StemCell Therapy

Treatment durability

Tumors commonly relapse regardless of strong initial therapeutic effects. Like most chemotherapies, stem cell therapy using a single agent generally cannot eliminate tumors. Therefore, an optimum drug combination should be rationally selected [6]. Many combination therapies have been tested to improve treatment durability. For example, IFN- immunotherapy combined with chemotherapy using a prodrug/suicide gene system has shown synergistic therapeutic effects against human colorectal cancer [69]. Irradiating tumor cells can induce production of factors that stimulate MSC invasion through integral basement membranes, increasing the number of MSCs in tumors [70]. Combining stem cell-based oncolytic virotherapy with chemoradiotherapy can minimize residual disease volumes and sensitize glioma cells to CRAd-S-pk7 (OV CRAd-Survivin-pk7) during radiotherapy [35]. Kim, et al. [71] found that TMZ sensitized glioma cells to TRAIL-induced apoptosis by modulating the apoptotic machinery, and enhanced MSC-TRAIL gene therapy antitumor effects. Epidermal growth factor receptor (EGFR), which is mutated and overexpressed in various tumors, is associated with poor prognosis and shortened survival [72]. TRAIL combined with stem cell-delivered immunoconjugates of EGFR-specific nanobodies enhanced treatment outcomes [73].

Normal stem cells share some characteristics with CSCs, including self-renewal, differentiation, and epithelial-to-mesenchymal transition capacities. Stem cell therapy may increase cancer risk, as evidence by tumor formation four years after fetal neural stem cell transplantation for ataxia-telangiectasia [74]. Thus, prevention of tumor formation by transplanted stem cells requires additional study [63]. However, whether stem cells promote the growth of certain tumors or form tumors themselves is uncertain. Karnoub, et al. demonstrated that bone-marrow-derived MSCs mixed with otherwise weakly metastatic human breast carcinoma cells increased the cancer cells metastatic potentials, allowing for tumor formation in subcutaneous xenografts [75]. The breast cancer cells promoted MSC secretion of chemokine CCL5, which acted in a paracrine fashion to increase cancer cell motility, invasion, and metastasis. Increased breast cancer cell metastatic capability was reversible and dependent on CCL5 signaling through the chemokine receptor, CCR5. Therefore, MSCs in the tumor microenvironment facilitated metastasis by reversibly changing cancer cell phenotypes.

Rosland, et al. [76] showed that spontaneous malignant transformation occurred in 45.8% (11/24) of bone marrow-derived MSC long-term (5106 weeks) cultures, indicating spontaneous malignant transformation. In vitro cell culture conditions may initiate stress-induced genomic instability, promoting the malignant phenotype. Mutation tendency has also been related to oxygen tension [77] and matrix elasticity [78]. Therefore, optimization of in vitro culture conditions is important for MSC expansion for clinical use. However, other groups present contradictory findings regarding MSC transformation tendencies. Bernardo, et al. reported that MSC remain stable and do not transform in long-term cultures [79]. Thus, stem cell fates may be largely dependent on culture environments, and implanted stem cells may contribute to the growth of certain tumors or produce tumors themselves.

Multipotent NSCs, MSCs, and HSCs appear safer for clinical use than ESCs and iPSCs. Most studies focus on pluripotent stem cells that may be highly tumorigenic. There are six strategies to eliminate any possibility of neoplastic transformation [80]. First, undifferentiated pluripotent stem cells, which are potentially tumorigenic, can be excluded from clinical preparations using antibodies that target specific surface-displayed biomarkers. Stem cell differentiation downregulates display of these biomarkers. Monoclonal antibodies may facilitate fluorescence activated cell sorting or magnetic activated cell sorting of undifferentiated, pluripotent stem cells modified with fluorochromes or superparamagnetic chelates, respectively. Second, directed differentiation of iPSCs includes monitoring the expression of differentiation lineage-specific genes. Successfully differentiated cells can be identified and sorted using recombinant reporter proteins. GFP and similar proteins work well as reporters of undifferentiated vs. differentiated cells. Undifferentiated pluripotent stem cells transformed to express GFP emit telltale fluorescence upon illumination with specific wavelengths as long as they remain undifferentiated. This facilitates their sorting out or eradication through laser ablation. Third, undifferentiated cells can be killed using toxic antibodies or antibody-guided toxins. For example, monoclonal antibodies against claudin-6, a biomarker for undifferentiated pluripotent ESCs and iPSCs, can guide toxins to these stem cells for selective, targeted killing [81]. Fourth, undifferentiated stem cells can be eradicated using cytotoxic agents, which can be applied to selectively kill pluripotent stem cells that could develop into tumors. PluriSIn#1 inhibits stearoyl-CoA desaturase-1, an enzyme involved in monounsaturated fatty acid metabolism, and induces apoptosis in treated cells [82]. PluriSIn#1 treatment selectively eliminates undifferentiated iPSCs and ESCs [83]. Fifth, potentially tumorigenic stem cells can be sensitized to prodrugs through transformation using suicide genes. The enzyme/prodrug cancer therapy strategy can also be adapted to kill undifferentiated stem cells. For example, hESCs engineered to express the HSV-TK gene were killed following GCV treatment, whereas non-transfected hESCs were unaffected [84]. Finally, differentiated refractive stem cells can be eliminated through self-induced transgenic expression of recombinant human DNases. To this end, and to improve treatment safeties and efficacies, a toxic reagent-independent feedback loop was developed to select for differentiated stem cells [85]. iPSCs were directed to differentiate into endothelial or myocardial lineages, and were then transfected with human recombinant DNASE1, DNASE1L3, DNASE2, and DFFB, guided by antiSSEA-4 and anti-TRA-1-60 synthetic antibodies. Transgenes were delivered only to pluripotent, differentiation-refractive stem cells. Thus, iPSCs that maintained their pluripotency and specific cell surface display profiles, and continued proliferating instead of differentiating, expressed the human recombinant DNases. Genomic DNA was degraded in these potentially tumorigenic stem cells, ultimately killing the cells. These six strategies could safeguard against tumor transformation in stem cell population.

Read more here:
Stem cells in cancer therapy: opportunities and challenges

This entry was posted on January 1, 2022 at 1:47 am and is filed under Death by Stem Cells. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |