Product Fact Sheet
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www.marijkelong.com 100% Black or c=0, m=0, y=o, k=100 - PANTONE 2654 C or c =40, m=36, y=o, k=5
60 Capsules per Bottle StemEnhance is the first-ever natural Adult Stem Cell Enhancer. It is the only nutritional supplement proven to support the natural release of adult stem cells from the bone marrow. StemEnhance is a patented blend of two proprietary botanical concentrates of Aphanizomenon flos-aquae (including Mobilin®). What StemEnhance Does: A double-blind study published in the highly respected journal, Cardiovascular Revascularization Medicine demonstrated that the consumption of just 1 gram (2 capsules) of StemEnhance increased the number of circulating adult stem cells by an average of 3 million more circulating adult stem cells!
Potential Users StemEnhance is safely enjoyed by men, women and children. It is highly recommended for those seeking optimal health and optimal fitness and performance.
FEATURES
BENEFITS
Proven adult stem cell enhancer
Supports the natural release of adult stem cells from the bone marrow. StemEnhance increased the number of circulating adult stem cells by an average of 3 million more circulating adult stem cells.
Aphanizomenon Flos-aquae (AFA)
100% natural botanical ingredient. AFA has been consumed for over 3 decades for its nutrient dense properties.
Proprietary concentrate
Nutrient dense concentrate containing proprietary components including Mobilin™
Mobilin™
L-selectin blocker/ligand. Supports adult stem cell release.
www.marijkelong.com
Product Fact Sheet INGREDIENTS / LABEL
USAGE Take 2 capsules orally, 1 to 2 times daily.
100% Black - c =0, m=0, y=o, k=5
for your information
100% Black 0r c =0, m=0, y=o, k=100
Vegan 2 part capsule
c =0, m=0, y=o, k=5
No sugar, artificial colors, artificial flavors, soy, dairy, yeast, or preservatives 100% Black or c=0, m=0, y=o, k=100 - PANTONE 2654 C or c =40, m=36, y=o, k=5
StemEnhanceLabel_092010-1.indd 1
Barcode
Certifications: Kosher, Halal, Organic AFA
11/9/10 3:04 PM
FAQ’s How does an increase in the number of circulating adult stem cells lead to optimal health? Stem cells form the core of body’s natural renewal system. When circulating, adult stem cells are signaled by organs and tissues in need. They migrate into the tissue, reproduce and transform themselves into healthy cells of that tissue.
Vitamin K in StemEnhance: Like many foods, StemEnhance contains naturally occurring vitamin K. Two capsules have approximately 40 mcg of vitamin K (equals about 1/2 cup of chopped brocolli).
How is StemEnhance® different from whole AFA? StemEnhance is a patented concentrate of AFA that concentrates the beneficial organic compounds found in whole AFA, including Mobilin™. StemEnhance is scientifically proven to support an increase in the number of naturally released circulating adult stem cells.
Label statement: Consult your physician if pregnant or nursing. (Many products carry such warnings out of an abundance of caution rather than any known pregnancy risk. We know of no evidence that consuming StemEnhance during pregnancy creates a health risk.)
Does StemEnhance help with any specific health condition? StemEnhance is a nutritional supplement, not a medication. It is not intended to be used to diagnose or treat any disease or illness. Results of scientific studies indicate that increasing the number of circulating adult stem cells is a key factor in maintaining optimal health. Can a person of any age take StemEnhance? Yes, just follow the directions on the label and do so under adult supervision.
Naturally occurring iodine: Unlike most algae, Aphanizomenon flos-aquae (AFA) has only a small amount of iodine, 0.39 mcg per gram. In comparison, one slice of bread has about 6 mcg.
For a comprehensive list of FAQs, go to: http://www.stemtech.com/FAQ_sub.aspx
PEA: StemEnhance contains a naturally occurring compound known as Phenylethylamine (PEA). PEA is naturally produced by the brain and known to support mood and mental energy. PEA is made by the brain whenever one feels content and happy; it has been described as the “molecule of joy”.
