Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells commonly isolated from bone marrow that can be mobilized to other tissues under certain physiological and pathological conditions.1 In response to injury-induced chemotactic signals, MSCs migrate to wound sites where they secrete cytokines and growth factors that promote immunosuppression, angiogenesis, and cell survival.2 MSCs also exhibit pathological homing to cancers in the breast, pancreas, and brain making them potential anticancer therapeutic delivery vehicles.3,4,5,6
Gliomas are frequently recurrent cancers of the brain and are primarily treated by surgical resection, radiation, and non-specific chemotherapies.7 The poor median survival time of 14.6 months underscores the need for more targeted therapies.7 To capitalize on the innate tumor tropism of MSCs for new glioma-specific therapeutics, the molecular mechanisms by which MSCs home to gliomas and their pro- and anti-tumorigenic effects within the tumor microenvironment must be better understood.
To evaluate the effects of MSCs in the glioma microenvironment, Ho, et al. analyzed tumor xenografts in mice.8 Compared to tumors derived from human glioma cells alone, co-injection of human MSCs and glioma cells produced smaller tumors with increased areas of glioma cell apoptosis and fewer microvessels expressing the endothelial cell marker, CD31. Subsequent in vitro studies modeling aspects of angiogenesis showed that conditioned media from MSCs or MSC/glioma cocultures reduced endothelial progenitor cell migration and vascular tube formation compared to glioma cell-conditioned media alone. In contrast to the pro-angiogenic effects of MSCs during wound healing, these data indicate that MSCs inhibit the vascular growth that may promote glioma progression.
To elucidate the mechanism by which MSCs inhibited angiogenesis, a proteome array was used to assess differences in secreted proteins in conditioned media from human MSC/glioma cocultures versus relevant controls. The results showed downregulation of the pro-angiogenic factors PDGF-BB, IGF-I, and IL-1 beta in the presence of MSCs. Importantly, within tumors derived from MSC/glioma cocultures, IL-1 beta levels were reduced 40-80% compared to controls, and the downstream signaling cascade including the cysteine protease Cathepsin B was correspondingly reduced.8 Given that Cathepsin B is upregulated in advanced human gliomas and is thought to remodel the extracellular matrix during angiogenesis, the MSC-dependent anti-tumorigenic effects on human gliomas may be mediated by Cathespin B reduction.9
The mechanism of MSC homing, specifically to tumors, is complex and an active area of investigation. TGF-beta is known to induce MSC migration during physiological processes such as bone regeneration. In addition, many cancer cells produce elevated levels of TGF-beta, suggesting that TGF-beta may mediate MSC tropism to tumors.5 To test this hypothesis, Shinojima, et al. investigated the role of TGF-beta in MSC homing to glioma cells.10 Transwell migration assays revealed that human MSCs migrated toward conditioned media from glioma cells expressing high levels of TGF-beta, a response that was attenuated following the addition of TGF-beta neutralizing antibodies. Consistent with these in vitro results, intravascularly delivered GFP-labeled human MSCs accumulated at mouse glioma xenograft sites but not at xenografts containing TGF-beta knockdown cells. Similar experiments utilizing MSCs expressing stably integrated short hairpin RNA revealed that MSC homing was mediated by TGF-beta RII and the co-receptor Endoglin/CD105, without effects on MSC proliferation or viability. Collectively, these findings suggest that TGF-beta contributes to the tumor tropism of MSCs in vivo.
The cancer stem cell hypothesis states that tumors, including gliomas, harbor rare populations of highly tumorigenic cancer stem cells.11 To assess whether MSC homing to glioma stem cells (GSCs) has relevance for human disease, the authors evaluated the ability of GFP-labeled human MSCs to home to patient-derived GSC xenografts.10 Xenograft tumors from three out of five GSC lines contained detectable numbers of MSCs with a direct correlation between TGF-beta expression levels in the tumor and the number of MSCs present. Previous laboratory and clinical experiments have shown that MSCs can be used as delivery vehicles for anticancer transgenes.12 Similarly, when MSCs were pre-loaded with the oncolytic adenovirus, Delta-24-RGD, and injected into tumor-bearing mice, survival was significantly increased.10 This therapeutic effect was negated when Delta-24-RGD-loaded MSCs deficient for TGF-beta RII were injected, indicating that TGF-beta signaling plays a significant role in this therapeutic MSC delivery application.
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Mesenchymal Stem Cells Home to Gliomas via TGF-beta Signaling and Suppress Angiogenesis within the Tumor Microenvironment. (1) The glioma microenvironment contains high levels of the pro-angiogenic cytokine, IL-1 beta. (2) Signaling through the NF-kappa B axis increases Cathepsin B expression and activates extracellular matrix remodeling programs that promote angiogenesis.9 (3) In addition, IL-1 beta enhances PDGF-BB signaling, which promotes endothelial progenitor cell migration. (4) Glioma stem cells within a tumor secrete TGF-beta and recruit MSCs via TGF-beta RII and the co-receptor Endoglin/CD105. (5) Within the glioma microenvironment, the presence of MSCs reduces IL-1 beta levels, downregulates Cathepsin B, and decreases PDGF R-beta signaling. The depression of these signaling cascades in the presence of MSCs is thought to inhibit angiogenesis, reduce microvessel density, and suppress glioma growth.
These findings suggest that therapeutic delivery via MSCs may have clinical relevance for human glioma treatment, specifically in eradicating GSCs, which are largely resistant to current therapies.7 The potential therapeutic effects may be enhanced by modulating the TGF-beta signaling axis to increase MSC glioma tropism. In addition to reducing pro-angiogenic cytokine production within the tumor milieu, further studies to uncover the mechanism by which MSCs exert anti-tumorigenic effects and restrict glioma progression may aid in the development of new targeted therapeutics.
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