title: Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts.
abstract: Mesenchymal stem/stromal cells (MSCs) represent an attractive tool for cell-based cancer therapy mainly because of their ability to migrate to tumors and to release bioactive molecules. However, the impact of MSCs on tumor growth has not been fully established. We previously demonstrated that murine MSCs show a strong tropism towards glioblastoma (GBM) brain xenografts and that these cells are able to uptake and release the chemotherapeutic drug paclitaxel (PTX), maintaining their tropism towards the tumor. Here, we address the therapy-relevant issue of using MSCs from human donors (hMSCs) for local or systemic administration in orthotopic GBM models, including xenografts of patient-derived glioma stem cells (GSCs).
  
  
  
  U87MG or GSC1 cells expressing the green fluorescent protein (GFP) were grafted onto the striatum of immunosuppressed rats. Adipose hMSCs (Ad-hMSCs), fluorescently labeled with the mCherry protein, were inoculated adjacent to or into the tumor. In rats bearing U87MG xenografts, systemic injections of Ad-hMSCs or bone marrow (BM)-hMSCs were done via the femoral vein or carotid artery. In each experiment, either PTX-loaded or unloaded hMSCs were used. To characterize the effects of hMSCs on tumor growth, we analyzed survival, tumor volume, tumor cell proliferation, and microvascular density.
  
  
  
  Overall, the AD-hMSCs showed remarkable tropism towards the tumor. Intracerebral injection of Ad-hMSCs significantly improved the survival of rats with U87MG xenografts. This effect was associated with a reduction in tumor growth, tumor cell proliferation, and microvascular density. In GSC1 xenografts, intratumoral injection of Ad-hMSCs depleted the tumor cell population and induced migration of resident microglial cells. Overall, PTX loading did not significantly enhance the antitumor potential of hMSCs. Systemically injected Ad- and BM-hMSCs homed to tumor xenografts. The efficiency of hMSC homing ranged between 0.02 and 0.5% of the injected cells, depending both on the route of cell injection and on the source from which the hMSCs were derived. Importantly, systemically injected PTX-loaded hMSCs that homed to the xenograft induced cytotoxic damage to the surrounding tumor cells.
  
  
  
  hMSCs have a therapeutic potential in GBM brain xenografts which is also expressed against the GSC population. In this context, PTX loading of hMSCs seems to play a minor role.
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy.|CNR-Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Pacioni
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Quintino Giorgio
authors.initials: QG
authors.lastname: D'Alessandris
authors.affiliation: Institute of Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giannetti
authors.affiliation: Institute of Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Morgante
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Coccè
authors.affiliation: Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bonomi
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mariachiara
authors.initials: M
authors.lastname: Buccarelli
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Perugia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pascucci
authors.affiliation: Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Alessandri
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Pessina
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy. marialaura.falchetti@cnr.it.
authors.forename: Maria Laura
authors.identifier: 0000-0002-8755-0042
authors.initials: ML
authors.lastname: Falchetti
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D017239:Paclitaxel
keywords: Glioblastoma; Human mesenchymal stromal cells; Orthotopic tumor xenograft