Recent Developments in Stem Cell Research and Breast Cancer
According to the Centers for Disease Control and Prevention, aside from non-melanoma skin cancer, breast cancer is the most common form of cancer in women. In 2005 (which is the most recent year for which statistics are available), 186,467 women were diagnosed with breast cancer and it was the seventh leading cause of death for women in the U.S.
Stem cells have played an important part in the fight against this deadly disease. High-dose chemotherapy with stem cell transplant is a treatment option that has been used for women with advanced metastatic or high-risk primary breast cancer since the 1990s. More than 15,000 women with advanced breast cancer have been treated using this method. Under this method of treatment, the use of stem cells allow women to receive higher doses of chemotherapy. Since bone marrow is not able to tolerate high doses of chemotherapy, stem cells from the patient are collected and frozen prior to chemotherapy to give back to the patient once high dose chemotherapy is completed. Although recent studies found that high-dose chemotherapy combined with stem cell therapy may have the same long term results as traditional chemotherapy, it is still being researched in specialized clinical trials and offers another option to women fighting the disease.
Another exciting development in the treatment of breast cancer is the use of stem cells to halt the metastasizing of breast cancer into the brain. Brain metastases are among the most feared complications in breast cancer. Despite today’s advances in early detection and treatment, nearly 30% of patients with advanced breast cancer are eventually diagnosed with brain lesions. In 2007, scientists began studying whether neural stem cells (NSCs), the body’s own mechanism for healing and regeneration in the brain, could aid in treating breast cancer that had spread to the brain. Previous studies had already confirmed that the NSCs knew how to seek out and “follow” the breast cancer. Recent test tube experiments have shown that these NSCs, armed with other drugs, can seek out and kill these proliferating breast cancer cells very efficiently. Employing the body’s own stem cells to target and deliver tumor-killing drugs is an exciting new application of stem cell biology.
Researchers at City of Hope and St. Jude Children's Research Hospital may have also found a way to more effectively treat aggressive cancers that have spread throughout multiple parts of the body using stem cell therapy. Patients with advanced cancer that has spread to several different sites often do not have many treatment options since they would be unable to tolerate the doses of treatment that are needed to kill the tumors. Researchers used modified neural stem cells to activate and concentrate chemotherapeutic drugs predominately at tumor sites, so that normal tissue surrounding the tumor and throughout the body remain relatively unharmed. "This approach could significantly improve future treatment options for patients with metastatic cancer," said Karen Aboody, M.D., assistant professor of Hematology/Hematopoietic Cell Transplantation and Neurosciences at City of Hope. "It not only has the potential to destroy residual tumor cells, but it should also improve patients' quality of life by minimizing toxic side effects such as nausea, diarrhea or bone marrow suppression." Aboody and her colleagues had previously published the efficacy of this technique in primary and metastatic tumors in the brain. This is the first research to demonstrate that it is also effective in a metastatic cancer model, targeting multiple solid tumor sites spread throughout the body. They speculate that the technique could also be applied to other malignant solid tumors, including colon, brain, prostate and breast cancer, and are planning future preclinical trials using those tumors as well.
In addition to treatment of breast cancer, stem cells have been used in the reconstruction of breast tissue after mastectomy and tumor removal. In a paper presented at the 30th Annual San Antonio Breast Cancer Symposium, at Texas, from December 13-16, 2007, Dr.Keizo Sugimachi, MD, President of the Kyushu Central Hospital in Fukuoka, Japan, reported that his team successfully used adipose-derived stem cells and regenerative cells for breast reconstruction after partial mastectomy. The approach is still experimental, but it holds promise for millions of women left with disfiguration after breast cancer surgery. The researchers performed the study on 21 metastasis-free women who had undergone partial mastectomy for breast cancer. The fat tissue was harvested from the women by liposuction under anesthesia and stem cells from the patient were then added to the fat tissue and reinserted as a filler into the patients’ breast area. At the third and sixth months after the stem cell augmented reconstruction procedure, the researchers measured the thickness of the reconstructed portion of the breast using 2D ultrasound. They observed a significant improvement in the breast tissue thickness at final assessment, compared to baseline. The procedure was also deemed to be safe and well tolerated, without any rejection or immune response. 79% of the patients reported that they were pleased with the results. "This is a pretty exciting topic right now in plastic surgery," said Dr. Karol Gutowski of the University of Wisconsin at Madison. Cytori Therapeutics, headquartered in San Diego, CA, has developed the Celution™ System to process autologous adipose stem cells and regenerative cells for use in breast reconstruction. In 2008, Cytori sponsored two clinical trials involving 90 patients in Europe (one clinical trial for patients who had a partial mastectomy and the other for patients with more severe damage following partial mastectomy with radiation). If approved by the FDA, may begin in the United States in the next few years.
