Human umbilical cord blood stem cells show PDGF-D-dependent glioma cell tropism in vitro and in vivo.
Despite advances in clinical therapies and technologies, the prognosis for patients with malignant glioma is poor. Neural stem cells (NSCs) have a chemotactic tropism toward glioma cells. The use of NSCs as carriers of therapeutic agents for gliomas is currently being explored. Here, we demonstrate that cells isolated from the umbilical cord blood show mesenchymal characteristics and can differentiate to adipocytes, osteocytes, and neural cells and show tropism toward cancer cells. We also show that these stem cells derived from the human umbilical cord blood (hUCB) induce apoptosis-like cell death in the glioma cell line SNB19 via Fas-mediated caspase-8 activation. From our glioma tropism studies, we have observed that hUCB cells show tropism toward glioma cells in vitro, in vivo, and ex vivo. We determined that this migration is partially dependent on the expression levels of platelet-derived growth factor (PDGF)-D from glioma cells and have observed that local concentration gradient of PDGF-D is sufficient to cause migration of hUCB cells toward the gradient as seen from our brain slice cultures. In our animal experiment studies, we observed that intracranially implanted SNB19 green fluorescent protein cells induced tropism of the hUCB cells toward themselves. In addition, the ability of these hUCBs to inhibit established intracranial tumors was also observed. We also determined that the migration of stem cells toward glioma cells was partially dependent on PDGF secreted by glioma cells and that the presence of PDGF-receptor (PDGFR) on hUCB is required for migration. Our results demonstrate that hUCB are capable of inducing apoptosis in human glioma cells and also show that glioma tropism and hUCB tropism toward glioma cells are partially dependent on the PDGF/PGGFR system.
Gondi
Christopher S
CS
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605, USA.
Veeravalli
Krishna Kumar
KK
Gorantla
Bharathi
B
Dinh
Dzung H
DH
Fassett
Dan
D
Klopfenstein
Jeffrey D
JD
Gujrati
Meena
M
Rao
Jasti S
JS
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002469:Cell Separation; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D008222:Lymphokines; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha
Leukemia. 2002 Oct;16(10):1984-91
12357349
Clin Cancer Res. 1997 Dec;3(12 Pt 1):2187-90
9815613
J Neurosci Res. 2000 Aug 15;61(4):364-70
10931522
Glia. 2001 Jul;35(1):26-34
11424189
Science. 1999 May 14;284(5417):1168-70
10325227
Lancet. 2004 May 1;363(9419):1432-7
15121406
J Cell Sci. 2002 May 15;115(Pt 10):2131-8
11973354
Cell Transplant. 2002;11(3):275-81
12075993
J Neurosci Methods. 1991 Apr;37(2):173-82
1715499
J Hematother Stem Cell Res. 2003 Jun;12(3):255-70
12857367
Nat Cell Biol. 2001 Mar;3(3):E81-8
11231595
Am J Physiol Gastrointest Liver Physiol. 2005 Dec;289(6):G1091-9
16051923
Blood. 2004 Mar 1;103(5):1669-75
14576065
Neurosurg Focus. 2005 Sep 15;19(3):E5
16190604
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2088-93
12576546
Stroke. 2001 Nov;32(11):2682-8
11692034
Nature. 2004 Feb 19;427(6976):740-4
14973487
Nature. 2002 Jul 4;418(6893):41-9
12077603
Science. 2000 Dec 1;290(5497):1775-9
11099418
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1364-9
12538864
Neoplasia. 2004 May-Jun;6(3):287-93
15153341
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10344-9
11504914
N Engl J Med. 2003 Aug 7;349(6):570-82
12904523
Cell Transplant. 2002;11(3):265-74
12075992
Science. 2000 Dec 1;290(5497):1779-82
11099419
Neoplasia. 2005 Jun;7(6):623-9
16036113
Exp Neurol. 2002 Mar;174(1):11-20
11869029
Science. 1999 Jan 22;283(5401):534-7
9915700
J Neurosci Res. 2004 Feb 15;75(4):573-84
14743441
N Engl J Med. 1989 Oct 26;321(17):1174-8
2571931
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10711-6
10485891
Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11854-60
12925733
Nat Med. 1998 Nov;4(11):1313-7
9809557
Exp Neurol. 2001 Sep;171(1):109-15
11520125
N Engl J Med. 2005 Aug 25;353(8):811-22
16120861
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4080-5
9108108
J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72
14748562
Nat Med. 2003 Apr;9(4):439-47
12627226
Nature. 1999 Sep 23;401(6751):390-4
10517639
Neuroreport. 2001 Nov 16;12(16):3523-7
11733704