channels are so tiny that only very small molecules and ions can pass

through them from cell to cell. For example, amino acids, water, simple sugars, and most

intracellular signal molecules freely move through gap junction channels, but larger

molecules such as proteins and fats cannot. The channels are formed by the end-to-end

attachment of two "half-channels" or connexons when cells are in close proximity. The

connexons on opposite cells are attracted to each other in some unknown way and

connect or "dock" tightly together. Once two connexons are docked properly, the

complete channel will open and ions and molecules can then freely move between the

neighboring cells. In most gap junctions, several complete channels cluster in one small

region resulting in a gap junction "plaque". (FIGURE 4).

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FIGURE 4. This electron micrograph depicts a portion of a coupled pair of cells in

which a cross-section of a “plaque” or island of hundreds of coupled connexons

aggregate to form a “ gap junction”. Each cell can have multiple numbers and sizes of

these gap junction plaques, depending on the physiological state of the tissue.

This cell-cell movement of ions and molecules through gap junction channels is known

as gap junctional intercellular communication (GJIC). It is very important for the health

of the cell and the organism. GJIC helps balance and maintain cellular levels of critical

ions and nutrients, helps to supply neighboring cells with building blocks for larger

molecules, and helps coordinate cellular activities. Within most tissues, several gap

junction plaques connect the cells and in turn each is comprised of hundreds to thousands

of channels. Thus, although they are tiny, there may be thousands of channels that

connect two cells and effectively, there is plenty of room for molecular flow between

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them. In cells that are well-connected by gap junctions, molecules and ions move very

quickly from cell to cell so that within tissues, groups of cells respond more like a

functional unit than individual cells. Thus, GJIC is the rapid, direct flow of molecular

and ionic information between cells and helps to integrate the activities of multi-cellular

tissues. (FIGURE 5).

Physiological Functions of Gap Junctions

Homeostasisbuffering/sharing of ions,nutrients, and water

Electrical couplinglow-resistance synapsesin neurons and muscle

Embryogenesistransfer of “morphogenic”factors amongst cells indevelopmental fields

Enhanced Tissue Responsetransfer of second messengers fromstimulated to unstimulated cells

Metabolic supportnutrient transfer toavascular tissues

Regulation of Cell Growthexchange of growth controllingsignals between neighboring cells

FIGURE 5. This figure illustrates a number of the physiological functions that gap

junctional intercellular communication plays during embryogenesis, development of the

fetus, neonate, sexual and adolescent maturation, and adult functions in both electrically-

coupled tissues (e.g., heart) or non-electrically-coupled tissues (e.g., liver).

In the context of the organism, GJIC has many important functions. It helps control the

rates of cell births and deaths so that tissue size and activity remain constant. GJIC also

helps trigger cellular differentiation. By passage of intracellular signal molecules from

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stimulated to non-stimulated cells, GJIC also increases the overall response of the tissue

to a stimulus. In addition, gap junctions are the electrical pathways that certain types of

connect muscle cells (e.g., the heart, uterus, and digestive tract) and some nervous tissue,

and, thus, are critical for normal heartbeat, birth, digestion, brain activity, and other

functions. Gap junctions are "shipping lanes" for nutrients and waste products in tissues

that are not well supplied with blood vessels such as the lens of the eye and hardened

bone. Gap junctions are also involved in numerous other important cellular functions.

Thus, when an individual inherits a mutated form of a connexin gene, the cells that

express that gene will be unable to form normal gap junction channels and disease may

result. Several human diseases are due to the inheritance of a mutant connexin gene.

These include forms of nerve degeneration, deafness, cataracts, cancer, birth defects, and

skin disorders. (FIGURE 6).

Diseases Associated with Defective Gap Junctions

Cardiac arhythmia

Peripheral neuropathy

Hereditary deafness

Cataracts

Infertility

Teratogenesis

Cancer

Dysfunctional labor

Diabetes

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Figure 6. This figure illustrates what might happen if gap junctional communication is

disrupted, either by genetic mutations in the genes that code for the connexin proteins or

by environmental chemicals that could modify the numbers or functions of gap junctions.

In summary, GJIC enables cells to rapidly share critical ions and molecules that are

needed to regulate whether the cell remains inactive, proliferates, differentiates, commits

cell suicide, or adapts in response to external signals. This form of intercellular

communication integrates cells within a tissue so that they work together. When gap

junctions are defective, disease may result.

