Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts

S. Pacioni, Q.G. D'Alessandris, S. Giannetti, L. Morgante, V. Coccè, A. Bonomi, M. Buccarelli, L. Pascucci, G. Alessandri, A. Pessina, L. Ricci-Vitiani, M.L. Falchetti, R. Pallini

Research output: Contribution to journalArticle

Abstract

Background: 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). Methods: 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. Results: 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. Conclusions: 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. © 2017 The Author(s).
Original languageEnglish
JournalStem Cell Research and Therapy
Volume8
Issue number1
DOIs
Publication statusPublished - 2017

Fingerprint

Glioblastoma
Mesenchymal Stromal Cells
Heterografts
Tumors
Growth
Stem cells
Neoplasms
Paclitaxel
Tropism
Cells
Rats
Injections
Cell proliferation
Glioma
Brain
Bone
Bearings (structural)
Stem Cells
Bone Marrow
Cell Proliferation

Keywords

  • Glioblastoma
  • Human mesenchymal stromal cells
  • Orthotopic tumor xenograft
  • green fluorescent protein
  • paclitaxel
  • animal cell
  • animal tissue
  • Article
  • bone marrow stroma cell
  • cancer inhibition
  • carotid artery
  • cell density
  • cell homing
  • cell migration
  • cell population
  • corpus striatum
  • cytotoxicity
  • femoral vein
  • glioblastoma
  • glioma stem cell
  • graft survival
  • human
  • human cell
  • human tissue
  • immune deficiency
  • mesenchymal stroma cell
  • nonhuman
  • orthotopic transplantation
  • protein expression
  • rat
  • tropism
  • tumor cell
  • tumor growth
  • tumor volume
  • tumor xenograft
  • animal
  • cell proliferation
  • drug screening
  • mesenchymal stem cell transplantation
  • mouse
  • multimodality cancer therapy
  • pathology
  • tumor cell line
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Combined Modality Therapy
  • Humans
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stromal Cells
  • Mice
  • Paclitaxel
  • Rats
  • Xenograft Model Antitumor Assays

Cite this

Pacioni, S., D'Alessandris, Q. G., Giannetti, S., Morgante, L., Coccè, V., Bonomi, A., ... Pallini, R. (2017). Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. Stem Cell Research and Therapy, 8(1). https://doi.org/10.1186/s13287-017-0516-3

Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. / Pacioni, S.; D'Alessandris, Q.G.; Giannetti, S.; Morgante, L.; Coccè, V.; Bonomi, A.; Buccarelli, M.; Pascucci, L.; Alessandri, G.; Pessina, A.; Ricci-Vitiani, L.; Falchetti, M.L.; Pallini, R.

In: Stem Cell Research and Therapy, Vol. 8, No. 1, 2017.

Research output: Contribution to journalArticle

Pacioni, S, D'Alessandris, QG, Giannetti, S, Morgante, L, Coccè, V, Bonomi, A, Buccarelli, M, Pascucci, L, Alessandri, G, Pessina, A, Ricci-Vitiani, L, Falchetti, ML & Pallini, R 2017, 'Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts', Stem Cell Research and Therapy, vol. 8, no. 1. https://doi.org/10.1186/s13287-017-0516-3
Pacioni, S. ; D'Alessandris, Q.G. ; Giannetti, S. ; Morgante, L. ; Coccè, V. ; Bonomi, A. ; Buccarelli, M. ; Pascucci, L. ; Alessandri, G. ; Pessina, A. ; Ricci-Vitiani, L. ; Falchetti, M.L. ; Pallini, R. / Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. In: Stem Cell Research and Therapy. 2017 ; Vol. 8, No. 1.
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abstract = "Background: 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). Methods: 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. Results: 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. Conclusions: 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. {\circledC} 2017 The Author(s).",
keywords = "Glioblastoma, Human mesenchymal stromal cells, Orthotopic tumor xenograft, green fluorescent protein, paclitaxel, animal cell, animal tissue, Article, bone marrow stroma cell, cancer inhibition, carotid artery, cell density, cell homing, cell migration, cell population, corpus striatum, cytotoxicity, femoral vein, glioblastoma, glioma stem cell, graft survival, human, human cell, human tissue, immune deficiency, mesenchymal stroma cell, nonhuman, orthotopic transplantation, protein expression, rat, tropism, tumor cell, tumor growth, tumor volume, tumor xenograft, animal, cell proliferation, drug screening, mesenchymal stem cell transplantation, mouse, multimodality cancer therapy, pathology, tumor cell line, Animals, Cell Line, Tumor, Cell Proliferation, Combined Modality Therapy, Humans, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Mice, Paclitaxel, Rats, Xenograft Model Antitumor Assays",
author = "S. Pacioni and Q.G. D'Alessandris and S. Giannetti and L. Morgante and V. Cocc{\`e} and A. Bonomi and M. Buccarelli and L. Pascucci and G. Alessandri and A. Pessina and L. Ricci-Vitiani and M.L. Falchetti and R. Pallini",
note = "Cited By :3 Export Date: 9 April 2018 Correspondence Address: Falchetti, M.L.; CNR-Institute of Cell Biology and Neurobiology (IBCN)Italy; email: marialaura.falchetti@cnr.it Chemicals/CAS: paclitaxel, 33069-62-4; Paclitaxel References: Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., Frolova, G.P., Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues (1968) Transplantation, 6 (2), pp. 230-247. , 1:STN:280:DyaF1c3ns1Ciug{\%}3D{\%}3D 5654088; Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Multilineage potential of adult human mesenchymal stem cells (1999) Science, 284 (5411), pp. 143-147. , 1:CAS:528:DyaK1MXitlCnu7o{\%}3D 10102814; Dominici, M., Le Blanc, K., Muellee, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Minimal criteria for defining multipotent mesenchymal stromal cells. 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year = "2017",
doi = "10.1186/s13287-017-0516-3",
language = "English",
volume = "8",
journal = "Stem Cell Research and Therapy",
issn = "1757-6512",
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}

