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In a message dated 5/22/09 11:21:53 PM Eastern Daylight Time,

karine_tadevosyan@... writes:

> Has anyone heard of this research?

>

> http://www1.wfubmc.edu/cancer/research/mice/part1.htm

>

Please can you copy and paste the information into you email if possible?

Some links disappear over time and some people cannot pull up websites.

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Here is the whole article very interesting

Kees

Spontaneous Regression of Advanced Cancer in Mice

Summary Part I: The SR/CR Mouse and Resistance to Cancer

Discovery of the Mouse

For the last few years, scientists in the Department of Pathology have

been engaged in a project that revolves around a unique mouse

serendipitously discovered at Wake Forest University School of Medicine in

1999 (the SR/CR Mouse). The original mouse of this type was part of an

experiment in which mouse cancer cells were being transplanted into the

abdominal cavity of other mice to produce cancer. This particular mouse, a

member of a highly inbred strain of mice (BALB/c, all of whom are

essentially identical twins genetically), did not develop the expected

tumor, even though it was injected with a large number of tumor cells.

When it was injected many times more with these cancer cells, it still

failed to develop a tumor (Figure 1). Since the cancer cells used for the

injections were from an extremely aggressive type of cancer (Sarcoma180, a

tumor derived from connective tissues of a mouse), this result was highly

unusual. To determine if this resistance was genetic, this mouse was bred

to other normal mice, and it was shown that this resistance to cancer was

inherited. The pattern of inheritance showed that it probably was caused

by a single mutation in a single gene and was “dominant” (it only required

one copy to work).

The SR/CR Mouse Colony and Its Genetics

After the initial experiments, breeding studies allowed this gene mutation

to be passed on to a large number of offspring from the original mouse

through multiple generations. In addition to the original BALB/c mouse

strain (an inbred laboratory white mouse), the cancer resistance could

also be bred into other inbred strains of mice with different genetic

backgrounds (C57BL/6, CAST/Ei). Since such mouse types have been

extensively studied for many years, scientists have techniques that can

distinguish the portions of their DNA with great accuracy and determine

from which mouse strain the DNA originated. Using this “genomics”

strategy, the cross-breeding of the original BALB/c SR/CR mice to normal

C57BL/6 mice allowed the determination of which of the mouse chromosomes

carried this cancer resistance gene. Further studies will allow the

precise mutation in the gene involved to be identified, although this is a

highly complex process.

Does the Resistance Gene in SR/CR Mice Work Against Other Types of Tumor?

An important initial question in studying these mice was whether the

resistance to cancer only worked against this unusual tumor type (S180

sarcoma), or would work against other types of cancer. Using several

different mouse cancer types, such as leukemia, lymphoma, liver cancer,

and lung cancer, it was shown that the SR/CR mouse was resistant to all of

them. Further, other experiments were done to show that, in addition to

tumors in the abdominal cavity, tumors that grow in other sites, such as

under the skin, were also rejected by this mouse.

What Happens to the Tumor Cells Injected into these Resistant Mice?

Because the initial experiments used tumor cells that were transplanted by

injection into the abdominal cavity of mice, the injected cells could be

recovered at a later time and examined. It was also possible to see if

other cell types from the resistant mouse were interacting with the tumor

cells directly. When this was done, it was found that injected cancer

cells in these mice were killed within the first day after they were

injected. In addition, other cells from the resistant mouse, mostly white

blood cell types, were found attached to these cancer cells prior to their

death forming “rosettes” around the tumor cell. (Figure 2).

The white blood cell types found in these rosettes included

polymorphonuclear leukocytes (a common white blood cell involved in

killing bacteria in infections, also called “polys”, “neutrophils” or

“PMN’s”), monocytes (a common white blood cell type that can also crawl

into tissues where it is called a “macrophage”) and a special type of

immune cell called a “natural killer cell” (NK cell). All of these cells

are part of what is referred to as the “innate immune system”, cells that

are active against many foreign organisms, such as bacteria, viruses and

fungi, without prior immunization. Suprisingly, very few of another type

of white blood cell -- lymphocytes (T cells or B cells) were found. Such

cells are normally part of the rejection of foreign cells by the immune

system, and are frequently involved in more familiar cell rejection

events, such as those seen in the rejection of poorly-matched tissues and

organs (kidney, bone marrow or skin transplants). Clearly, something other

than normal tissue transplant rejection was happening in these

cancer-resistant mice.