Another exciting possibility for the future is the ability to use stem cells to grow breast tissue outside of the breast for implantation. Researchers do not know yet whether any adult stem cells can generate new breast cells but research has shown that adult stem cells can be induced to produce cell types of a variety of tissues. For instance, researchers have recently been able to cause adult stem cells taken from other parts of the body to “differentiate” into heart tissue. If stem cells could develop into breast tissue, it could one day obviate the need for saline or silicone implants.
It is likely that the main role of stem cells in the treatment of breast cancer will be in combination with other already existing treatments; however, stem cell therapies have been shown to be an important ally in the fight.
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Recent Advances in Real Life Applications for Stem Cells in the Treatment of Disease
For many years, scientists and physicians have researched ways that non-controversial stem cells can treat and/or cure people afflicted with various injuries and diseases, including: heart disease, spinal cord damage, diabetes, cancer, Parkinson’s, Alzheimer’s and Lou Gehrig’s Disease (ALS). Research has generally focused on using stem cells in three ways: 1) in the laboratory, to create an infinite variety of living human cells to better test the disease-fighting ability of new drugs in test tubes; 2) as patch kits, with cells injected to repair injured body parts, such as spinal cord or heart muscle cells; and 3) to create transplants and tissue that could be used to replace damaged body parts. Recent developments show that scientists’ and physicians’ efforts are paying off.
In November 2008, Dr. Gero Hutter and Dr. Eckhard Thiel, blood cancer specialists at Charite Hospital in Berlin, Germany, reported that a 42 year-old American man living in Germany who had AIDS was cured after receiving a transplant of stem cells from a donor with a rare gene variant known to resist the deadly disease. Doctors have not been able to detect the virus in his blood for more than 600 days, despite his having ceased all conventional AIDS medication. The transplant also cured his leukemia, researchers reported.
In February 2009, Macie Morse, a high school sophomore who previously had a rare disorder that caused her to have 20/4000 vision in one eye and only light perception in the other was able to drive a car for the first time due to an experimental stem cell treatment she received in July 2008. Morse received spinal injections of cord blood stem cells each week for six weeks. After her third treatment, she realized she could read and knew the treatments were working. According to Morse’s mother, shortly after the treatments began, “She looked at me and said, ‘Mom, I know that you have green eyes.’ That was a huge step for her in making that human connection. They say you can see the soul through the eyes.” Morse’s take on the treatment: “I always wondered what it would be like to see my friends.”
There are also several recent developments showing success in the treatment of leukemia through stem cell therapy. For example, in January 2009, it was reported that Adolfo Gonzales, a two year old child from Miami, Florida is free of signs of juvenile myelomonocytic leukemia (JMML), a very rare form of pediatric leukemia, seventeen months after receiving a transplant with cord blood. The child’s treatment included chemotherapy to destroy his leukemia cells followed by a cord blood stem cell transplant. He did endure some complications, but approximately two weeks after he had received the infusion of the stem cells, his white cell count began to return to normal. He currently has no signs of leukemia. “Adolfo Gonzalez would most likely not be alive today if it weren't for the cord blood transplant,” Dr. Gary Kleiner, a pediatric immunologist at the University of Miami School of Medicine, said in a statement.
