p27 modulates tropism of mesenchymal stem cells toward brain tumors

Gao,Yun; Gu,Chunyu; Li,Shaoyi; Tokuyama,Tsutomu; Yokota,Naoki; Nakayama,Keiichi I.; Kitagawa,Masatoshi; Namba,Hiroki

doi:10.3892/etm_00000107

p27 modulates tropism of mesenchymal stem cells toward brain tumors

Authors:
- Yun Gao
- Chunyu Gu
- Shaoyi Li
- Tsutomu Tokuyama
- Naoki Yokota
- Keiichi I. Nakayama
- Masatoshi Kitagawa
- Hiroki Namba
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Affiliations: Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Published online on: July 1, 2010 https://doi.org/10.3892/etm_00000107
Pages: 695-699

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Abstract

Mesenchymal stem cells (MSCs) have inherent tumor-tropic properties in the brain and seem to be a useful tool for cellular therapy for brain tumors. However, the mechanisms involved in MSC migration are not fully understood. The tumor suppressor p27, an inhibitor of cyclin-dependent kinase complexes, not only plays a crucial role in cell cycle regulation but also has cell cycle-independent functions, such as differentiation and migration of cells. In fact, p27 has been alternatively reported to inhibit or stimulate cell migration in cells of different types. Therefore, in the present study, we investigated whether p27 is involved in the tumor-tropic activity of MSCs using MSCs from p27-null mice. It was found that p27−/− MSCs showed a decreased motility in the wound healing assay and displayed increased numbers of stress fibers. To compare the in vivo migratory activity of p27−/− and p27+/+ MSCs toward glioma, we injected C6 glioma cells into one side of the mouse brain and BrdU-labeled p27−/− or p27+/+ MSCs into the other side. Significantly fewer labeled p27−/− MSCs were observed in the tumor area compared with p27+/+ MSCs. The present study suggests that p27 works as a stimulator of the in vitro and in vivo migration process of MSCs toward tumors. These findings are important when the efficacy of stem cell-based strategies for glioma therapy is considered.

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1.	DeAngelis LM: Brain tumors. N Engl J Med. 344:114–123. 2001. View Article : Google Scholar
2.	Kim SM, Lim JY, Park SI, et al: Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer Res. 68:9614–9623. 2008. View Article : Google Scholar : PubMed/NCBI
3.	Kinoshita Y, Kamitani H, Mamun MH, et al: A gene delivery system with a human artificial chromosome vector based on migration of mesenchymal stem cells towards human glioblastoma HTB14 cells. Neurol Res. 2009, (E-pub ahead of print).
4.	Kucerova L, Altanerova V, Matuskova M, Tyciakova S and Altaner C: Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 67:6304–6313. 2007. View Article : Google Scholar : PubMed/NCBI
5.	Lee J, Elkahloun AG, Messina SA, et al: Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector. Cancer Res. 63:8877–8889. 2003.PubMed/NCBI
6.	Menon LG, Kelly K, Yang HW, Kim SK, Black PM and Carroll RS: Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells. 27:2320–2330. 2009. View Article : Google Scholar : PubMed/NCBI
7.	Miletic H, Fischer YH, Litwak S, et al: Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther. 15:1373–1381. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Nakamizo A, Marini F, Amano T, et al: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 65:3307–3318. 2005.PubMed/NCBI
9.	Nakamura K, Ito Y, Kawano Y, et al: Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther. 11:1155–1164. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Sasportas LS, Kasmieh R, Wakimoto H, et al: Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA. 106:4822–4827. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Uchibori R, Okada T, Ito T, et al: Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med. 11:373–381. 2009. View Article : Google Scholar : PubMed/NCBI
12.	Wu X, Hu J, Zhou L, et al: In vivo tracking of superparamagnetic iron oxide nanoparticle-labeled mesenchymal stem cell tropism to malignant gliomas using magnetic resonance imaging. Laboratory investigation. J Neurosurg. 108:320–329. 2008. View Article : Google Scholar
13.	Yuan X, Hu J, Belladonna ML, Black KL and Yu JS: Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma. Cancer Res. 66:2630–2638. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Amano S, Li S, Gu C, et al: Use of genetically engineered bone marrow-derived mesenchymal stem cells for glioma gene therapy. Int J Oncol. 35:1265–1270. 2009.PubMed/NCBI
15.	Gu C, Li S, Tokuyama T, Yokota N and Namba H: Therapeutic effect of genetically engineered mesenchymal stem cells in rat experimental leptomeningeal glioma model. Cancer Lett. 298:256–262. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Bloom J and Pagano M: Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol. 13:41–47. 2003. View Article : Google Scholar : PubMed/NCBI
17.	Philipp-Staheli J, Payne SR and Kemp CJ: p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res. 264:148–168. 2001. View Article : Google Scholar : PubMed/NCBI
18.	Gao Y, Kitagawa K, Hiramatsu Y, et al: Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 66:11623–11631. 2006. View Article : Google Scholar : PubMed/NCBI
19.	Rodier G, Montagnoli A, DiMarcotullio L, et al: p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J. 20:6672–6682. 2001. View Article : Google Scholar : PubMed/NCBI
20.	Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K and Nakayama KI: Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem. 277:14355–14358. 2002. View Article : Google Scholar
21.	Li S, Tokuyama T, Yamamoto J, Koide M, Yokota N and Namba H: Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther. 12:600–607. 2005. View Article : Google Scholar : PubMed/NCBI
22.	Chen J, Zhang ZG, Li Y, et al: Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 92:692–699. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Nakayama K, Ishida N, Shirane M, et al: Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 85:707–720. 1996. View Article : Google Scholar : PubMed/NCBI
24.	Nobes CD and Hall A: Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol. 144:1235–1244. 1999. View Article : Google Scholar : PubMed/NCBI
25.	Besson A, Gurian-West M, Schmidt A, Hall A and Roberts JM: p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev. 18:862–876. 2004. View Article : Google Scholar : PubMed/NCBI
26.	Aboody KS, Brown A, Rainov NG, et al: Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA. 97:12846–12851. 2000. View Article : Google Scholar : PubMed/NCBI
27.	Li S, Gao Y, Tokuyama T, et al: Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites. Cancer Lett. 251:220–227. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Xu G, Jiang XD, Xu Y, et al: Adenoviral-mediated interleukin-18 expression in mesenchymal stem cells effectively suppresses the growth of glioma in rats. Cell Biol Int. 33:466–474. 2009. View Article : Google Scholar : PubMed/NCBI
29.	Ho IA, Chan KY, Ng WH, et al: Matrix metalloproteinase 1 is necessary for the migration of human bone marrow-derived mesenchymal stem cells toward human glioma. Stem Cells. 27:1366–1375. 2009. View Article : Google Scholar : PubMed/NCBI
30.	Zhao D, Najbauer J, Garcia E, et al: Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol Cancer Res. 6:1819–1829. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Bexell D, Gunnarsson S, Tormin A, et al: Bone marrow multi-potent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol Ther. 17:183–190. 2009. View Article : Google Scholar : PubMed/NCBI
32.	Webb DJ and Horwitz AF: New dimensions in cell migration. Nat Cell Biol. 5:690–692. 2003. View Article : Google Scholar : PubMed/NCBI
33.	Baldassarre G, Belletti B, Nicoloso MS, et al: p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell. 7:51–63. 2005. View Article : Google Scholar : PubMed/NCBI