More Evidence that the Cancer Resistance is Not Due to Normal Tissue

Rejection

Rejection of transplanted organs between two individuals that are not

precisely “matched” (that is, are not identical twins) involves a special

group of white blood cells called “T-lymphocytes.” Such T cells (T stands

for “thymus”, the organ involved in their maturation) have been

extensively studied over the past 30 years, and can detect small

differences between cells from different types of mice, and could have

been responsible for the rejection of the cancer cells that originally

came from another mouse. In other words, it was possible that cancer cells

were rejected, not because they were cancer, but because they were

foreign. To rule this out, a cross-breeding experiment was done, in which

one mouse with the SR/CR cancer resistance trait was bred with a mouse

that was genetically deficient in T cell function (a so-called “nude”

mouse, since these immune deficient mice fail to grow hair normally).

Several generations later, the offspring from that mating including some

mice that had the SR/CR cancer resistance trait, yet were still defective

in normal organ rejection. They were “nude” and thymus-deficient, and yet

were still cancer-resistant. This showed that the cancer resistance

mechanism operates even in a mouse that cannot reject mismatched organ

transplants. Thus the resistance mechanism doesn't use T-cells. This is

not totally a surprise, however, since these “nude” SR/CR mice,still have

other cells of the “innate” immune system, such as those seen attached to

the cancer cells prior to their death.

A Big Surprise: Cancer Resistance in These Mice is Dependent on Age

When enough SR/CR mice were bred to create a larger colony of these mice,

other types of experiments were done. The original cancer resistance

occurred in mice that were six weeks old --just post-adolescent for a

mouse). However, it was now possible to wait longer before injecting

cancer cells to see how well older mice responded. When testing for cancer

resistance was delayed until 5 months of age, the mice that had inherited

the resistance gene began to grow tumors, just as normal mice do. However,

when the tumors reached a detectable size at 2-3 weeks, many of these mice

showed a sudden decrease in tumor size in a day or two, followed by

disappearance of the tumor completely. In some cases, this “spontaneous

regression” of cancer (Figure 3) was quite dramatic -- a very large tumor

mass disappeared overnight. What appeared to be happening in these older

mice was that the cancer could grow until the anti-cancer mechanism

finally “kicked” in, ultimately killing all of the cancer cells.

If these spontaneously regressing mice were then re-injected with new

cancer cells, they appeared now to be completely resistant. Thus, they had

been primed by the prior rejection of tumor cells. In a sense, they had

been vaccinated against cancer. These primed mice can be repeatedly

injected with cancer cells and remain resistant throughout their normal

lifespan. If, however, the mice reached the age of 1 year before being

exposed for the first time to cancer cells most of these mice were not

cancer resistant, even though they clearly had the gene mutation (since

their offspring were resistant when tested at an early age). This

surprising result is discussed further in the next section, under the

topic: why does cancer incidence rise with increasing age?

When Cancer Cells Die in the SR/CR Mice, How Does It Happen?

The failure of cancer to grow in the completely resistant young SR/CR mice

could be due to some property of the mice that prevented growth of tumor

cells, or it could be due to active killing of cancer cells even though

they could initially grow. The spontaneous regression seen in older SR/CR

mice, in fact, strongly pointed to a killing mechanism, rather than just

preventing growth. When the cancer cells of the resistant mice were

recovered, the cancer cells showed rupture of the cell surface membrane, a

process referred to as cytolysis. Other experiments showed that this

rupture probably involves toxic proteins that are manufactured and

secreted by cells of the immune system. Two of these toxic proteins

(perforin and granzyme B) were found in the fluid around the cancer cells.

A further important question in understanding how these mice killed cancer

cells was whether the killing required live cells from the resistant

mouse, or could be mediated by some floating molecule independent of

intact immune cells. One way of studying this issue is to isolate cells

involved in the killing mechanism from the resistant mouse and transfer

them either into a normal mouse (Figure 4), or into a test tube with

living cancer cells. In both of these tests, the cells from the resistant

mice killed cancer cells, but the soluble materials did not. This strongly

suggests that cells of the mouse directly attack and kill cancer cells. It

also shows that resistant immune cells can be transferred to a normal

mouse and, at least transiently, make that normal mouse cancer-resistant.

This experiment, called 'adoptive transfer,' could be the model for a

similar approach to treat cancer in people if such resistant immune cells

could be generated in large numbers.