In January 2009, a major Australian newspaper reported that a man who had battled a rare and deadly form of leukemia that could not be treated by chemotherapy, is now cured and enjoying time with his wife and two young children, all thanks to stem cells derived from cord blood. Having spent nine months searching for a compatible bone-marrow donor and being told he had weeks to live, Graham Barnell had all but given up hope. The normal channel for bone-marrow donation, a sibling, was not an option for the adopted Mr. Barnell. Mr. Barnell therefore traveled to Seattle to become the eighth person in the world to undergo a pioneering transplant technique that uses stem cells grown in a laboratory from a donated umbilical cord to regenerate bone marrow. “A year ago I was having to try and deal with the idea I wasn't going to see my kids grow up, and I can tell you that is a really difficult thing to do,” Mr Barnell said. “But then to be given the news that you will, after all -- well, nothing beats that.”
Treatments of other diseases through stem cell therapies have also been reported in the last couple of months. As reported on January 30, 2009, in The Lancet, a British medical journal, an experimental therapy using bone marrow stem cells stabilized and in some cases reversed early-phase multiple sclerosis in 21 patients. Dr. Richard Burt, Chief of Immunotherapy for Autoimmune Diseases at the Feinberg School at Northwestern University in Chicago, led a team of scientists in clinical trials of eleven women and ten men who had not responded to standard drug treatments. The scientists rebuilt the patients’ immune systems by removing faulty white blood cells and replacing them with stem cells derived from the patients’ own bone marrow. After an average follow-up period of three years, 17 of the 21 patients improved by at least one point on a standard disability scale and all patients had stabilized. Five of the patients relapsed but achieved remission after receiving other immunosuppressive therapy, The Lancet reported. “This is the first time we have turned the tide on this disease,” said Dr. Burt. “In MS the immune system is attacking your brain. After the procedure, it doesn't do that anymore.”
Stem cells have also recently been used to reduce the risk of rejection in at least one transplant procedure. According to a November 2008 article also in The Lancet, a woman in Barcelona had undergone surgery in June 2008 to relieve shortness of breath and damage to her airway caused by tuberculosis. During the procedure, physicians transplanted a human windpipe, using stem cells from the recipient’s own bone marrow to reline the donor trachea and prevent its rejection by her immune system. As of November 2008, the woman’s operation was reported a success. “We are terribly excited by these results,” said Professor Paolo Macchiarini of the University of Barcelona, who performed the operation. The graft “immediately provided the recipient with a functional airway, improved her quality of life, and had a normal appearance and mechanical properties at 4 months.” There were also no issues with rejection.
In addition to their ability to cure diseases and aid in transplant procedures, a September 2008 study out of Tulane University has shown that stem cells may have anti-inflammatory properties that could someday minimize the brain damage effects of a stroke. During the experiment, scientists injected non-controversial stem cells into the oxygen-deprived portions of the brains of mice who had had strokes. Although the injected stem cells disappeared after just five days, the researchers found that they had a lasting effect on surrounding brain cells. Mice treated with stem cells experienced 60 percent less cell death compared with mice who did not receive the treatment. According to Darwin Prockop, a scientist involved in the study, stem cells “have this marvelous ability to sense and adjust to their environment.” As such, they were able to react to the stroke by essentially turning down inflammation and immune system responses that would have caused greater brain damage. According to Prockop, “It was quite amazing.” The hope is that this study will develop into clinical trials for human treatment soon.