The highly coordinated systems of extra-, intra-, and intercellular communication are

characteristic of all multicellular organisms including humans. But the sciences of extra-

cellular and intracellular communication have had a long history of research (the

disciplines of physiology and biochemistry, respectively), whereas that of GJIC is a

relatively new area of research. This is in spite of the fact that gap junctions are found in

nearly all cells of the human body and throughout the animal kingdom including the most

primitive organisms such as sponges and jellyfish. In fact, gap junctions have been

around since multicellular organisms evolved from unicellular ones. Thus, gap junctions

are truly, "the original cellular phone."

CELLULAR PHONE NUMBERS: Now there might seem to be a problem with this

analogy between telephones and biological cellular phones. When humans call someone,

they dial a unique phone number for that person and in turn, each person in the USA has

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their own personalized phone number (sometimes more than one). But our cells only

have about twenty potential cellular phone “numbers” (the connexins) for 100 trillion

cells in the body. How can the cells communicate in a specific way? Well, it turns out

many cells “share” the same phone number (same type of gap junction) as in the old days

when there were “party lines”. Other cells, by virtue of expressing more than one

connexin and making connexon hemi-channels that contain combination of connexins,

communicate only with cells that make similar connexons.

Therefore, as an example, hepatocytes within the liver can communicate with other

hepatocytes because they both express a connexin known as connexin32, but not with

bile ductal liver cells that express connexin43. But these two groups of cells can still

communicate using extracellular communication, such as secreted growth factors or

hormones. Things, however, get a bit more complicated because combinations of the

twenty connexins provide even more specific communication routes. If more than one

connexin is expressed in a cell, there is the potential for several types of six-membered

connexons to be made: those containing only one type or a mixture of two or more.

But does this diversity of channel types have any relevance? Absolutely! The biological

reason for these twenty different connexins is that the various types of channels have

unique characteristics. Some molecules and ions pass through one type of channel better

than another. The expression (activity) of the connexin genes and the formation,

opening, and stability of the channels are controlled or regulated in different ways.

Lastly, only certain types of connexons can form functional channels with other types of

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connexons on adjacent cells. Sometimes gap junctions are "party lines" that allow many

cells to communicate; at other times they are highly specific with only a few cells "on the

line".

In many organs, cells of one type can communicate with other types of cells. What might

be the point of this? Cells have five basic cell choices or fates. Some cells have the

capacity to proliferate. Other cells need to differentiate into a highly specialized cell.

Still others, once terminally differentiated such that they cannot divide, must be able to

perform their differentiated function(s) and adapt to changing conditions such as

pancreatic cells that produce insulin when blood sugar levels increase. Other cells in

solid tissues must commit to undergo "cell suicide" or “programmed cell death” such that

tissue modeling or replacement with new, healthy cells can occur. Lastly, some cells are

destined to senesce, that is, to become non-proliferating, low activity, end-stage cells.

GJIC has been implicated in the determination of all of these cell fates. For example, in

the testes, developing sperm cells communicate by gap junctions with Sertoli cells. The

purpose of this is to trigger the differentiation process of the spermatocyte into a mature

sperm. The Sertoli cell is like a “nurse cell” and provides a molecular signal that triggers

the spermatocyte differentiation.

Disconnected Cellular Phones: Adaptive Response or Disease?

Gap junction-connected cells do not always stay that way. Sometimes, this is a normal,

biological process; other times, it is not. What happens when the biological cellular

phone is disconnected?

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Cells uncouple and re-couple with each other all the time as part of normal cellular

functions. Gap junction proteins are short-lived molecules and last only a few hours

before they are removed from the cell surface and digested inside the cell. As another

example, when cells are stimulated to divide by a growth factor, gap junction channels

close. Soon after the growth stimulus is received (extracellular signal), the cell must

"decide" (using intracellular signaling) whether to proliferate or remain quiet. To pursue

the first choice, the cell must disconnect its gap junctions so that it can disregard the

molecular signals or "influence" from neighboring cells that otherwise would keep the

stimulated cell inactive. Once the cell divides, the new daughter cells, if there is no more

growth stimulus, will form gap junctions with neighboring cells and "join the

community".

In other cases, gap junctions may be uncoupled at inappropriate times or the cells may be

incapable of forming functional gap junctions. The latter would be the case in cells that

harbor a mutant connexin gene. The former might be caused by factors generated inside

the body or might be due to outside agents that we are exposed to. If for any reason,

genetic, internal, or environmental - that GJIC is altered, serious consequences may occur

such as embryo lethality, birth defects, cancer, etc. This is true when there is GJIC at the

wrong time and place or when GJIC is deficient.