Another test is to remove the immune cells from the mouse and see whether

cancer could now grow. When this “immunodepletion” experiment was done,

and more of the immune cells were removed, the mice gradually lost their

resistance to cancer. However, when the depletion treatments were stopped,

the mouse regained its immune system and the tumor regressed. This is

direct evidence that the killing of cancer cells in these mice is due to

cells of the immune system.

SR/CR Mice are Healthy and Live a Normal Lifespan

The type of mouse in which this resistance mechanism was first studied,

BALB/c mice, have a normal lifespan of around 2 years. An important

question in the study of the cancer resistance mechanism was whether the

resistant mice were healthy. So far, studies of these mice have not shown

any shortening of their lifespans. In fact, the original mouse with this

trait which had been injected with large numbers of cancer cells many

times during its life lived to be 26 months old and had many offspring.

Another important question is whether the ability to resist cancer is

accompanied by some other disease problem. For example, special

genetically altered mice have been developed with highly active immune

systems that can reject tumors, but they usually also show evidence of

rejecting normal tissue cells, a process referred to as “autoimmunity.”

Autoimmune mechanisms are the basis for several serious human diseases,

such as lupus erythematosus and rheumatoid arthritis. However, the SR/CR

mice have shown no signs of these autoimmune complications. The cancer

resistant mechanism in these mice is surprisingly selective, apparently

only affecting cancer cells. This selective property is of great interest

to scientists studying these events, since it suggests that such

selectivity can actually exist and be the basis of future anti-cancer

therapies.

The SR/CR Mouse Mutation as a “Handle” to Study Cancer Resistance

Since the resistance seen in the SR/CR mice is an inherited trait, and

appears to involve a mutation in a single gene, then the identification of

the mutation and the gene which contains it can provide important clues as

to how it might work. Since all of the genes of the mouse and the human

have been identified from the various genome projects in the last few

years, it will be possible to examine the exact mutation in the mouse and

to correlate it with possible changes in similar genes in people. Mice and

people have similar immune systems. It is likely that if we can understand

the mechanism that is used by this mutation in mice, we will be able to

apply this knowledge to identify and manipulate similar mechanisms in

patients. The key to this study is the exact nature of the mutation

present in these mice. Multiple studies are underway to identify this

mutation and its consequences. While there are no guarantees that we can

use this knowledge to treat human cancer, we can speculate on the future

secrets that this information could reveal, as described in the next

section.

Spontaneous Regression of Advanced Cancer in Mice

Summary Part II: Speculations

What Might this Unique Mouse Tell Us About Cancer?

Immune Surveillance

For many years, scientists have debated whether our immune systems can

identify cancer or other abnormal cells and destroy them spontaneously.

This concept, called “immune surveillance,” suggests that throughout life

the immune system constantly examines the surfaces of cells in the body

and can tell when a cell becomes abnormal. When it finds an abnormal cell,

the immune system has machinery that can attack that cell and destroy it.

This clearly can happen with cells infected by viruses, or with cells and

tissues transplanted from a non-matched individual. However, there has

been debate as to whether this happens constantly with cancer cells.

Further, there has been debate as to whether a failure of this system

actually could have a role in leading to clinically significant cases of

human cancer.

Many years ago, scientists developed mice with defects in their immune

systems, such as “nude mice.” If immune surveillance were important, one

might expect that mice with poor immunity might have a higher incidence of

spontaneous cancers. Surprisingly, when these nude mice were followed for

a long time, only a few rare tumor types developed. This result dampened

enthusiasm for the existence of such a surveillance system.

However, in recent years, other types of immune deficient mice have been

developed and it is now understood that the immune system is more

complicated than first thought. The nude mice, for example, while not

having T-cells, do have an intact “innate” immune system of other cell

types, and are not really completely immunodeficient. When completely

immune deficient mice were examined, such as ones that are missing the

genes for perforin as described earlier, they do, in fact, develop common

tumors at a faster rate. As a result, the last decade has seen a renewed

interest in the concept of immune surveillance.

The concept suggests that as cancer cells develop, they are detected by

the immune system at a very early stage (perhaps at the stage of a single

cell or a few cells) and are then killed and cleared from the body. This

actually makes some sense from what we now know about the properties of

cancer cells. A hallmark feature of cancer cells is the loss of control of

the accurate duplication of their genes, such that they constantly gain

mutations. Those mutations that are an advantage to the cancer cell will

allow it to survive, so cancers constantly become more and more bizarre as

they develop. Such bizarre changes should make the surface of cancer cells

very different from normal cells and make them easier for the immune

system to detect. This assumes, however, that the cancer cells also do not

develop some other property that makes them either invisible to the immune

system or actively able to kill immune cells. Both of these defensive

tricks by cancer cells may occur.

