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MMP-2 mediates mesenchymal stem cell tropism towards medulloblastoma tumors

Gene Therapy volume 18, pages 692–701 (2011)Cite this article

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Abstract

Matrix metalloproteinases (MMPs) are a family of proteinases known to have a role in cell migration. In the present study, we evaluated the role of MMP-2 on tropism of human umbilical cord blood-derived stem cells (hUCBSCs) in a human medulloblastoma tumor model. Consequences of MMP-2 inhibition on stem cell tropism towards medulloblastoma were studied in terms of stem cell migration by using cell culture inserts, transwell chamber assay, western blotting for MMP-2 and migratory molecules, and immunohistochemistry. Conditioned medium from Daoy/D283 cells infected with adenoviral vector encoding MMP-2 small interfering RNA (siRNA) (Ad-MMP-2 si)-reduced stem cell migration as compared with conditioned medium from mock and scrambled vector (Ad-SV) infected cells. In addition, MMP-2 inhibition in the tumor cells decreased the expression of stromal cell-derived factor 1 (SDF1) in the tumor-conditioned medium, which results in impaired SDF1/CXCR4 signaling leading to decreased stem cell tropism towards the tumor cells. We further show that MMP-2 inhibition in the tumor cells repressed stem cell tropism towards medulloblastoma tumors in vivo. In summary, we conclude that hUCBSCs can integrate into human medulloblastoma after local delivery and that MMP-2 expression by the tumor cells mediates this response through the SDF1/CXCR4 axis.

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Abbreviations

Ad:

Adenoviral

ECM:

extracellular matrix

FITC:

fluorescein isothiocyanate

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

hUCBSCs:

Human umbilical cord blood stem cells

H&E:

haematoxylin and eosin

MMP-2:

matrix metalloproteinases 2

PBS:

phosphate-buffered saline

RIPA:

Radioimmunoprecipitation assay

SV:

scrambled vector

siRNA:

small interfering RNA

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Acknowledgements

We acknowledge Shellee Abraham for manuscript preparation, Sushma Jasti and Diana Meister for manuscript review. This research was supported by National Cancer Institute Grant CA132853 (to SL). Contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

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Authors and Affiliations

  1. Department of Cancer Biology and Pharmacology, Program of Cancer Biology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL, USA

    P Bhoopathi, C Chetty, V R Gogineni, J S Rao & S S Lakka

  2. Department of Pathology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL, USA

    M Gujrati

  3. Department of Neurosurgery, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL, USA

    D H Dinh & J S Rao

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  1. P Bhoopathi
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  2. C Chetty
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Correspondence to S S Lakka.

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Bhoopathi, P., Chetty, C., Gogineni, V. et al. MMP-2 mediates mesenchymal stem cell tropism towards medulloblastoma tumors. Gene Ther 18, 692–701 (2011). https://doi.org/10.1038/gt.2011.14

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