While stem cells have been largely publicized for their ability to cure diseases, recent research reveals that stem cells may also offer new hope for patients who are recovering from injuries. Bioengineers and material science experts at the University of California San Diego reported in a paper published in the Proceedings of the National Academy of Sciences (PNAS) in late January 2009 that they may have discovered a way to help accelerate bone growth through the use of nanotubes and stem cells. This new finding could lead to quicker and better recovery by orthopedic patients. During their research, the group of UC San Diego scientists used a nano-bio technology method of placing non-controversial stem cells on top of very thin titanium oxide nanotubes in order to control the development of the stem cells into osteoblasts or bone building cells. “If you break your knee or leg from skiing, for example, an orthopedic surgeon will implant a titanium rod, and you will be on crutches for about three months,” said Sungho Jin, co-author of the PNAS paper and a materials science professor at the Jacobs School of Engineering. “But what we anticipate through our research is that if the surgeon uses titanium oxide nanotubes with stem cells, the bone healing could be accelerated and a patient may be able to walk in one month instead of being on crunches for three months. The next step for engineers will be to work with orthopedic surgeons and other colleagues at the UC San Diego School of Medicine to study ways to translate this breakthrough research to clinical application, said Shu Chien, a UC San Diego bioengineering professor and director of the university’s new Institute of Engineering in Medicine (IEM).
Similarly, in a study published in December 2008 in Artificial Organs, researchers in China reported that adult stem cells can be used in the construction of artificial skin. These findings mark a significant advancement in wound healing technology. Researchers grafted skin made of natural materials and stem cells to burn wounds on a pig (pig skin is thought to be most similar to human skin). When grafted to the burn wounds, the engineered skin containing stem cells showed better healing, less wound contraction and better development of blood vessels.
Non-controversial adult stem cells can be found in several places in the human body, and while scientists have regularly harvested such cells from bone marrow, in recent years, the multipotent-stem-cell-rich blood found in the umbilical cord has proven useful in treating the same types of health problems as those treated using bone marrow stem cells. For example, in 2008, a research group from the Universities of Granada and Len confirmed that stem cells from human umbilical cord blood can be as useful as bone marrow stem cells in the treatment of hepatic diseases such as hepatitis.
Umbilical cord blood stem cell transplants are less prone to rejection than either bone marrow or peripheral blood stem cells. This is probably because the cells have not yet developed the features that can be recognized and attacked by the recipient's immune system. Also, because umbilical cord blood lacks well-developed immune cells, there is less chance that the transplanted cells will attack the recipient's body, a problem called graft versus host disease. Both the versatility and availability of umbilical cord blood stem cells makes them a potent resource for transplant therapies.
As reported in the Los Angeles Times on June 7, 2008, using stem cells from umbilical cord blood and bone marrow, researchers apparently cured a fatal genetic disease in a 2-year-old Minneapolis boy. For the first time in his life, Nate Liao, who suffered from epidermylosis bullosis, a rare disease which caused him to lack a critical protein that anchors the skin and lining of the gastrointestinal system to the body, is wearing normal clothes, eating food that has not been pureed and playing with his siblings. “Nate’s quality of life is forever changed,” said Dr. John Wagner of the University of Minnesota Medical School, who performed the treatment. “Maybe we can take one more disorder off the incurable list.” The idea of using circulating stem cells to treat the condition was developed by Dr. Angela M. Christiano of Columbia University Medical Center. “I have watched Nate improve every day,” said his mother, Theresa Liao.
A two year old girl who was diagnosed with cerebral palsy at nine months old is now jumping off beds, putting barrettes in her dolls’ hair and speaking new words every day after receiving stem cell treatment at Duke University in May 2008. Before the treatment, Chloe Levine had speech problems and the right side of her body was nearly paralyzed. The Levines were buckling down for years of physical and occupational therapy for Chloe. Then Levine's sister-in-law sent a story about an experimental therapy at Duke, using a child's banked cord-blood stem cells to treat cerebral palsy. Chloe received a one-time transplant of her cord blood through an IV in her arm and her progress has been remarkable. According to Jenny Levine, her mother, “It’s a miracle. To hear your baby’s voice is a gift.”
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How Do You Mend A Broken Heart?