This concept implies that we are constantly getting cancer (one cell at a

time) but the cancer cells do not survive because our immune systems

detect and kill them. But only the cancer cells die; normal cells are

unharmed. That this could happen with such precision was at first

difficult to believe. However, the SR/CR mouse is a direct demonstration

that such immune-mediated killing can occur in an otherwise healthy

animal. For this reason, this unique mouse provides another bit of

evidence that immune surveillance is probably a normal process that

protects us from constantly developing cancer.

Cancer Resistance Genes

This mouse also shows that, just as immune deficiency can be genetically

determined (inherited immune deficiencies), immune protection can also be

genetically determined. We all know that the risk for some types of cancer

can be inherited, such as families who have a high frequency of breast

cancer, ovarian cancer, etc. Most of the identified familial risk genes

are ones that cause tumor cells to grow and survive. Few have been

identified that affect how our immune systems can influence cancer

incidence although, some inherited immune deficiencies do increase the

risk of developing certain forms of cancer.

On the other hand, how would we know that a particular family has a gene

that resists cancer? Rather than having a higher incidence of cancer, that

family would simply not have cancer. Could we spot such a family? Probably

not, since we think of not having cancer as a normal characteristic. The

only way to identify such people might be to look at someone with high

risk for cancer development, such as through some form of risky exposure

(environmental carcinogens) and/or old age (where cancer statistically

would be more common).

The SR/CR mouse demonstrates that cancer resistance genes exist and can

have dramatic effects on responses to cancer development. This suggests

that we should look more carefully for such cancer resistance genes in

people, since identifying them (or their absence) could tell us a great

deal about how susceptible to cancer we really are.

Why Does Cancer Incidence Rise with Increasing Age?

The difference in efficiency of the cancer resistance mechanism in the

SR/CR mice with aging brings up an interesting concept. We think of the

increased incidence of cancer in the aging population as a demonstration

that mutations are constantly occurring during our lifetimes. It is

certainly true that many cancers actually develop over many years before

they become clinically detectable. It is also true that many cancers

develop as the result of accumulation of stepwise multiple mutations in

important genes that control growth of cancer cells. But is this the whole

story?

The SR/CR mice show resistance at an early age to cancer cells that have

developed advanced and bizarre mutations that allow them to grow in normal

mice. Yet, the immune system in the SR/CR mice still can kill them all.

But as the SR/CR mice age without being exposed to tumor cells, they

naturally lose the effectiveness of this resistance mechanism. Could the

same thing influence cancer development in people? Could it be that we

constantly reject cancer cells by immune surveillance throughout our lives

and, as we age, that mechanism becomes weaker and weaker, until finally

one cancer cell overcomes those controls? The SR/CR mouse provides support

for the concept that cancer develops not only because of accumulated

mutations in cancer cells, but also because immune rejection begins to

fail with age. By understanding how this mouse rejects cancer when it is

young, we may be able to boost the immune rejection of cancer cells in

later life. This might make it possible to do a similar thing in people,

and add to our weapons to fight disease in cancer patients.

Spontaneous Regression of Human Cancer

For many years, reports of the spontaneous disappearance of advanced

cancer have appeared in the scientific literature. While some could be

dismissed as mistaken diagnoses, or unexpected treatment successes, there

is a clear body of evidence that such things do, in fact, occur. It

happens so rarely that scientists have no hope of being able to study it,

since the patient is cured at the time it is recognized and there is no

way to do further investigation. What has been lacking in this field is an

appropriate animal model in which the regression events could be

repeatedly produced and studied in detail. The SR/CR mouse is perhaps such

a model and demonstrates at least one way in which this event could

happen. Further, it is controlled genetically in an otherwise healthy

animal.

Potential Therapies of Human Cancer

The SR/CR mouse is only an animal model. Its use is limited to the

laboratory and perhaps only special circumstances, such as transplantation

of mouse cancers. For example, we have yet to show that this mouse could

reject a tumor that developed in its own tissues, although those

experiments are currently under way. Considering that the transplanted

tumors used previously are from essentially genetically identical animals,

it is probably likely that rejection of naturally occurring tumors will

occur. However, a more compelling question is how the knowledge gained

from this mouse could be used to benefit human patients.