TY - JOUR

T1 - Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts

AU - Pacioni, S.

AU - D'Alessandris, Q.G.

AU - Giannetti, S.

AU - Morgante, L.

AU - Coccè, V.

AU - Bonomi, A.

AU - Buccarelli, M.

AU - Pascucci, L.

AU - Alessandri, G.

AU - Pessina, A.

AU - Ricci-Vitiani, L.

AU - Falchetti, M.L.

AU - Pallini, R.

N1 - Cited By :3 Export Date: 9 April 2018 Correspondence Address: Falchetti, M.L.; CNR-Institute of Cell Biology and Neurobiology (IBCN)Italy; email: marialaura.falchetti@cnr.it Chemicals/CAS: paclitaxel, 33069-62-4; Paclitaxel References: Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., Frolova, G.P., Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues (1968) Transplantation, 6 (2), pp. 230-247. , 1:STN:280:DyaF1c3ns1Ciug%3D%3D 5654088; Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Multilineage potential of adult human mesenchymal stem cells (1999) Science, 284 (5411), pp. 143-147. , 1:CAS:528:DyaK1MXitlCnu7o%3D 10102814; Dominici, M., Le Blanc, K., Muellee, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Minimal criteria for defining multipotent mesenchymal stromal cells. 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PY - 2017

Y1 - 2017

N2 - Background: 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). Methods: 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. Results: 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. Conclusions: 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. © 2017 The Author(s).

AB - Background: 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). Methods: 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. Results: 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. Conclusions: 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. © 2017 The Author(s).

KW - Glioblastoma

KW - Human mesenchymal stromal cells

KW - Orthotopic tumor xenograft

KW - green fluorescent protein

KW - paclitaxel

KW - animal cell

KW - animal tissue

KW - Article

KW - bone marrow stroma cell

KW - cancer inhibition

KW - carotid artery

KW - cell density

KW - cell homing

KW - cell migration

KW - cell population

KW - corpus striatum

KW - cytotoxicity

KW - femoral vein

KW - glioblastoma

KW - glioma stem cell

KW - graft survival

KW - human

KW - human cell

KW - human tissue

KW - immune deficiency

KW - mesenchymal stroma cell

KW - nonhuman

KW - orthotopic transplantation

KW - protein expression

KW - rat

KW - tropism

KW - tumor cell

KW - tumor growth

KW - tumor volume

KW - tumor xenograft

KW - animal

KW - cell proliferation

KW - drug screening

KW - mesenchymal stem cell transplantation

KW - mouse

KW - multimodality cancer therapy

KW - pathology

KW - tumor cell line

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Combined Modality Therapy

KW - Humans

KW - Mesenchymal Stem Cell Transplantation

KW - Mesenchymal Stromal Cells

KW - Mice

KW - Paclitaxel

KW - Rats

KW - Xenograft Model Antitumor Assays

U2 - 10.1186/s13287-017-0516-3

DO - 10.1186/s13287-017-0516-3

M3 - Article

VL - 8

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

SN - 1757-6512

IS - 1

ER -