It was mentioned that there are now 20 known connexin genes. They are needed to

provide general and unique functions to all the hundreds of cell types and functions of the

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human body. With the development of modern genetic techniques, mice can be produced

that have one or more of their connexin genes permanently inactivated (connexin "knock-

out” mice). When certain connexin genes were knocked out, the resulting embryo or

fetus died before birth. This suggests these connexins are critical for normal embryonic

or fetal development. When other connexin genes were knocked-out, embryonic and

fetal development occurred normally. But shortly after birth, the mice died because of

defects in the organs in which the knocked-out connexins should have been expressed.

Finally, when other connexin genes were knocked out, the mice survived to adulthood,

but then developed diseases such as peripheral neuropathy, liver cancer, and cataracts.

In a manner similar to the "knockout" of a connexin gene or inheritance of a mutant

connexin, embryos or fetuses that are exposed to natural or synthetic chemicals, may

have their gap junctions altered (either increased or decreased inappropriately). This may

result in birth defects. Alcohol and thalidomide are two drugs that affect gap junctions

and cause birth defects.

Other chemical agents that are carcinogenic in animals alter gap junction formation and

function in cell- and connexin-specific ways. These include natural chemicals such as

the oil of the Croton plant; pollutants such as polybrominated biphenyls; drugs such as

phenobarbital; nutrients, such as unsaturated fatty acids, retinoids, and carotenoids;

pesticides such as DDT; metals such as cadmium; hormones such as estrogens; and

growth factors such as epidermal growth factor. These agents inhibit or enhance gap

junction formation or function, depending on the type and state of the cell and the

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connexin expressed. This effect may contribute to alterations of cell proliferation, cell

suicide, and cell differentiation and the development of diseases such as cancer.

Chemical alterations of GJIC in adult organisms may contribute to other diseases as well

(Figure 7).

Chemicals that inhibit gap junction function in the nervous system could be

neurotoxins. Other chemicals that inhibit gap junction function in the testes or ovary

could be reproductive toxicants. Still others that affect gap junctions in the immune

system could lead to decreased immunity. Gap junctions in the lens of the eye are

necessary for lens cells to receive nutrients and remove wastes and inhibition of this GJIC

may contribute to cataract formation.

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Figure 7. This panel of photographs illustrates an assay to detect whether cells are

communicating with each other via gap junctions. The lower right panel is a phase

micrograph of normal rat liver cells through which a razor blade cut a path through a

layer of cells grown in a plastic dish and not exposed to the fluorescent dye. The panel at

the top left shows that cells, which were not treated with any chemical (in this case, TPA,

a powerful skin tumor promoter) could transfer a fluorescent dye molecule which entered

the membranes of cells along the cut edge. Once in the cell, the fluorescent dye was

transferred to the neighboring cells via gap junctions. In a period of 5 minutes, the dye

went from the cut edge cells to about 10 cells away from the edge. This demonstrates that

the control normal rat liver cells could communicate well. In the subsequent panels

labeled with increasing concentrations of TPA, one sees a dramatic dose response

reduction in the cells ability to transfer the fluorescent dye from the cells along the cut

edge. This demonstrates that TPA, a known toxicant, could inhibit gap junctional

intercellular communication in a threshold, but dose- dependent fashion.

These examples do not prove in a strict scientific manner that chemical alteration

of gap junctions is the causative factor of a disease (“correlation does not mean

causation”). But since several known human diseases are due to the inheritance of a

mutant connexin gene, it is very likely that chemical alteration of GJIC contributes to

noninherited forms of these and other diseases.

An Evolutionary Perspective of Biological Cellular Communication

To put cell-cell communication in perspective, especially as it relates to maintaining

normal development, maturation and health, one can gain much by the insights that

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evolutionary theory provides. Clearly, a single bacterium is a living cell. This bacterium

can, indeed, communicate with its neighbors by the secreted molecules that enter the

medium in which it resides. It also has the means to communicate changes in the

environment to its internal cellular machinery. In other words it has the capacity for

extracellular and intracellular communication. This single cell organism survives

changes in its environment by its ability to proliferate and within its community of other

bacteria, it will continue to proliferate until either physical (temperature) or chemical

(nutrients) restrictions cause it to cease. Since the bacterium does not terminally

differentiate, it is essentially an “immortal” cell. If the environment puts real life-

threatening restrictions on this community of single cells, a bacterium that happened to

acquire a spontaneous or induced mutation in a critical gene that enabled their survival

would be the progenitor of the new bacterial community.