There are several possibilities. First, the mutation in this mouse will be

identified in the future, and a similar gene almost certainly exists in

humans. Whether a similar mutation introduced into that human gene would

have the same benefit is unknown, but that is the first possible strategy

to employ this knowledge. For example, one could take white blood cells of

the appropriate type from a cancer patient and one could introduce that

mutated human gene into the patient’s cells outside of the body (ex vivo),

and then give them back to the same patient. In this way, perhaps, the

transferred immune cells might be more effective against the patient’s

cancer. Such strategies are complex and will take many years to develop.

Another strategy is to understand the pathways and mechanisms that are

used in the mouse to detect and reject cancer cells, and then employ those

in a more general way in patients. That is, if a drug could be developed

that would enhance a similar immune system component in people, it might

be predicted to be an effective anti-cancer therapy.

Another concept is that the loss of resistance to cancer with aging in

this mouse may be under some form of predictable regulation. The mouse

model may provide a way of understanding how aging affects immune system

function. With that knowledge in hand, it might be possible to prevent

that loss of function and decrease the rate of development of human

cancer.

Conclusions

Whether this mouse model can yield important clues to human cancer will

await future experimental results. There are some features, however, that

give reasons for at least guarded optimism. The resistance trait is

dominant (only one copy of the mutation is needed to see the effect), is

very dramatic, and is effective against highly aggressive forms of

experimental cancer. The mice are otherwise healthy and have a normal

lifespan. The mechanism responsible for resistance can be boosted and can

keep older animals resistant much longer than they otherwise would be. In

studying this mouse model, we start from a highly successful “phenotype”

and only have to work back to understand what is already a successful

mechanism. Nature has done the hard part in creating the mutation; it is

only up to the scientists studying the mouse to keep an open mind and

understand how it did it. We can only be grateful that Nature never read

our textbooks.

Spontaneous Regression of Advanced Cancer in Mice

Summary Part III: Cancer in Normal Mice Can Be Cured by Treatment with

Cells from Cancer-Resistant Mice

Using a previously described mouse model of cancer resistance, scientists

in the Comprehensive Cancer Center have described new findings in

Proceedings of the National Academy of Science USA in which they

demonstrate the ability to cure cancer in normal mice by transferring

purified immune cells (white blood cells) from cancer resistant mice.

These studies show that specific types of innate immune cells, such as

macrophages, can migrate to the site of cancer in a normal mouse and

selectively kill all of the cancer cells without harming normal cells.

Such studies suggest that this type of mechanism might one day be used to

help design a new strategy for cancer therapy in humans.

Here is an explanation of the research prepared by the scientists:

Subsequent to our original publication in 2003, genetic cancer resistance

has been propagated into four more strains of mice and shown to work

against a wide variety of cancer types. While cancers injected into these

unique mice are rejected, several questions needed answering about how

this worked. For example, while the mutant mice rejected tumors, it was

not clear if this was an event mediated by specific cells in the mice, or

if this mechanism could somehow be transferred to normal mice as a

treatment for cancer at distant sites. Findings presented in our second

publication in Proceedings of the National Academy of Sciences USA in 2006

demonstrate the results of experiments to address these questions, and

provide more in-depth information about how these unusual mice avoid

cancer.

Experimental Cancers in Mice

There are several different strategies for studying cancer in mice, and

they vary in their ability to predict the behavior of cancers or

therapies in human patients. For example, one can divide the types of

mouse cancer models into five major categories: 1) inducing endogenous

(naturally occurring) cancer in mice using chemical carcinogens, 2)

inducing endogenous cancer in mice using genetic manipulation, 3)

allowing mice to grow old and get spontaneous cancers, 4) transplanting

human cancers into immune-deficient mice that cannot reject cells from a

different species and 5) transplanting aggressive cancers from other

mice. This last group represents the type of model we used in our

experiments. Some therapies that work for the first four categories have

difficulty treating these more aggressive mouse cancers. The SR/CR

cancer resistant mouse was originally identified using these aggressive

mouse cancers and, therefore, had to be a very effective resistance

mechanism to have been detected. One might predict that such an

effective mechanism might not only be able to kill cancer cells in the

original mutant mouse, but perhaps one could transfer this mechanism to

normal mice, as well.

If SR/CR Immune Cells Kill Cancer, Will They Work In a Normal Mouse?

Even though our in vitro (test tube) experiments suggested that the innate

immune cells themselves were responsible for tumor killing, it was still

possible that this killing might only work if the rest of the mouse also

expressed the same mutation. Therefore, we placed cancer cells and immune

cells from spontaneous remission/cancer resistant (SR/CR) mice together in

a normal mouse to determine whether the cancer cells could survive.

