Vetnews | Augustus 2024 14 « BACK TO CONTENTS 2. Assessing the In Vivo Tumor-Associated Risk of MSCs: A Potential Area of Concern? The potential tumor promotion of MSCs during in vivo use has been a subject of discussion in the fields of regenerative and veterinary medicine. The mechanisms underlying tumor promotion are diverse and complex, however; thus, investigating the role of MSC therapy in tumor development is a complex task. In practice, distinguishing whether an emerging tumor originated from stem cells or the patient’s own cells is exceedingly challenging. It is difficult to predict how stem cells will interact with various cytokines and signaling pathways in vivo, primarily because in vivo conditions differ substantially from in vitro settings. Immune system weakening can theoretically increase the susceptibility to tumor development [21]. Several studies have investigated stem cell tumorigenicity in immunodeficient mice. In NOD/SCID mice, canine adipose-derived stem cells were subcutaneously injected, and after a 40 d observation period, no tumor formation was observed in contrast to the positive control group, which received HeLa cells [22]. Similarly, in nude mice, various doses of human adipose-derived MSCs were injected and monitored for 13 weeks after intravenous injection and 26 weeks after subcutaneous injection. In all dose groups, including the high-dose group, no toxicities or tumorigenesis instances were observed [23]. Additionally, canine adipose-derived MSCs were injected into 30 balb/c-nu mice for a safety and tumorigenesis evaluation of MSCs and monitored for 6 months. There were no tumorigenesis cases in the treatment group, whereas all mice in the control group that had been injected with A-431, an epidermoid carcinoma cell line, showed tumorigenesis [24]. A research reported that human adipose tissuederived mesenchymal stem cells inhibit the growth of T-cell lymphoma by switching cell-cycle progression and inducing apoptosis in nude mice [25]. Although these results suggest that direct tumorigenicity from MSCs through subcutaneous and systemic injections is unlikely, concerns regarding the sensitivity of in vivo tumorigenicity assays remain [26]. Therefore, it is crucial to further scrutinize these results and explore the remaining key factors that may influence the reliability of such analyses in predicting tumorigenic outcomes, as taking these steps can ensure a comprehensive evaluation of the potential risks associated with stem cell therapies and address any existing uncertainties in their safety profiles. 3. Harnessing the Dual Nature of MSCs: Tumor Promotion Implication and Cancer Treatment MSCs have a dual nature, exhibiting both pro-tumorigenic and antitumorigenic effects. Understanding these mechanisms is crucial to assessing the risks associated with MSC therapy in veterinary oncology. Tumorigenesis involves the entire tumor formation process, including the initiation, promotion, and progression stages. Tumor promotion refers to the stage in which initiated cells are stimulated to proliferate and survive, thereby promoting their development. The pro-tumorigenic characteristic of MSCs can be attributed to various mechanisms, such as immunosuppression, creating a favorable microenvironment for tumor cells to evade immune surveillance. Moreover, MSCs can interact with tumor cells and contribute to their resistance through chemoresistance by chemotherapy agents, thereby negatively impacting the effectiveness of treatments [27]. The promotion of angiogenesis is also crucial for tumor growth, as it ensures a sufficient blood supply to the tumor, aiding in its sustenance and expansion and enhancing tumor cell survival and proliferation [28]. MSCs can also undergo a phenotypic transition to become tumorassociated fibroblasts in response to secreted growth factors and extracellular matrix components [29,30]. furthermore, cancer stem cell correlation, metastasis facilitation, cancer cell apoptosis inhibition, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation collectively support MSC tumor growth through an epithelial– mesenchymal transition [31,32]. In contrast, MSCs can also be used in cancer treatments. Brain tumors, characterized by a high fatality rate, are notoriously challenging for delivering anti-cancer agents because of the blood–brain barrier (BBB) [31]. However, MSCs can act as a‘Trojan horse;’through this mechanism, they allow the delivery of cytotoxic compounds to brain tumor cells, offering an anti-tumor treatment to patients with brain tumors [33]. Han et al. demonstrated that engineered MSCs can exert anti-cancer properties. IFN-β-transduced canine adipose tissue derived MSCs inhibited the growth of canine melanoma cells in an in vitro direct/indirect co-culture system [34,35]. Furthermore, in vivo studies incorporating BALB/c nude mouse xenografts have revealed that combining these engineered MSCs with chemotherapy enhances their anti-tumor efficacy [35]. MSCs inhibit tumor growth via mechanisms such as cell cycle arrest, inflammatory cell infiltration, cancer cell apoptosis, and regulation of WNT/AKT signaling [31]. 4. Exploring Boundless Potential: MSC Therapy Unveils Promising Applications Recent advances in regenerative medicine have prompted a paradigm shift from cellbased therapies to cell-free therapies using MSC-derived substances [36,37]. Extracellular vesicles, particularly exosomes, which are derived from MSCs and are a small member vesicle, play a pivotal role in intercellular communication by transferring bioactive molecules. The use of MSC-derived exosomes has emerged as a promising approach for therapeutic interventions, and several aspects noted in previous studies highlight the importance of exosomes in regenerative medicines [38]. The administration of MSC-derived exosomes can exert divergent dual effects on tumor growth. MSC-derived cytokines or exosomes can promote tumor growth via multiple mechanisms. Conversely, MSC-derived exosomes, which contain specific miRNAs, have shown promise in facilitating cancer screening, diagnosis, and early detection [39]. Conventional tumor diagnosis primarily relies on procedures such as fine-needle aspiration for cytology and tissue biopsies for histology [40]. However, these approaches have limitations owing to the small scope of the information they offer and their invasive nature. In contrast, exosomes offer convenient liquid biopsy-based testing and can serve as both diagnostic and prognostic biomarkers [41]. Detecting tumor-related miRNAs within exosomes facilitates cancer screening, diagnosis, and early detection [42–46]. Specific miRNAs are associated with tumor treatment prognosis in the TNM (tumor, node, and metastasis) stage and resistance to radiation therapy [47,48]. Exosomes exhibit an excellent BBB permeability and lower immunogenicity than stem cells do. Thus, the former are promising therapeutic agents. MSC-derived exosomes can serve as effective drug carriers for targeted cancer therapies [49]. MSC-derived nanoparticles contain specific miRNAs that can inhibit angiogenesis, migration, and metastasis in glioblastomas [35]. Thus, researchers are actively studying the use of engineered MSC exosomes to address the two-sided effects of exosomes on tumor growth. They are also advancing tumor treatments by developing exosome mimetics to overcome the limitations of smallscale natural exosomes. Article
RkJQdWJsaXNoZXIy OTc5MDU=