Early in the evolution of multicellular organisms from unicellular ones, the acquisition of

new survival traits had to occur. The early multicellular organism was probably a loose

collection of very similar cells. To evolve further, it had to develop means to control cell

proliferation, cell differentiation into various types of specialized cells, and cellular

suicide when cells were no longer needed or were damaged. The multicellular organism

also needed to keep on hand stem cells to replace old cells, and to produce gametes (eggs

and sperm) for reproductive success and continuation of the species.

But there was a “Faustian price” to pay for these new adaptive survival traits of multi-

cellular organisms. That price was a limited lifespan. The bacterium can be conceived of

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as immortal because if it has no internal restrictions on growth; it divides indefinitely to

produce other bacteria like itself. By becoming multicellular, however, the lifespan of

the organism became finite or “mortal”.

The point might be better illustrated by comparing a cancer cell to a single cell bacterium.

The cells of normal multicellular organisms have growth control, differentiate, undergo

cellular suicide, and have GJIC. The bacterium has no intrinsic growth control, cannot

terminally differentiate, is “immortal”, and lacks GJIC. More like a bacterium, cancer

cells lack growth control, do not terminally differentiate, are immortal, and lack normal

GJIC. Could the cancer cell be perceived as “reverting” back to an evolutionary stage of

the single bacterium? It is interesting to remember that a human being can become sick

and die from an uncontrolled bacterial infection (septicemia) or from an uncontrolled

“infection” of cancer cells (metastasis).

The transition from single cell organisms to multicellular ones required new genes for

intercellular communication in addition to those necessary for extra- and intracellular

communication. Arguably, the evolutionary invention of connexin genes and gap

junctions in the primitive multicellular organism could be viewed as one of the most

important steps in the transition from unicellular to multicellular life.

Preventing the Disconnection of Our Biological Cellular Phones

If one assumes that GJIC plays fundamental and critical roles in development, cell

proliferation, differentiation, etc., and that alteration of GJIC leads to diseases and other

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negative effects on the organism, it would be important to identify agents that restore

normal GJIC in affected tissues. In the laboratory, many chemicals have been identified

that prevent other chemicals from altering GJIC or that increase GJIC in cells with low

levels. These "good" chemicals block the effects of inhibitory chemicals and/or increase

the expression of connexin genes and formation of gap junctions. (Figure 8).

Vehicle Dicumyl-peroxide

Resveratrol + Dicumylperoxide

Effect of resveratrol on peroxide-induced inhibition of GJIC

FIGURE 8. These photographs, using the in vitro assay to measure gap junctional

intercellular communication, illustrate how a chemical, resveratrol, found in grape skins

and red wine, can prevent the inhibitory effect on GJIC by a tumor promoter,

dicumylperoxide. The panel at the top left illustrates that normal rat liver cells can

transfer a fluorescent dye which entered the scraped cells along the cut edge of a layer of

cells. Within 5 minutes the dye transferred from those cells to about 10 cells away from

the cut edge. This illustrates that normal rat liver cells, treated only with a non-toxic

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solvent ( “vehicle”) can communicate very well via gap junctions. The top right panel

shows that these cells, treated with non-cytotoxic concentrations of a tumor promoter,

dicumylperoxide, completely inhibited the transfer of the fluorescent dye. The bottom

panel demonstrates that the cells treated with both dicumylperoxide and resveratrol,had

higher levels of GJIC than cells treated only with dicumylperoxide. This suggests that

resveratrol could be a cancer chemo-preventive agent.

The task today is to identify the mechanisms by which disease-causing agents alter GJIC

and ways to prevent or correct that. There likely will never be a single “silver bullet”

since multiple agents and processes are involved. But published research data indicate

that agents that prevent or reverse negative effects on GJIC can prevent or reverse

disease. Clearly, however, this field is in its infancy and more research is necessary. But

its likely that in the near future, connecting and disconnecting our cellular phones will be

viewed as important tools to improve human health.

References:

J.E. Trosko and R. J. Ruch, “ Role of cell to cell communication in carcinogenesis”.

Frontiers in Bioscience 3: 208-236, 1998.

J.E. Trosko and R.J. Ruch, “ Gap junctions as targets for cancer chemoprevention

and chemotherapy”. Current Drug Targets 3: 465-482, 2002.

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