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limitations due to their dose-dependent toxicities and drug resistance. Thus, over the past decades, veterinary oncologists have searched for novel therapies to achieve a more efficient tumor treatment. Among them, MSCs transplantation is considered a highly valuable and promising approach for a variety of neoplasia [4]. The positive aspects of MSCs (easily isolated, extensive proliferation, and the differentiation capacity into various cell types) have been previously described in clinical application [16,121]. In addition, genetically modified MSCs can accumulate at the site of cancer and be utilized for cancer gene therapy, which is effective for the cellular delivery of anticancer agents and/or molecules including cytokines, interferons, or pro-drugs that inhibit tumor growth and angiogenesis [122-124]. Gene therapy using genetically modified stem cells has been demonstrated in several human cancer studies. However, few studies have been performed in veterinary medicine. Canine splenic hemangiosarcoma (HSA) is a highly metastatic malignant tumor, and either splenectomy alone or adjuvant chemotherapy have been considered as the treatments of choice. In one clinical case, human neural stem cells (hNSCs) were used with 5-fluorocytosine in a dog with HSA lung metastasis [125]. Significant reduction in the size and number of metastatic lung nodules with fewer side effect was observed 2 weeks after the hNSCs were treated with 5-fluorocytosine. The injected hNSCs had been engineered to express the cytosine deaminase gene, which can converts the prodrug 5-fluorocytosine into the active form. This led to a significant size reduction of the metastatic lung nodules [126]. In addition, hNSCs delivered an anticancer agent to the neoplasm, including the metastatic lesions. Another study demonstrated the use of MSCs combined with recombinant human bone morphogenetic protein 2 (rhBMP-2) and chemotherapeutic agents in a canine osteosarcoma model [127]. The results showed that the MSCs/rhBMP-2/chemotherapeutic agent's injected groups experienced more effective tumor size reduction and neoplastic cell infiltration than the conventional treatment group. This preliminary test result indicates the potential for a promising new modality in cancer treatment, but further studies and clinical trials are necessary. In the aspects of hematological tumor, leukemia and lymphoma have been considered a refractory malignant neoplasia, even though several chemotherapy protocols have been known [128]. Suter et al. [129] reported the first clinical case of suspected acute lymphocytic leukemia treatment with allogeneic hematopoietic cell transplantation (HCT) with dog leukocyte antigen-matched CD34+ cells (from related siblings). Because acute leukemias https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 11/22 Stem-cell therapy in dogs and cats are rare aggressive neoplasms of immature lymphopoietic or hematopoietic progenitor cells, the prognosis is poor and treatment outcomes are limited. The dog in this study presented favorable clinical outcomes within the 2-year follow-up period, and this pilot case report provides valuable clinical possibilities for the use of allogeneic HCT in dogs. Lymphoma is a well-recognized lymphoid origin neoplasm in dogs. Canine T-cell lymphoma has a poorer prognosis than that of B-cell lymphoma, and the median survival time is 6–9 months and 8–16 months with multiagent chemotherapy, respectively [130]. Two clinical trials used apheresis and peripheral blood HCT (PBHCT) in canine B- and T-cell lymphoma [131,132]. Both studies used CD34+ cells after total body irradiation as a treatment for lymphoma and recommended PBHCT in B- and T-cell lymphoma as a valuable alternative treatment (Table 6). Because of the natural occurrence and biological similarities of cancer in animals and humans, the field of comparative oncology would benefit from a focus on companion animals for the development of new cancer therapy. Few therapeutic approaches for spontaneous cancer in dogs have revealed promising effects of treatment with stem cells. However, the utility of stem cells for targeted cancer therapy is still vague in veterinary medicine due to the low number of clinical studies and the unclear mechanisms of action. FUTURE DIRECTIONS FOR VETERINARY CLINICAL STEM CELL TRIALS Regenerative medicine is an emerging field in both human and veterinary medicine. Dogs have been usually used in experimental models and preclinical studies for stem cell treatments in humans. The need for stem cell treatment has expanded in veterinary medicine, and clinical applications are being continuously attempted. This study reviewed 6 clinical categories of stem cell application in clinically ill dog and cats. Among them, major progress in stem cell application has been made in the field of neurology and musculoskeletal disease. The most promising results were found by studies conducted on spinal cord injuries and osteoarthritis using autologous MSCs from bone marrow- or adipose tissue. Some of the studies provided controls for more efficient evaluations, but treatment frequency, interval, and stem cell dosages varied, making it difficult to generalize the application. Other clinical trials looking at tissue and organ repair/regeneration effects of stem cells were
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