© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Mesenchymal Stem Cells: Potential Precursors for Tumor Stroma and Targeted-Delivery Vehicles for Anticancer Agents
Affiliation of authors: Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas M. D. Anderson Cancer Center, Houston
Correspondence to: Michael Andreeff, MD, PhD, Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 448, Houston, TX 77030 (e-mail: mandreef{at}mdanderson.org).
We appreciate the interest of Dr. Wolf and colleagues in our work. We understand their concerns related to the xenogenic nature of our model. However, we think that the data presented in their letter do not undermine the concept or conclusions presented in our article.
Wolf and colleagues used a syngeneic murine model (murine tumors, murine mesenchymal stem cells [MSC]) as their experimental system and suggest that murine MSC engraft into syngenic tumors as well as at additional sites. It is well established that murine "MSC", which are also known as "mouse adherent bone marrow cells," contain substantial proportions of other cell types, particularly adherent macrophages and endothelial cells, in addition to MSC (1). The proportions of these other cell types are particularly high in MSC from BALB/c mice (1), which Wolf and colleagues used in their experiment. The authors do not say whether they separated the murine MSC from the bulk adherent cell culture before labeling with PKH-26 and injecting into mice. Therefore, the images presented may not specifically represent the distribution of labeled MSC. These other cell types may have nonspecific and unpredictable distributions in the animals, making it difficult to interpret the data presented by Wolf and colleagues. By contrast, we used human adherent bone marrow cells, which make up a nearly pure population of MSC devoid of other cell types (2,3).
We are also concerned about the reliability of using the membrane-bound fluorescent dye PKH-26 to follow the injected cells. This method may not distinguish between viable MSC engrafted in tissues and dead cells or cell debris nonspecifically phagocytized by the reticuloendothelial system (RES) of the host. On the basis of our findings from SP-DiI–labeled human MSC injected into mice (Fig. 1), we believe that a substantial proportion of the fluorescence observed in spleen and liver (also shown by Wolf and colleagues in their figure 1, B) represents dead cells or cell debris phagocytized by the RES. In both figures, the fluorescence distribution colocalizes with the marginal zone at the borders of germinal centers and red pulp in the spleen. This distribution pattern is typical for host-derived macrophages that ingest foreign material (4,5), which, in this case, is the injected MSC and their remnants. Moreover, cells labeled with PKH-26 tend to lose their fluorescence during cell division, and as we have previously demonstrated (6), MSC proliferate and divide in tumors. Therefore, PKH-labeled MSC engrafted in tumors will become undetectable over time by the fluorescence microscopy approach used by Wolf and colleagues.
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On the other hand, our approach—to analyze the distribution of human MSC in mouse tissue—may have limitations for investigating the selectivity of stem cell engraftment in tumors. In this regard, our hypothesis that stromal fibroblasts in tumors are derived from bone marrow cells is also supported by the elegant work of Ishii et al. (7) in a syngenic mouse model. Overall, we believe that the concept proposed by us, that MSC can be used as delivery vehicles for anticancer agents into tumors, is valid and worthy of further investigation.
REFERENCES
(1) Phinney DG, Kopen G, Isaacson RL, Prockop DJ. Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem 1999;72:570–85.[CrossRef][Medline]
(2) Pittenger MF, Mackay AM, Beck SC Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.
(3) Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Champlin RE, et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004;96:1593–603.
(4) Kotani M, Matsuno K, Miyakawa K, Ezaki T, Hayama T, Ekino S. Migration of macrophages from the marginal zone to germinal centers in the spleen of mice. Anat Rec 1985;212:172–8.[CrossRef][Medline]
(5) Kraal G. Cells in the marginal zone of the spleen. Int Rev Cytol 1992;132:31–74.[Web of Science][Medline]
(6) Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002;62:3603–8.
(7) Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun 2003;309:232–40.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2005 97: 540-541.
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