Guest guest Posted May 22, 2009 Report Share Posted May 22, 2009 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. ************** Recession-proof vacation ideas. Find free things to do in the U.S. (http://travel.aol.com/travel-ideas/domestic/national-tourism-week?ncid=emlc ntustrav00000002) Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 22, 2009 Report Share Posted May 22, 2009 Has anyone heard of this research? http://www1.wfubmc.edu/cancer/research/mice/part1.htm I know they wanted to test it on humans in 2008 and would like to know if anyone knows about the recent developments? The new approach to cancer is very interesting. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 22, 2009 Report Share Posted May 22, 2009 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 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. > > > > ************** > Recession-proof vacation ideas. Find free things to do in the U.S. > (http://travel.aol.com/travel-ideas/domestic/national-tourism-week?ncid=emlc > ntustrav00000002) > > > Quote Link to comment Share on other sites More sharing options...
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