Research/Reports/Articles
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
Visit www.stemtechbiz.com/study.aspx - contains links to: National Library of Medicine’s PubMed database: Mobilization of human CD34+ CD133+ and CD34+ CD133(-) stem cells in vivo by consumption of an extract from Aphanizomenon flos-aquae--related to modulation of CXCR4 expression by an L-selectin ligand? Study summary: “A novel cyanobacterial ligand for human L-selectin extracted from Aphanizomenon flos aquae – potential role for stem cell biology in vitro and in vivo?” CHRISTIAN DRAPEAU, HUAIYU MA, ZHIJIAN YANG, LI TANG, ROBERT M. HOFFMAN and DAVID J. SCHAEFFER (2009) The Stem Cell Mobilizer StemEnhance® Does Not Promote Tumor Growth in an Orthotopic Model of Human Breast Cancer. ANTICANCER RESEARCH 29: 443-448.
For More Information: Product brochures Websites: stemtech.com and stemsport.com Weekly conference calls: Tues 6pm and 7pm Pacific (see website for dial-in numbers)
Sabelli HC and Javaid JI (1995) Phenylethylamine modulation of affect: therapeutic and diagnostic implications. J Neuropsychiatry Clin Neurosci 7(1): 6-14. Copyright © 2011 Stemtech International, Inc.
Rev. 2011
Click on image to listen to interview:
Christian Drapeau, Stemtech Chief Science Officer When Christian Drapeau first posited that Adult Stem Cells were the very foundation of the body's natural healing system, scientific study in the field was in its infancy. His hypothesis that Adult Stem Cells, created by bone marrow, flowed to any tissue or organ needing regeneration and morphed into healthy cells of that location, was initially ridiculed by medical science. Since 2006 however, Christian's position gained not just momentum but widespread acceptance in scientific circles as study after study reveals that Adult Stem Cell science holds phenomenal promise in all arenas of human healing. In his interview he shares, reports, analyzes and forecasts how the latest breakthroughs in Adult Stem Cell science will improve our lives.
For more information on Christian's work: www.christiandrapeau.com www.crackingthestemcellcode.com Click HERE for Stemtech information
A novel cyanobacterial ligand for human L-selectin extracted from Aphanizomenon flos aquae – potential role for stem cell biology in vitro and in vivo?
Introduction
The objective of this study was to evaluate the in vitro and in vivo effects of StemEnhance™, an extract from Aphanizomenon flos-aquae (AFA) enriched for a novel ligand for human L-selectin, on stem cell physiology. L-selectin is a cell adhesion molecules involved in cellular migration, cellular adhesion, and the retention versus release of bone marrow stem cells into the blood circulation. Stimulation of L-selectin leads to the externalization of pre-formed CXCR4 chemokine receptors, which are specific for the chemokine Stromal Derived Factor-1 (SDF-1) (Figure 1). Binding to SDF-1 to CXCR4 leads to the externalization of adhesion molecules that anchor the stem cell in the bone marrow. SDF-1 acts as a potent attractant for stem cells and therefore assists in retaining stem cells within the bone marrow environment. It was demonstrated that any interference with the CXCR4/SDF-1 axis is one of several contributing mechanisms involved in the release of stem cells from the bone marrow. Therefore, any compound that interferes with CXCR4 or SDF-1 has the potential of acting as a stem cell mobilizer.
Figure 1
There are many ways to support stem cell mobilization. For example, Granulocyte Colony-Stimulating Factor (G-CSF), the natural compound in the body stimulating stem cell mobilization works at least in part by raising the level of specific proteolytic enzymes that degrade SDF-1, thereby disrupting the CXCR4/SDF-1 axis. Other compounds such as AMD-3100 promote stem cell mobilization by blocking CXCR4, once again disrupting the CXCR4/SDF-1 axis. Finally, L-selectin blockers reduce the density of CXCR4 on the surface of the stem cells’ membrane, thereby down-regulating the CXCR4/SDF-1 axis. Due to the physiological processes involved in each of these mechanisms of action, the mobilizations triggered by each of these mechanisms show different magnitude, time of onset, and duration. Mobilization triggered by G-CSF and AMD-3100 begins within a few days, last for a few days and can lead to an increase in the number of circulating stem cells by up to 100-fold. Conversely, mobilization triggered by L-selectin blockers is more transient and of a much lesser magnitude. The mobilization observed after consumption of StemEnhance was rapid, transient and mild, therefore we hypothesized that AFA contained an L-selectin blocker.