According to the CDC’s National Center for Health Statistics, heart disease is the number one cause of death of both men and women in the United States. Because heart muscle cells do not replace themselves naturally, those who have suffered from a heart attack, congenital heart disease, or congestive heart failure have few treatment options. Adult stem cells, however, offer new hope in the fight against heart disease. Current research indicates that it may be possible to “fix a broken heart.” Adult stem cells may be used to help replace damaged heart muscles, heart tissue, valves and establish new blood vessels to supply them. The American Heart Association estimates that 58 million people who currently suffer from cardiovascular disease might one day be cured or treated through stem cell breakthroughs.
Here’s How It Works
Stem cells are the parent cells for all tissues and organs of the body. Stem cells can be found in a person’s blood, muscles, bone marrow, and organs such as the brain and liver. Stem cells are also found in umbilical cord and menstrual blood. The primary role of an adult stem cell is to maintain and repair the tissue in which it is found but stem cells also have the remarkable potential to develop into many different cell types in the body. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such a heart cell.
One important heart cell is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart's main pumping chamber (the ventricle). Two other cell types that are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. These two specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged. Researchers now know that stem cells can be coaxed into developing as new cardiomyocytes and vascular endothelial cells. Scientists are interested in developing this ability to provide replacement tissue for a damaged heart.
What is the evidence that such an approach to restoring cardiac function might work?
About a decade ago, scientists began testing the effectiveness of stem cells in regenerating heart tissue by simulating heart attacks in mice and rates and then repairing the damage with heart cells grown from stem cells. In 2001, doctors reported that after they injected adult bone marrow into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, which in turn developed into coronary arteries, arterioles, and capillaries. The newly formed arteries, arterioles and capillaries occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead tissue with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells.
In 2003, sixteen-year-old Dimitri Bonnville became the first human to receive experimental stem cell therapy to revive his damaged heart tissue. Bonnville had been accidentally shot in the heart with a nail gun while doing home repair, undergone open-heart surgery and suffered a massive heart attack. In lieu of heart transplant surgery, Bonnville’s parents opted for stem cell therapy to repair his damaged heart. Doctors at the William Beaumont Hospital in Michigan harvested stem cells from Bonnville’s blood. Using a heart catheter, they transplanted the stem cells into the artery that supplies blood to the front of the heart. Following the procedure, Bonnville experienced significant improvement in heart function.
In 2004, the FDA approved the first clinical trial in the United States to test stem cell therapy for severe heart failure. Prior to this clinical trial, scientists in Brazil had already tested the treatment on fourteen patients in Brazil. That study, published in Circulation Research, showed that the procedure is safe and significantly improves heart function. “We saw significant improvements in exercise capacity,” said Emerson Perin at the Texas Heart Institute in Houston, Texas. “This is measured in terms of peak oxygen capacity, which went from 17 percent to 24 percent in treated patients.”
On February 11, 2009, officials with the University of Louisville and Jewish Hospital & St. Mary’s Healthcare Inc. announced that they will be the first to host to an FDA-approved clinical trial that targets heart disease with the use of cardiac stem cells. A group of twenty patients with advanced heart disease who are already undergoing bypass surgery will be recruited for the study. During surgery, physicians will remove a small piece of heart tissue and send it to Harvard University, where the cardiac stem cells will be extracted. After a three- to four-month recovery period, the stem cells will be injected into scar tissue on the hearts of the patients. Physicians will follow the patients’ progress for at least a year, measuring heart function and blood flow. The dimensions of the heart, which becomes enlarged after heart failure, also will be measured, along with the size of scar tissue, said study leader Roberto Bolli, distinguished chair in cardiology at the Jewish Hospital Heart and Lung Institute.
