Regenerative medicine, the buzzword for stem-cell therapy and the like, has given birth to the possibility of a pain-free life for orthopedic patients. Thousands of veterinarians in North America are learning to treat degenerative joint conditions using adipose-derived mesenchymal stem cells (MSCs).1 The implied translational benefits for humans are compelling.
According to one account, nearly 2,000 dogs suffering from osteoarthritis and other musculoskeletal ailments have received intra-articular injections of autologous, pre-processed stem cells.2 A majority responded favorably and about one-third no longer needed anti-inflammatory medication.3 Media hype suggests that a veritable fountain of youth giving old dogs new joints may have been unearthed.4–5–6–7
While hope for an arthritis cure springs eternal, if stem cells do, a problem blossoms, and that is neoplasia. This has happened and is raising questions about the safety of stem-cell therapy. The authors of a paper released in October 2010 wrote, “Understanding the conditions in which MSCs enhance tumor growth and metastasis is crucial, both to safely develop MSCs as a therapeutic tool and to advance our understanding of the role of tumor stroma in carcinogenesis.” 8In 2009, a teenager developed a brain tumor from a neural stem-cell transplant. 9Could cancer result from canine stem-cell treatments?
Cells at Work
The process of regenerating tissue parallels that of forming tumors. Both require a pass from the immune system for cells to escape destruction. MSCs’ immunosuppressive effects abbreviate inflammation and limit fibrosis. While it works in the patient’s favor for arthritis, it could in the same vein allow wayward cells to evade the host’s protective surveillance mechanisms.
Once they grow to a certain size, regenerating structures as well as tumors need nourishment through additional vasculature. MSCs construct these vessels by secreting matrix-building proteins and cytokines such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).10
While fibroblasts from MSCs build tissue, they also build tumors. MSCs can be recruited regionally or step out of a circulating population and turn into tumor fibroblasts. Once in the tumor’s environment, MSCs acquire expression of tumor-associated fibroblast antigens and assist with growth. MSCs may cause further changes in tissue via paracrine signaling agents that modify the ability of tumor cells to successfully metastasize.
MSCs are drawn to tumors, though perhaps this tumor tropism can turn into a positive feature. Scientists are exploring ways to utilize MSCs as cellular delivery vehicles for tumor-fighting drugs. Curiously, MSCs also may suppress tumor growth.11 They do so through a number of pathways, such as reducing cell proliferation, colony formation and oncogene expression. They can alter cell cycle progression with increased rates of G1-phase arrest in certain cell lines and promote apoptosis as well as abrogate tumor growth. The recipient tissue microenvironment, genetic predisposition toward cancer and mechanical forces placed upon implanted MSCs12 determine stem cells’ fate, too.
Treat With Caution
Certainly, the veterinary pioneers in regenerative medicine deserve credit for their compassionate campaign to relieve suffering and discover safer, less painful ways to treat orthopedic disease than surgery. Stem-cell processing laboratories that fund humane, independent research in animals with naturally occurring disease are helping non-humans and ultimately, perhaps, humans. But experimental treatments require a hefty dose of caution.
The International Society for Stem Cell Research (ISSCR) weighs in on the side of safety and this year issued an advisory, “Top Ten Things to Know About Stem Cell Treatments.”13 The list urges consumers to “be wary of clinics that offer treatments with stem cells that originate from a part of the body that is different from the part being treated,” stating it is “unlikely that a single cell type could be used to treat a multitude of unrelated diseases that involve different tissues or organs.”
They continue, “A major warning sign that a clinic may not be credible is when treatments are offered for a wide variety of conditions but rely on a single cell type.” They advise against relying on patient testimonials as evidence of effectiveness, noting that until adequate preclinical and clinical testing is performed, the potential for unforeseen dangerous side effects exists.
Further, the ISSCR emphasizes that even if stem cells are injected back into the originating individual, cellular behavior following processing could turn unpredictable. They explain: “If [stem cells] are grown in culture [a process called expansion], the cells may lose the normal mechanisms that control growth or may lose the ability to specialize into the cell types you need. The cells may become contaminated with bacteria, viruses or other pathogens that could cause disease. The procedure to either remove or inject the cells also carries risk, from introducing an infection to damaging the tissue into which they are injected.”14
As noted in the ISSCR Patient Handbook on Stem Cell Therapies, “We have all heard about the extraordinary promise that stem-cell research holds for the treatment of a wide range of diseases and conditions. However, there is a lot of work still needed to take this research and turn it into safe and effective treatments. The International Society for Stem Cell Research is very concerned that stem-cell therapies are being sold around the world before they have been proven safe and effective. Stem-cell therapies are nearly all new and experimental.”
Dr. Robinson, DVM, DO, Dipl. ABMA, FAAMA, oversees complementary veterinary education at Colorado State University.
1. Vet-Stem website. Obtained at http://www.vet-stem.com/locatevet/.
2. Gaynor, JS. Current application in the stem cell therapy. Small animal and exotics. Proceedings of the North American Veterinary Conference, Orlando, Florida, USA, 16-20 January 2010; Gainesville: The North American Veterinary Conference, 2010, 1078-1079.
3. Gaynor JS. Canine athlete or weekend warrior: a new therapy for an old disease. NAVC Conference Proceedings. January 16, 2010.
4. ABC News/Health. A dog’s stem cell life. Golden Retriever Shows Quick Improvement after Being Injected with his Own Stem Cells. Obtained at http://abcnews.go.com/Health/story?id=4109559&page=2 on 11-21-10.
5. Peters SL. Stem cell therapy offers hope for pets dogged by pain. USA Today. 2/12/08. Obtained at http://www.usatoday.com/news/health/2008-02-12-dog-arthritis_N.htm on 11-21-10.
6. Black R. Stem cells for doggies? Super-expensive pet medical treatments revealed. NY Daily News.com . Obtained at http://www.nydailynews.com/lifestyle/pets/2010/07/22/2010-07-22_stem_cells_for_doggies_inside_the_crazy_medical_treatments_for_pets.html on 11-21-10.
7. Lee-St.John J. Stem-cell treatments for pets. Time. Obtained at http://www.time.com/time/health/article/0,8599,1817572,00.html on 11-24-10.
8. Klopp AH, Gupta A, Spaeth E, et al. Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2010 [Epub ahead of print].
9. Amariglio N, Hirshberg A, Scheithauer BW, et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine. Obtained at http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000029 on 11-23-10.
10. Klopp AH, Gupta A, Spaeth E, et al. Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2010 [Epub ahead of print].
11. Klopp AH, Gupta A, Spaeth E, et al. Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2010 [Epub ahead of print].
12. Castillo AB and Jacobs CR. Mesenchymal stem cell mechanobiology. Curr Osteoporos Rep. 2010;8:98-104.
13. International Society for Stem Cell Research. A closer look at stem cell treatments. Obtained at http://www.closerlookatstemcells.org/Top_10_Stem_Cell_Treatment_Facts.htm on 11-21-10.
14. International Society for Stem Cell Research. A closer look at stem cell treatments. Obtained at http://www.closerlookatstemcells.org/Top_10_Stem_Cell_Treatment_Facts.htm on 11-21-10.