Methods & Results AFA contains a ligand for human L-selectin In order to determine whether AFA contained an L-selectin ligand (binding molecule), paramagnetic Dynabeads coated with human L-selectin were incubated with a water extract of AFA (AFA-W) (Figure 2). After incubation, Dynabeads were washed and any bound material from the AFA extract was detached from the L-selectin molecules and run on gel-electrophoresis.
Figure 2
This process revealed that AFA contains an L-selectin ligand that appears to be a dimer made of two proteins having apparent molecular weights of 57 and 54 kDa respectively (Figure 3). Using the same protocol on Spirulina, it was determined that Spirulina does Figure 3
not contain an L-selectin ligand.
AFA-W specifically reduces TQ1 immunostaining of L-selectin on human PMN cells L-selectin possesses one specific binding site whose activation leads to the externalization of CXCR4. In order to determine whether the L-selectin ligand present in AFA was binding to the active binding site of L-selectin, we tested the effect of AFA-W on the binding properties of TQ1 anti-human L-selectin monoclonal antibody. TQ1 is an antibody that specifically binds to the physiological active binding site of L-selectin. Incubation of lymphocytes with AFA-W reduced the binding of TQ1 by approximately 50-fold, indicating that the AFA L-selectin ligand does bind to the active binding site of L-selectin.
AFA-W inhibits the fucoidan-induced CXCR4 expression on CD34+ cells from bone marrow It was important to determine whether the L-selectin ligand found in AFA was a stimulant or an inhibitor of L-selectin. We know that stimulation of L-selectin leads to an increase in the externalization of CXCR4, which can be quantified by measuring the density of CXCR4 receptors on the surface of stem cells. Incubation of bone marrow stem cells with AFA-W did not have any effect on CXCR4 density, indicating that the AFA L-selectin ligand was not a stimulant of L-selectin (Figure 4; green line).
Figure 4
CXCR-4 Expression (MFI)
35 30 25 20 15
Untreated Fucoidan Fucoidan w ith AFA AFA Alone
10 5 0 0
15
30
45
60
Time (min)
To investigate whether the ligand was a blocker of L-selectin we tested the effect of AFA-W on fucoidan-induced increase in CXCR4 density (Figure 4). Fucoidan is a sulfated polysaccharide known to stimulate L-selectin. Fucoidan triggered an 8-fold increase in CXCR4 density (blue line) which was inhibited (≈50%) by incubation with AFA-W (red line). Therefore, AFA contains a blocker of L-selectin.
Consumption of StemEnhance™ resulted in a transient increase of circulating CD34+ cells. As previously described in the scientific literature, L-selectin blockers have the potential of being effective stem cell mobilizers by modulating the CXCR4/SDF-1 axis. Therefore, we tested the mobilizing ability of the AFA L-selectin ligand in humans. Using a double-blind cross-over paradigm, the level of circulating CD34+ stem cells was compared in 15 individuals before and after ingestion of 1 gram of StemEnhanceTM or placebo. StemEnhanceTM (StemTech HealthSciences, Inc., CA) is a proprietary blend of
the cytoplasmic and cell wall-rich fractions of the whole plant biomass, enriched approximately 5-fold in content of the L-selectin ligand compared to the raw AFA biomass. 130%
Consumption of StemEnhanceTM
Figure 5 p<0.0001 125%
resulted in a 25 Âą 1% increase in the 120%
number of circulating stem cells at 60
number of circulating CD34+ stem cells returned to baseline level around 3-4 hours after consumption. This was in
% of Start
minutes (p< 0.0001) (Figure 5). The 110%
100%
contrast to placebo, which resulted in only minor fluctuations of the levels of CD34+ cells in the blood circulation over
90% 0
30
2 hours.
60
90
Time (min)
Figure 6 In order to test the repeatability of the effect of consumption of StemEnhanceTM on the levels of CD34+ cells in the peripheral blood, 16 separate experiments were performed on one volunteer. The average increase in the number of circulating stem cells was 53 Âą 16%, with a median of 36% and a highest and lowest increase of 233% and 4%, respectively (Figure 6).
