Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res

Department of Neurosurgery, Brain Tumor Center, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Research (Impact Factor: 9.28). 05/2005; 65(8):3307-18. DOI: 10.1158/0008-5472.CAN-04-1874
Source: PubMed

ABSTRACT The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.

Download full-text


Available from: Frank C Marini, Aug 18, 2015
1 Follower
  • Source
    • "The amount of the systemically administered therapeutic cells necessary to home to the tumor is estimated to less than 10% of the tumor mass [95] [96]. Therefore, it is reasonable to use repeated injections of the therapeutic cells to achieve tumor regression during systemic treatments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use.
    Biochimie 06/2014; 105C. DOI:10.1016/j.biochi.2014.06.016 · 3.12 Impact Factor
  • Source
    • "Resection is not always successful in eradicating gliomas because glial tumor cells are able to disseminate and intersperse themselves in brain parenchyma far from the original tumor mass, making resection ineffective in reducing reemergence. Neural stem cells (NSCs) engineered to secrete IL-12, and bone marrow derived stem cells (BMSCs), have shown the ability to track migrating tumor cells (Ehtesham et al., 2002; Nakamizo et al., 2005), thereby allowing the targeting of interspersed tumor cells. Glioma stem cell tumorspheres have low GJC, and inducing the expression of Cx43 inhibited self-renewal and invasiveness (Yu et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gap junctions (GJs) are conglomerates of intercellular channels that connect the cytoplasm of two or more cells, and facilitate the transfer of ions and small molecules, including second messengers, resulting in metabolic and electrical coordination. In general, loss of gap junctional communication (GJC) has been associated with cellular damage and inflammation resulting in compromise of physiological functions. Recently, it has become evident that GJ channels also play a critical role in the pathogenesis of infectious diseases and associated inflammation. Several pathogens use the transfer of intracellular signals through GJ channels to spread infection and toxic signals that amplify inflammation to neighboring cells. Thus, identification of the mechanisms by which several infectious agents alter GJC could result in new potential therapeutic approaches to reduce inflammation and their pathogenesis.
    Frontiers in Cellular Neuroscience 05/2014; 8:122. DOI:10.3389/fncel.2014.00122 · 4.18 Impact Factor
  • Source
    • "From clinically applied stem cells, mesenchymal stem cells (MSCs) have been described as well-characterized stem cells that can be isolated from adult tissues (Jiang et al., 2002). Positive indications of their applications in various diseases have made them clinically promising (Bang et al., 2005, Garcia-Olmo et al., 2005, Kuo et al., 2008, Le Blanc et al., 2008, Nakamizo et al., 2005, Pisati et al., 2007). Many advantages in their application over the embryonic stem cells has made them potential candidates in regenerative medicine (Thomson et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell therapy in recent years has gained much attention as being the modern therapeutic approach to treat diseases. Mesenchymal stem cells (MSCs) are seen as the most reliable cells applied in therapy over other stem cells because of their versatility. Bone and cartilage diseases (osteo-diseases) are the major target of therapy using MSCs. In this perspective, we have analyzed statistically data available on clinical trials registry databases. We report that MSC therapy for osteo-diseases needs optimization in its standards to achieve acceptable results so that we can apply it in daily routine clinical practice.
    Cell Biology International 05/2014; 38(10). DOI:10.1002/cbin.10293 · 1.64 Impact Factor
Show more