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Adult Stem Cells Used in Reconstructive Breast Surgery

MIT Technology Review, April 6, 2009

In the U.K., 49-year-old Irene MacKenzie was displeased with the hollow concavity that was left in her breast following a lumpectomy that she underwent for early-stage breast cancer. Eager to do something to correct the situation, Irene enrolled in a clinical trial and became the first woman in Britain to undergo reconstructive therapy with her own adult stem cells. Since Irene, a total of eleven patients have now been treated with the same procedure, which utilizes adult stem cells derived from the adipose (fat) tissue of each patient. The procedure was performed at the Glasgow Royal Infirmary, under the direction of consulting plastic surgeon Dr. Eva Weiler-Mithoff.

The mother of 3, Irene describes her experience. "When I was diagnosed with breast cancer in my left breast five years ago, I had a lumpectomy, removing the tumor and a healthy margin of tissue. I naturally wanted to preserve as much of my breast as possible. Immediately after surgery my breast didn't look that bad, but this was because the hole left by the lumpectomy had filled with fluid from the surgery wound. Then I had six weeks of radiotherapy, which dried up a lot of the fluid. The tissue around the area shrank and hardened, pulling the overlying skin deeper into the hollow. I was left with a dense mass, the size of half a plum. Sometimes it caused a painful dragging sensation. I was very self-conscious about it and I went to specialist bra shops for fittings, but I was never comfortable with them."

The stem cell procedure is relatively simple, as it begins with the extraction of approximately one pint of fat via liposuction from the patient's stomach. This pint is then divided into two halves, one of which is temporarily set aside while the adult stem cells are extracted from the other half. The stem cells are then combined with the fat from the first half, and the new mixture is injected back into the hollow depression that is commonly left in breasts by lumpectomies. In Irene's case, after 3 months the stem cell mixture had been assimilated to such an extent that the breast looked and felt like a complete, normal breast once again.

As Irene explains, "Initially, my breast and tummy felt bruised and swollen, but after a few weeks, this went down. Three months later, my stem-cell-treated breast looked and felt like normal breast tissue, even slightly firmer. I had a follow-up appointment at three months and at six months. Mrs. Weiler-Mithoff thought my breast should be topped up slightly because some of the fat had been reabsorbed, so I had more liposuction. Now it looks fantastic and it's changed my whole outlook."

Previous procedures have already existed in which liposuctioned fat, without stem cells, was used for reconstruction of the breast, but such procedures have a low graft survival rate of only 30 to 50%, and such techniques are often associated with further problems such as calcification, lump formation and necrosis (death) of the adipose tissue. By contrast, adding adult stem cells to the adipose tissue brings the graft survival up to 80% or higher, since the adult stem cells promote angiogenesis (the growth of new blood vessels) which provides a blood supply to the new tissue, without which the tissue would die.

As Dr. Weiler-Mithoff describes, "We have treated eleven patients so far as part of a European trial into stem cell fat transfer treatment to fill breast defects, and I am very pleased with the results. The patients come to us with mild, but to them, upsetting, contour defects. If you looked at the breast in silhouette, you'd notice a dip. Immediately after a lumpectomy, the area may not look that different. But if it is treated with radiotherapy, it shrinks and pulls in the overlying skin, forming a crater. Until three years ago when some surgeons started filling these craters with fat liposuctioned from one part of the body, there was not much we could do. Now we can inject stem cell-enriched fat into the dip. The big advantage of this over plain liposuctioned fat is that it boosts its chances of survival. Ordinary fat can struggle to get a decent blood supply and it can either die or be absorbed back into the body, or it can calcify and feel like another lump. But if you put stem cells into the breast, they become fat and blood vessels. This stem cell-enriched fat also seems to restore the softness of the breast tissues. It almost uncrumples the skin, undoing some of the radiotherapy damage, and women are reporting that their pain has eased, too, possibly because it makes the skin more supple. Patients have an MRI scan at six and 12 months to check breast volume - if some fat has been reabsorbed a top-up may be required. Patients have another mammogram at the one-year mark."

Doctors at Leeds General Infirmary, and also at Norfolk and Norwich University Hospitals, are scheduled to begin recruiting more patients for the U.K. trial. Qualifying patients will have had a cancererous tumor that measured 3 centimeters or less in size and which has not spread to the lymph nodes.

Every year more than 31,000 women in the U.K. alone have lumpectomies for early-stage breast cancer. According to Dr. Kefah Mokbel, a breast surgeon at the London Breast Institute at the Princess Grace Hospital, "This is a very exciting advance in breast surgery. The breasts feel more natural because this tissue has the same softness as the rest of the breast." By contrast, Dr. Mokbel explains, "Implants are a foreign body. They are associated with long-term complications and require replacement. They can also leak and cause scarring."

The technology was developed by Cytori Therapeutics and is being commercialized in partnership with GE (General Electric) Healthcare. In Japan, doctors at the Seishin Regenerative Medicine Centers in Tokyo and Osaka have already been using this reconstructive procedure for the past 6 years, with an 80% satisfaction rate. Their patients include not only women who have undergone lumpectomies but also women who simply desire cosmetic augmentation.