120
Discussion Dietary strategies for supporting stem cell biology represent an emerging field of nutritional and medical research. The cyanobacterium AFA has been studied for its antioxidant properties and immuno-modulatory effects both in human and in vitro. AFA contains a number of compounds that have been subject to much research, including the potent antioxidant phycocyanin, a complex polysaccharide with potent immunomodulatory properties, and the neuromodulator phenylethylamine responsible for the experience of mental energy reported by consumers. It is reported here that AFA also contains a novel compound that specifically binds to the ligand-binding area of human L-selectin. It is composed of two subunits with apparent molecular weight around 54-57 kDa. This ligand for human L-selectin, obtained from AFA water extract, was able to modulate the functional response on human lymphocytes in vitro. The expression of the chemokine receptor CXCR4, which is induced by the known L-selectin ligand fucoidan, was down-regulated when fucoidan and AFA water extract were added simultaneously, indicating that the L-selectin ligand from AFA was competing with fucoidan for binding to L-selectin. A double-blinded placebo-controlled cross-over study showed that consumption of StemEnhanceTM resulted in a small but significant increase in the number of circulating CD34+ stem cells, peaking at 1 hour after consumption. The effect was statistically significant (p<0.0001). There is however a significant fluctuation from one day to another in the effect of StemEnhanceTM or in the ability to quantify the effect accurately. Therefore, in order to test the nature of this fluctuation, we tested one individual on 16 different experimental days. The increase in the number of circulating stem cells after consumption of StemEnhance™ averaged 52 ± 16% and varied greatly from 96% to 333% of baseline value. Interestingly, the average response in the one individual tested repeatedly and the average response to StemEnhance™ in the double-blind randomized study involving 12 people were similar, indicating the relative consistency of the response and that the double-blind trial may in fact have understated the effect of
StemEnhanceTM. Recent studies have put in evidence the potential role of stem cell mobilizers in the maintenance of optimal health. Recently, a number of studies concluded that the level of circulating CD34+ stem cells was a good indicator of health.
Mobilization of bone marrow stem cells with StemEnhanceÂŽ improves muscle regeneration in cardiotoxin-induced muscle injury
Introduction It was shown that stem cells released from the bone marrow can migrate into injured tissues, supporting the process of tissue repair. In this process, the number of circulating stem cells was shown to be a critical factor. In a number of studies addressing various health conditions, higher numbers of circulating stem cells have been associated with greater health. An increase in the number of circulating stem cells was shown to improve various health conditions.
Based on this information, it was claimed that the natural stem cell mobilizer StemEnhance had the ability to support optimal health by increasing the number of circulating stem cells. StemEnhance is an extract from the aquatic botanical Aphanizomenon flos-aquae that was shown in a double-blind crossover study to increase the number of circulating stem cells by 25-30%.
This study was aimed at confirming the effect of StemEnhanceâ&#x201E;˘ on tissue repair.
Methods In brief, thirty 8-10 weeks old female mice were lethally irradiated before receiving a bone marrow transplant with stem cells marked with green-fluorescent protein (GFP). After transplantation, animals were randomly separated into two groups of 15 animals, one group received placebo while the other received 300mg/kg/day. At day 16 and 30 1
after transplantation, mice from each group were randomly selected for hematological tests to see the effect of StemEnhance on hematopoiesis. The remaining mice in each group (n=6) were injured by injection of 10Âľm Cardiotoxin in 100 Âľl PBS directly into the anterior tibia muscles of right leg. Five weeks after the injury, the mice were sacrificed and using open imaging (Olympus OV 100 Small Animal Imaging System), the mice were evaluated for incorporation of GFP cells into tissues, including heart muscle, liver, kidneys, intestinal wall, brain, skin and lung. The incorporation of GFPpositive muscle fibers was quantified with Photoshop 7.0.
Results No significant difference was observed between the treated (StemEnhance) group and untreated (PBS) group regarding average hemoglobin content as well as WBC, RBC platelet and reticulocytes counts. Therefore StemEnhance did not appear to have an effect on hematopoietic recovery.
In the injury part of the study, the extent of the recovery was
Control
evaluated by measuring the area covered by fluorescence in the recovering muscles. The group receiving StemEnhance showed greater regeneration of the tibialis muscle (p<0.05), though both PBS and StemEnhance groups showed very
StemEnhance
significant recovery. The difference between the two groups was also noted behaviorally by a greater strength in the leg of the StemEnhance group while being handled, though this was not quantified. Contralateral leg
Less fluorescence was seen in the contralateral left tibialis muscle of both groups, indicating that migration of bone marrow stem cells was more significantly directed toward the injury.