Without the SR/CR immune cells, such cancers grow rapidly in normal mice

and the mice die in 3-4 weeks. But, when these cancer cells were injected

together with the SR/CR immune cells, the tumor was killed. Thus, the

environment in a normal mouse still allowed these cells to work. This

suggests that no other cell type or soluble factor in the mice is required

to allow the immune cells to function and kill cancer.

A more difficult experiment was to inject a normal mouse with cancer cells

and allow the tumor to implant and grow, then inject the SR/CR immune

cells at a later time. Again, the mutant immune cells killed the cancer

cells selectively, without harming the normal mouse. Finally, we

performed the most difficult challenge (shown in Figure 5), which was to

inject the normal mice with cancer cells at one site (e.g., subcutaneously

on the back), and then later inject the SR/CR immune cells at another site

(e.g., intraperitoneally or into the abdomen). This meant that the

injected immune cells would have to migrate to the tumor and kill it at a

distant site, all the while being in a normal mouse tissue environment.

Surprisingly, this strategy worked, and the established cancer in the

normal mouse was killed by the SR/CR immune cells injected elsewhere.

Initially, the cancers on the back actually appeared to get slightly

bigger after the immune cells were injected into the peritoneal cavity,

but after a few days the cancer began to shrink. The initial swelling may

reflect an initial influx of active white blood cells into the tumor. The

cancers disappeared completely in two weeks. As controls, other mice

injected with similar immune cells from a normal non-resistant mouse

showed no tumor shrinkage, and all of these control mice died at the

expected time. The surviving recipient mice were " cured " of their tumors

(the tumor never recurred, even after a year – half a lifetime in mouse

terms). Thus, we can say with confidence that the killing of cancers by

the SR/CR immune cells requires only the immune cells (and not something

else) and is remarkably tumor-specific without causing significant harm to

normal tissues.

Figure 5. SR/CR Immune Cells Transferred to a Normal Mouse Can Cure Cancer

Present at a Site Distant. A solid cancer was formed in a normal mouse by

injection of cancer cells under the skin of the back. Active white blood

cells (immune cells from spleen, bone marrow or the peritoneal cavity)

from an SR/CR mouse were harvested after they has killed a cancerous tumor

in the resistant mouse, and then injected into the peritoneal cavity of a

normal mouse bearing the subcutaneous tumor. Following this immune cell

injection, the subcutaneous tumor on the back gradually regressed, and the

cancer never recurred, even after very long follow-up. In mice not

treated with immune cells, or treated with immune cells from a normal

mouse, the tumor on the back continued to grow.

Does A Specific Type of Cell Mediate Cancer Resistance?

The immune system in mammals is composed of many different specialized

immune cells. Some immune cells are specialized to recognize only foreign

things and relay that message to other immune cells. Some immune cells

require prior exposure before they acquire the ability to protect the

host. Others are natural-born killers without needing any prior

immunization. Some immune cells are specialized to kill pathogenic cells

by rupturing them, and others are specialized to eat enemy cells and kill

them later. If we knew which type of immune cell was responsible for

cancer resistance, we might be able to design more efficient therapy for

cancer patients. One could enrich and expand this cancer-killing cell

type to deliver maximum efficacy for cancer therapy. One could also

remove any potentially inhibitory cell types from the mixture, or immune

cells that might potentially harm normal tissues, to achieve a better

result.

This question can be addressed in two ways. First, one or two types of

immune cells can be removed from a mouse to see if the protection against

cancer is still there in the resistant mice. If removal of one cell type

but not others could abolish the resistance, it could be guessed that this

cell type was solely responsible for resistance. When selective cell

types were depleted from SR/CR resistant mice, however, no single cell

type seemed to be necessary for cancer resistance. When all immune cell

types were depleted, however, resistance disappeared.

An alternative strategy is that specialized immune cells can be isolated

to high purity and tested for cancer-killing activity. After

purification, one cell type, but not others, might be able to kill cancer

cells. We previously found that cells of the innate immune system,

neutrophils, macrophages and NK natural killer cells, seemed to be the

ones that attacked tumor cells. If that were true, one might predict that

one of these cell types might be the mediator of tumor cell killing, and

that type of cell could be purified and tested alone. Experiments showed

that cancer killing could be also observed in the test tube (i.e., in

vitro), rather than only in the intact mouse. Both cells and tissue

fluids were tested, and it was clear that it was the cells alone (not

fluids) that were responsible for killing cancer. However, when

individual immune cells were isolated and tested for cell killing, we were

surprised to find that no one cell type alone was needed, but that several

types of innate immune cells from the SR/CR mice could kill cancer cells.