Meanwhile, however, scientists hope to be able to develop other, better ways to regenerate breast tissue more naturally, more thoroughly, and more efficaciously, although such possibilities have not yet been easily attainable. For years, the mere search for a resident population of human breast stem cells remained without tangible results, although scientists are gradually making progress. According to a report published in January of 2005 by researchers at the University of Manchester in the U.K., breast epithelial stem cells are thought to be the primary targets in the etiology of breast cancers, most of which express cellular estrogen and progesterone receptors and are therefore regulated by these and other hormones in ways that are not yet fully understood. Similarly, in March of 2002, scientists at the University of Copenhagen in Denmark, in collaboration with scientists at the Lawrence Berkeley National Laboratory of the University of California, succeeded in isolating and expanding a stem cell line from endogenous human breast stem cells, i.e., from stem cells that naturally reside within the breast. The scientists focused their study on the terminal duct lobular unit (TDLU), which is a branching mammary structure with luminal epithelial cells on the inside and myoepithelial cells on the outside, from which Dr. Ole William Petersen and his colleagues were able to isolate a luminal epithelial cell population which they referred to as MUC-/ESA+, named after the types of identifying cell surface markers that distinguish the cells. After establishing a MUC-/ESA+ cell line, the researchers were then able to show that these cells can be differentiated into both luminal epithelial cells and myoepithelial cells, and that even a single MUC-/ESA+ cell is capable of generating a TDLU-like structure in vitro, and also in vivo in mice. Additionally, the scientists discovered that these cells also express the keratin K19 protein, as does a subpopulation of luminal epithelial cells in normal breast tissue. Their findings, which were published in the March, 2002 issue of the journal Genes and Development, suggest that the highly elusive human breast stem cell may exist within this subpopulation of the luminal epithelial cell lineage. No doubt a further understanding of breast stem cells would also shed light on the cellular mechanisms at work in transforming otherwise normal cellular tissue into the various types of cancers and malignancies of the breast.

The real question, of course, is not merely how to repair tissue for cosmetic purposes, but how to regenerate the tissue for functional purposes as well. Someday, with regenerative medicine, such a goal may be achievable.

Phrased another way, much more important that mere cosmetics is the possibility of a full regeneration of a breast that was lost to masectomy. After all, to focus exclusively on cosmetic appearance is to lose sight of the fact that breasts, in all mammalian species, are designed to perform a specific biological function which is critical for the survival of that species, namely, to produce a specialized - and in many cases, the only - source of nutrition for newborns. While the repair of an indentation left by a lumpectomy is certainly to be applauded, the ultimate goal is not merely the external appearance of the breast but rather it is the full restoration and regeneration of the entire mammary gland, complete with full physiological function. Some day, regenerative medicine may be able to do exactly that, which would then also result, secondarily, in a restoration of the visual wholeness of the mammary gland, not as an objective in and of itself but as a natural consequence of having restored the entire breast to its original state of physiological wholeness. If scientists can already regenerate fingers with adult stem cells (please see the related news articles on this website, entitled, "Grow Your Own Replacement Parts" dated February 6, 2008, and "Growing Miracles", dated February 7, 2008, each originally reported by CBS Evening News, and "Growing a New Heart With Adult Stem Cells", dated March 18, 2009), then it is just a matter of time before the right stem cell is found, such as perhaps an endogenous breast stem cell, which can be utilized after a masectomy to regenerate the entire breast, such that the breast is anatomically and physiologically complete with its full venous, arterial, lymphatic, nerve and milk duct systems as well as papilla, so that the breast would even be capable of lactogenesis and lactation, if necessary, with alveoli, lobules, lactiferous ducts and galactophores that can support colostrum as well as milk production and which are responsive to all the myriad hormones that are involved in pregnancy and lactation. The point is not so much whether or not lactation would ever actually be needed, but rather the point is simply the restoration of natural wholeness. As with any other part of the body, the best way to restore cosmetic appearance is by restoring the internal integrity of physiological tissue and its corresponding function. Restoring complete anatomical and physiological wholeness, with functional viability of the entire mammary gland, would therefore be the best way to restore complete wholeness of cosmetic appearance. Otherwise, just having something that resembles a "breast" in visual appearance but which consists merely of surgically implanted adipose tissue that lacks the precise physiological functionality of a real breast, would be akin to having an artificial prosthesis for a limb, when clearly the real, healthy limb would be more desirable. To continue with the analogy, when a person loses a leg, for example, prosthetics are not necessarily designed to be visually attractive, but, more importantly, they are designed to be able to bear weight and to move in a walking motion and to resemble as closely as possible the functional purpose of a real leg. If all the bones, vessels, veins, tendons, ligaments, musculature and other tissue of the entire, natural leg could be regenerated, that would be even better. Similarly, any woman who has lost an entire breast or even part of a breast would prefer to have the original form and function restored in its natural entirety, not merely in an artificial external form for visual appearance. To be capable of such a medical procedure, however, scientists and physicians would first need to attain control not merely of angiogenic (blood vessel-forming) stem cells, but also of stem cells that form lymphatic tissue, nerve and lactiferous duct systems, among other anatomical and physiological objectives. Then, the correct medical terminology would be "regenerative breast procedure", rather than "reconstructive breast procedure".

Although regenerative medicine has not yet advanced to the stage where entire limbs, organs, and glands such as breasts can be regrown, the field is rapidly progressing in that direction.



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