2
Some fluorescence was also seen in most of the main organs, such as the heart, brain, kidney, liver and lung, though no difference was seen between the two groups.
Discussion StemEnhance did not seem to have an effect on hematopoietic recovery, as it did not increase the number of red blood cells, white blood cells and platelets soon after irradiation.
However, StemEnhance did enhance recovery from cardiotoxin-induced
muscle injury. Reliable measurements of fluorescence were not made during the healing process, therefore it is not possible to discriminate whether StemEnhance accelerated the repair process or enhanced the overall repair process. Studies have reported that bone marrow stem cell mobilization accelerates the healing of skin burn and bone fracture. On the other hand, it was reported that scar formation appears to take place when not enough stem cells are available to support full repair process. So it is likely that the effect of StemEnhance was an acceleration of the repair process, which in some conditions could also lead to a greater overall repair by reducing scar formation.
While StemEnhance enhanced recovery, significant recovery was nonetheless seen in the control group indicating stem cells derived from the bone marrow naturally contribute to the repair of injuries. Furthermore, in both StemEnhance and control group, incorporation of GFP-muscle cell was much less in the contralateral left tibialis muscle, indicating that stem cells migrate predominantly towards sites of injury. Therefore, this study confirms three key aspects of stem cell physiology: 1) stem cell migration in an injured tissue is a natural process that takes place without any stimulation, 2) increasing the number of circulating stem cells accelerates the repair process, and 3) stem cells primarily migrate to sites of injuries.
In conclusion, this study confirmed the hypothesis that StemEnhance supports the natural process of tissue repair by supporting the release of stem cells from the bone marrow. 3
Daily consumption of StemEnhance helps reduce hair graying
Introduction
Many consumers of StemEnhance reported, after a few months of daily consumption, reduction of hair graying. Consumers reported a slow return to oneâ&#x20AC;&#x2122;s natural hair color. Although such reports were first received with skepticism, a brief search of the scientific literature rapidly provide evidence that bone marrow stem cells have the ability of differentiating into melanocytes responsible for hair pigmentation, therefore providing for a mechanism of action behind such observation. Altering hair color by restoring oneâ&#x20AC;&#x2122;s natural hair color has little relevance when considering human health, however such an effect would constitute a strong indication of the rejuvenating properties of StemEnhance. In this study we investigated the effect of daily consumption of StemEnhance on the density of white in the hair of middle age men.
Methods In brief, 6 healthy men between 46 and 61 years of age exhibiting significant hair graying were selected. The participants were provided StemEnhance and were instructed to consume 2 capsules three times daily. The subjects were instructed to report any adverse reaction. Finally, participants were instructed not to change their hairstyle, grooming products or schedule of haircuts for the duration of the study.
1
At baseline and once monthly visual and instrumental hair color evaluations were conducted using Matched Scientific Photography. The technicians involved in this study were all certified by a Board Certified Ophthalmologist using the Farnsworth-Munsell 100 Hue Test, which determine a personâ&#x20AC;&#x2122;s ability to discern color against a black background. Finally, at each visit the participants were asked to fill a SF-36 Quality of Life Questionnaire.
Results No adverse effects or unexpected reactions of any kind were observed on any of the participants. Most participants empirically reported a greater level of energy and an overall greater level of well being for the duration of the study, which was objectively measured using the SF-36 Quality of Life Questionnaire. Stat and graph.
A
reduction
in
the
density of white was seen in all participants in both sides of the head and in the back. Although the effect was more pronounced on the sides of the head (19%) than in the back (17.5%), the difference was
not
significant.
Therefore, the data was pooled and on average the reduction in white density gradually reached -18.5% after 6 months of consumption, ranging between -11% and -28.6%. The difference measured
2
was statistically significant (p<0.001). In at least three participants empirical observations also suggested a thickening of the hair, although this was not quantified.
Discussion
As mentioned previously, reversal of hair graying does not carry much relevance to overall health. Hair graying is a natural process associated with aging and many people with graying hair have very good health. Yet, hair color is a symbol of rejuvenation and so far nothing is known which, when taken orally, can naturally bring back oneâ&#x20AC;&#x2122;s natural hair color. Therefore the effect of StemEnhance on hair graying reported in this study can have far-reaching implications.