Similar cell types from normal mice tested in this same way were

ineffective, showing that the effects of the mutation in the SR/CR mice

was being expressed in all of these cell types, even in vitro.

Long-term protection in ordinary mice

The types of white blood cells we injected into the normal mice are

thought to have a rather short lifespan (a few days or weeks). Thus, we

were surprised to see continued cancer resistance in the normal mice for

months after they received SR/CR white blood cells. There is more than

one theoretical way in which this could happen, but one which we favor is

that the purified white blood cells we injected contained a small fraction

of stem cells, and that these gradually became part of the mouse's immune

system. Since we did these transfer experiments between SR/CR and normal

mice of the same inbred strain, this is not entirely unexpected. By

performing these experiments using immune cells from a male SR/CR mouse

and transferring them into a female recipient normal mouse, the injected

immune cells could be identified later, because they contained a " y "

chromosome. In this way, we were able to show that some of the injected

immune cells survived for a very long time and were probably involved

directly in killing the distant cancer.

What Do These Results Mean For Human Cancer Therapy?

First, we should point out that in this mouse system the donor and

recipient mice were both in the same in-bred laboratory strains of mice.

Thus, except for the SR/CR mutation, they are genetically identical. Our

transfer of immune cells between these mice is basically a transplantation

experiment between identical twins. If we tried this therapy in human

patients, the transferred immune cells would probably not survive, since

the donor and recipient would be very different genetically.

However, these results show that the concept would work under the right

circumstances. For example, if we identified the gene, it might be

possible to take immune cells from a patient and insert that mutant gene

into those cells in the test tube, then give these cells back to the same

patient; this would then perhaps allow the mutant immune mechanism to

work to reject tumor cells without the loss of the immune cells due to

transplant rejection. However, this is a complex strategy that can have

many potential problems.

A more important message from this work is that such a mechanism is

actually possible in intact animals, and that a thorough understanding of

the underlying molecular events could potentially lead to a new strategy

for more specific cancer therapy.

There is second important message from this work. The fact that the

cancer-resistant immune cells can specifically sort out cancer cells for

rapid destruction suggests a fundamental difference between cancer cells

and normal cells. We can say with confidence that the killing of cancers

by the SR/CR immune cells is remarkably tumor-specific without causing

significant harm to normal tissues in an otherwise normal mouse. For some

reason, the immune cells from these special mice are capable of detecting

these differences. An important question is: “What are the common

properties of different cancer cells that allow them to be distinguished

by these special immune cells?” While it is possible that cancer cells

express something that activates these SR/CR white blood cells, it is also

possible that these cancer cells may fail to inhibit these SR/CR white

blood cells. That is, the success of cancer growth may be through the

ability of cancer cells to inhibit controls that normally limit the growth

and spread of cells. The SR/CR immune cells may ignore this common

inhibitory function released by cancer cells, and treat them like any

other out-of-control tissue. We hope that by understanding this

interaction between cells we can uncover clues to these underlying

molecular mechanisms.

The Next Steps: Identification of the Mutation, Molecular Mechanism and

Treatment of Endogenous or Naturally Occurring Cancer

Considerable work together with several collaborative groups has already

been performed to identify the gene mutated in these resistant mice;

however, this task is complex and still requires further work. Other

strategies to identify the altered molecular pathways include analysis of

the genes expressed by purified populations of immune cells, comparing

normal mouse cells to those from resistant mice before and after challenge

with cancer. Preliminary results of those experiments are very

encouraging. A further step is to document that this resistance mechanism

works against endogenous cancer, as well as transplanted cancers.

Preliminary results from one mouse model of endogenous cancer are

encouraging, suggesting that this mechanism is also active against

spontaneous endogenous cancer. Thus, through a variety of strategies, we

hope to unravel the underlying molecular events responsible for this

remarkable mouse, and eventually use this knowledge to design more

effective therapies for human cancer patients.

Spontaneous Regression of Advanced Cancer in Mice

Original Publication in PNAS, May 2006

Publications & Related Press Coverage

A June, 2004, article by Dr. Cui and Dr. Willingham, " The effect of aging

on cellular immunity against cancer in SR/CR mice, " published in the

journal Cancer Immunology, Immunotherapy.