A stem cell company in Columbia, Md., on February 12, 2009, reported the final two-year results for its Phase I clinical trial evaluating the safety of a stem cell treatment for acute myocardial infarction (heart attack). The treatment, called Prochymal, is a proprietary formulation of adult stem cells designed to provide therapeutic benefit by controlling inflammation, promoting tissue regeneration, and preventing scar formation. The double-blind, placebo-controlled study, which evaluated safety and preliminary efficacy in 53 patients, found heart attack patients receiving the intravenous therapy had lower rates of adverse events and significantly improved heart function. Although stem cell therapy to repair damaged hearts is still being tested, most studies that have been conducted to date show that stem cell therapy reduced the impact of a heart attack and improved the heart's ability to pump. A 2007 article in the International Journal of Cardiology, for example, reported on a study that divided 70 cardiac patients into two equal groups: One group received injected stem cells and the other group received a placebo. Six months later, the patients treated with stem cells had a significant improvement in left ventricular pumping, and in the control group, there was no improvement. Twenty-five patients experienced complications, but none died.
With these advances in the use of stem cell therapy to repair damaged heart tissue, another recent welcome finding is the discovery that a popular statin drug may help stem cells perform this job even more effectively. In a paper published in the January 2009 issue of Circulation Research, scientists at the University of Buffalo’s Center for Research in Cardiovascular Medicine reported that Pravastatin, a statin drug used to treat cholesterol, may have an added benefit of preventing the development of heart disease by regenerating diseased heart tissue. The drug appears to mobilize bone marrow progenitor cells – blood stem cells that are able to transform into many different types of cells -- which infiltrate the heart and develop into cardiac muscle cells, thus improving cardiac function. “The finding that a drug with an excellent safety profile used widely to lower blood cholesterol is effective in improving cardiac function in hibernating myocardium is a welcome finding,” said Gen Suzuki, M.D., Ph.D., UB research assistant professor of medicine and first author on the study.
In addition to being able to repair heart damage through the transplantation of stem cells into the affected area, doctors have been able to grow heart parts in the lab to eventually be placed in a damaged heart. In 2007, Sir Magdi Yacoub, a world famous heart surgeon based at Imperial College London and a team of physicists, pharmacologists, cellular and clinical scientists, developed heart valve cells by taking adult stem cells from bone marrow. They used collagen to hold the valve tissue in shape as it grew into one-inch disc-shaped valves. Although plastic heart valves do exist, stem cell-grown valves offer a distinct advantage: "[B]ecause the patient's own stem cells are used it eliminates the problem with rejection that happens when a heart has been donated by another person."
Presenting at the American Heart Association's (AHA) annual scientific sessions in New Orleans in November 2008, cardiac surgeon Dr. Ralf Sodian reported that his team had also used stem cells to create tissue-engineered heart valves. His team stored stem cells derived from umbilical cord blood for twelve weeks and then seeded them onto eight heart valve scaffolds which then grew tissue that nearly mirrored human heart valve tissue. Adult stem cells collected at birth from the umbilical cord may help doctors fashion new heart valves for children born with heart valve defects. The tissue-engineered valves would have the advantage of growing with the child, said researchers at the University Hospital of Munich. "If we replace a valve in a child, they will need surgery several times in their lifetime, because they will grow out of the devices, so the ultimate goal is to have a construct which is able to grow with the child and only have to do the surgery once," said Dr. Sodian. In addition, stem cell-based valves offer the advantage of not experiencing the wear and tear issues related to metal and plastic valves.
In addition to the creation of heart valves, scientists have also discovered a way to generate functioning, beating heart cells from stem cells. In February 2009, researchers at the University of Wisconsin-Madison announced that they had taken skin cells and grown them into pulsing heart cells. In Circulation Research, Timothy Kamp, co-director of UW’s Stem Cell & Regenerative Medicine Center, reported that the reprogrammed heart cells made in the laboratory performed some key functions of the heart cells inside our bodies. They generated electrical pulses, and in response to these pulses, they contracted. It is the collective contraction of all these cells that enables the heart to beat. "It's an encouraging result because it shows that those cells will be useful for research and may someday be useful in therapy,'' said Kamp. "If you have a heart failure patient who is in dire straits — and there are never enough donor hearts for transplantation — we may be able to make heart cells from the patient's skin cells, and use them to repair heart muscle. That's pretty exciting."
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