These observations lend a strong support to the fact that stem cells from the bone marrow can migrate in various tissues and become cells of these tissues. Although no clinical test was used to actually quantify the increased density of melanocytes associated with hair follicles, the fact that the effect was seen in all participants strongly suggests that the reduction in white density was caused by the migration and differentiation of stem cells into melanocytes. Given the irrelevance of hair color in health, it is fair to assume that if stem cells have migrated to become melanocytes, the body has certainly guided many stem cells to migrate and become other types of cells, further supporting the regenerative properties of StemEnhance.
Although this was not the purpose of the study, the fact that StemEnhance is the only product taken orally that was shown to affect hair color, this study lends support for a entirely new application of StemEnhance in cosmetology. Furthermore, empirical observations made in this study support prior reports that StemEnhance elevates mood and enhances overall quality of life.
3
Increase in the number of circulating stem cells by StemEnhance® does not promote tumor growth
Introduction While bone marrow stem cells have been shown to play an important role in tissue repair, the role of stem cells in tumor formation has also been intensely investigated. Some scientists have suggested that bone marrow-derived stem cells (BMDSCs) might be involved in the process of tumor formation. The link between chronic inflammation and cancer has long been recognized, as cancer has been called a “wound that never heals,” and a wound is known to attract stem cells. It has been proposed that BMDSCs could become tumor cells or enhance the development of existing tumors by contributing to the formation of blood vessels in the tumor. If circulating stem cells were to contribute to tumor vasculature and tumor growth, then increasing the number of circulating stem cells should accelerate tumor growth.
StemEnhance® is a novel mobilizer of bone marrow stem cells that was shown to increase the number of circulating stem cells by 25%. Therefore, we investigated the effect of daily consumption of StemEnhance® on the growth of human breast tumor implanted in a mouse model.
Methods In brief, fluorescent human MDA-MB-435 cancer cells were grown into tumors, which were later transplanted by surgical implantation into the mammary fat pad of forty female
mice. Twenty-one days after implantation, mice were randomly separated in two groups. For a duration of six weeks, experimental animals were fed with 300 mg/kg of StemEnhance while controls were fed placebo. Tumor growth was monitored using live whole body fluorescence imaging. At the end of the study, tumors were excised and weighed.
Results There was no evidence of toxicity due to StemEnhance. Animals in both groups showed identical body-weight growth patterns and no visual or behavioral differences could be seen between the two groups.
At the start of the feeding
P<0.007
Ctrl
trial, tumor areas for both
PBS P<0.018
control and experimental
SE P<0.016
group were statistically P<0.04
identical. Changes in tumor area, and rates of
SE
P<0.004
P>0.3
increase from weeks 1 to 6, were determined using repeated measures analysis of variance. Tumor growth was approximately linear, as determined by orthogonal polynomial regression. Tumor growth rate was slower in the StemEnhance group (P=0.014) when compared to the control group. The reduction in tumor growth was significant by week 2 and at week 6 tumor areas were 40% larger in the control group (1.70 cm2) than in the StemEnhance group (1.25 cm2) (P<0.01). Metastasis was not seen in either group. At the end of the study, tumors were carefully excised and weighed. Mean tumor weight in the StemEnhancetreated-group (0.44 Âą 0.21) was 35% smaller than in the control (0.68 Âą 0.42) (P < 0.03).
Ctrl SE
These results for tumor mass are consistent with the analyses of tumor area.
Discussion Animals received 300 mg/kg of StemEnhance , which is roughly 10 times the daily intake normally recommended for humans. Even at that high level, growth was normal and animals showed no signs of toxicity. Daily consumption of the stem cell mobilizer StemEnhance reduced the rate of human breast cancer growth without affecting growth pattern. No metastases were seen, at least in the conditions of this study.
Little data exist to suggest how circulating stem cells could contribute to reducing tumor growth. It is possible that after migrating in a tumor, attracted by cytokines, and after proliferating and differentiating in cells of the target tissue, stem cells could secrete cytokines inhibiting cellular division.
Other compounds in StemEnhance could have contributed to the effect observed in this study, such as phycocyanin and specific polysaccharides. Nevertheless, based on these results, increasing the number of circulating bone marrow stem cells does not promote the growth of breast cancer.