Dr. Cui wrote an essay, " The winding road to the discovery of the SR/CR

mice " for the journal Cancer Immunity, published by the Academy of Cancer

Immunology in October, 2003.

The first major scientific publication based on this research was

published in the journal Proceedings of the National Acadamy of Sciences:

Cui Z, Willingham MC, Hicks AM, - MA, TD, Hawkins

GA, MS, Weir HM, Du W, DeLong CJ. Spontaneous regression of

advanced cancer: identification of a unique genetically determined,

age-dependent trait in mice. Proc Natl Acad Sci U S A. 2003 May

27;100(11):6682-7.

Abstract:

We have established and studied a colony of mice with a unique trait of

host resistance to both ascites and solid cancers induced by

transplantable cells. One dramatic manifestation of this trait is

age-dependent spontaneous regression of advanced cancers. This powerful

resistance segregates as a single-locus dominant trait, is independent of

tumor burden, and is effective against cell lines from multiple types of

cancer. During spontaneous regression or immediately after exposure,

cancer cells provoke a massive infiltration of host leukocytes, which form

aggregates and rosettes with tumor cells. The cytolytic destruction of

cancer cells by innate leukocytes is rapid and specific without apparent

damage to normal cells. The mice are healthy and cancer-free and have a

normal life span. These observations suggest a previously unrecognized

mechanism of immune surveillance, which may have potential for therapy or

prevention of cancer.

Full text of the article can be read online here.

A printable version of the article can be downloaded here.

Selected Coverage of May 8, 2006 Announcement

Injected Cells Cure Tumors in Mice, Los Angeles Times, May 9, 2006-05-09

A Strain of Mice Appears Able to Resist Cancer Cells, New York Times, May

9, 2006

Cancer Resistance Found to be Transferable in Mice, Scientific

American.com May 9, 2006

Researchers Cure Lethal Cancer in Mice, Voice of America, May 8, 2009

Mice Put Cancer on Ice, Newsday, May 9, 2006

Cell Therapy Treatment is Curing Cancer in Mice, Winston-Salem Journal,

May 9, 2006

Some Related Articles and Press Coverage from April 2003 Announcement:

BBC News article April 28, 2003.

NewScientist.com article April 28, 2003.

Listen to an interview with Dr. Cui on the CBC Radio Show 'As It Happens'

April 29, 2003. Click on Listen to Part 1 of As It Happens - note that the

seven-minute interview starts almost 21 minutes into the show: advance

your audio player's counter to 20:55 to skip the previous interviews.

Science Daily article April 29, 2003.

Listen to an interview with Dr. Willingham on the CBC Radio Show 'Quirks

and Quarks' May 3, 2003. Click on the link and scroll down to 'Mighty

Mutant Mouse' about halfway down the page.

Scientific American article April 30, 2003.

Spontaneous Regression of Advanced Cancer in Mice

The Research Team

Click on the highlighted names to learn more about the article's authors:

Zheng Cui, MD PhD

Mark C. Willingham, MD

Martha A. -, PhD

J. DeLong

Wei Du

A. Hawkins, PhD

Amy M. Hicks

D. , PhD

Mark S. , PhD

Holly M. Weir

The team also thanks Barrett, Ken Grant, and Liya Qin for

technical assistance and Dr. Dennis K. for helpful advice. This

project represents the efforts of faculty, staff, and graduate students in

the following departments at Wake Forest University Baptist Medical

Center:

Pathology (Research Pathology)

Comprehensive Cancer Center

Microbiology & Immunology

Center for Human Genomics

Biochemistry

Cancer Biology

Funding Acknowledgements:

Intramural grants from the Office of Research and Comprehensive Cancer

Center of Wake Forest University.

Extramural grants from the Charlotte Geyer Foundation and the National

Cancer Institute (Grant R55CA93868 to Dr. Cui).

DeLong and Amy Hicks were supported by Signal Transduction and

Cellular Function Training Grant CA-09422 from the National Institutes of

Health.

Holly Weir has been supported by a graduate scholarship from the

Department of Biochemistry at Wake Forest University.

> In a message dated 5/22/09 11:21:53 PM Eastern Daylight Time,

> karine_tadevosyan@... writes:

>

>

>> Has anyone heard of this research?

>>

>> http://www1.wfubmc.edu/cancer/research/mice/part1.htm

>>

>

> Please can you copy and paste the information into you email if possible?

> Some links disappear over time and some people cannot pull up websites.

>

>

>

> **************

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