MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

Nikita G. Alexiades, Brenda Auffinger, Chung Kwon Kim, Tanwir Hasan, Gina Lee, Marc Deheeger, Alex L. Tobias, Janice Kim, Irina Balyasnikova, Maciej S. Lesniak, Karen Aboody, Atique U. Ahmed*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.

Original languageEnglish (US)
Pages (from-to)598-607
Number of pages10
JournalStem Cell Research
Volume15
Issue number3
DOIs
StatePublished - Nov 1 2015

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Vascular Endothelial Growth Factor Receptor
Neural Stem Cells
Glioma
Neoplasms
Brain Neoplasms
Focal Adhesions
Therapeutics
Tumor Burden
Matrix Metalloproteinases
Heterografts
Microsatellite Repeats
Vascular Endothelial Growth Factor A
Phosphotransferases
Down-Regulation
Animal Models
Gene Expression
Cell Line
Membranes

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

Alexiades, Nikita G. ; Auffinger, Brenda ; Kim, Chung Kwon ; Hasan, Tanwir ; Lee, Gina ; Deheeger, Marc ; Tobias, Alex L. ; Kim, Janice ; Balyasnikova, Irina ; Lesniak, Maciej S. ; Aboody, Karen ; Ahmed, Atique U. / MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells. In: Stem Cell Research. 2015 ; Vol. 15, No. 3. pp. 598-607.
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abstract = "Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.",
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Alexiades, NG, Auffinger, B, Kim, CK, Hasan, T, Lee, G, Deheeger, M, Tobias, AL, Kim, J, Balyasnikova, I, Lesniak, MS, Aboody, K & Ahmed, AU 2015, 'MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells', Stem Cell Research, vol. 15, no. 3, pp. 598-607. https://doi.org/10.1016/j.scr.2015.10.005

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells. / Alexiades, Nikita G.; Auffinger, Brenda; Kim, Chung Kwon; Hasan, Tanwir; Lee, Gina; Deheeger, Marc; Tobias, Alex L.; Kim, Janice; Balyasnikova, Irina; Lesniak, Maciej S.; Aboody, Karen; Ahmed, Atique U.

In: Stem Cell Research, Vol. 15, No. 3, 01.11.2015, p. 598-607.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

AU - Alexiades, Nikita G.

AU - Auffinger, Brenda

AU - Kim, Chung Kwon

AU - Hasan, Tanwir

AU - Lee, Gina

AU - Deheeger, Marc

AU - Tobias, Alex L.

AU - Kim, Janice

AU - Balyasnikova, Irina

AU - Lesniak, Maciej S.

AU - Aboody, Karen

AU - Ahmed, Atique U.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.

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Alexiades NG, Auffinger B, Kim CK, Hasan T, Lee G, Deheeger M et al. MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells. Stem Cell Research. 2015 Nov 1;15(3):598-607. https://doi.org/10.1016/j.scr.2015.10.005