Recent literature suggests that mesenchymal stem/stromal cells (MSC) could be used as Trojan Horses to deliver “death-signals” to cancer cells. Herein, we describe the development of a novel multichannel cell migration device, and use it to investigate the relative migration rates of bone marrow-derived MSC and breast cancer cells (MCF-7) towards each other. Confluent monolayers of MSC and MCF-7 were established in adjacent chambers separated by an array of 14 microchannels. Initially, culture chambers were isolated by air bubbles (air-valves) contained within each microchannel, and then bubbles were displaced to initiate the assay. The MCF-7 cells migrated preferentially towards MSC, whilst the MSC did not migrate preferentially towards the MCF-7 cells. Our results corroborate previous literature that suggests MSC migration towards cancer cells in vivo is in response to the associated inflammation rather than directly to signals secreted by the cancer cells themselves.
Herzog, E.L.; van Arnam, J.; Hu, B.; Zhang, J.; Chen, Q.; Haberman, A.M.; Krause, D.S. Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J. 2007, 21, 2592–2601, doi:10.1096/fj.06-7861com.
[7]
Weiss, D.J.; Bertoncello, I.; Borok, Z.; Kim, C.; Panoskaltsis-Mortari, A.; Reynolds, S.; Rojas, M.; Stripp, B.; Warburton, D.; Prockop, D.J. Stem cells and cell therapies in lung biology and lung diseases. Proc. Am. Thorac. Soc. 2011, 8, 223–272.
[8]
Albera, C.; Polak, J.; Janes, S.; Griffiths, M.; Alison, M.; Wright, N.; Navaratnarasah, S.; Poulsom, R.; Jeffery, R.; Fisher, C.; et al. Repopulation of human pulmonary epithelium by bone marrow cells: A potential means to promote repair. Tissue Eng. 2005, 11, 1115–1121, doi:10.1089/ten.2005.11.1115.
[9]
Barbash, I.M.; Chouraqui, P.; Baron, J.; Feinberg, M.S.; Etzion, S.; Tessone, A.; Miller, L.; Guetta, E.; Zipori, D.; Kedes, L.H.; et al. Systemic delivery of bone marrow—Derived mesenchymal stem cells to the infarcted myocardium. Circulation 2003, 108, 863–868, doi:10.1161/01.CIR.0000084828.50310.6A.
[10]
Lee, R.H.; Seo, M.J.; Reger, R.L.; Spees, J.L.; Pulin, A.A.; Olson, S.D.; Prockop, D.J. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc. Natl. Acad. Sci. USA 2006, 103, 17438–17443, doi:10.1073/pnas.0608249103.
[11]
Hara, M.; Murakami, T.; Kobayashi, E. In vivo bioimaging using photogenic rats: Fate of injected bone marrow-derived mesenchymal stromal cells. J. Autoimmun. 2008, 30, 163–171, doi:10.1016/j.jaut.2007.12.007.
[12]
Chapel, A.; Bertho, J.M.; Bensidhoum, M.; Fouillard, L.; Young, R.G.; Frick, J.; Demarquay, C.; Cuvelier, F.; Mathieu, E.; Trompier, F.; et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J. Gene Med. 2003, 5, 1028–1038, doi:10.1002/jgm.452.
[13]
Plytycz, B.; Seljelid, R. From inflammation to sickness: Historical perspective. Arch. Immunol. Ther. Exp. (Warsz) 2003, 51, 105–109.
[14]
Houghton, J.M.; Morozov, A.; Smirnova, I.; Wang, T.C. Stem cells and cancer. Semin. Cancer Biol. 2007, 17, 191–203, doi:10.1016/j.semcancer.2006.04.003.
[15]
Loebinger, M.R.; Eddaoudi, A.; Davies, D.; Janes, S.M. Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res. 2009, 69, 4134–4142.
[16]
Kanehira, M.; Xin, H.; Hoshino, K.; Maemondo, M.; Mizuguchi, H.; Hayakawa, T.; Matsumoto, K.; Nakamura, T.; Nukiwa, T.; Saijo, Y. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther. 2007, 14, 894–903, doi:10.1038/sj.cgt.7701079.
[17]
Chen, X.; Lin, X.; Zhao, J.; Shi, W.; Zhang, H.; Wang, Y.; Kan, B.; Du, L.; Wang, B.; Wei, Y.; et al. A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs. Mol. Ther. 2008, 16, 749–756, doi:10.1038/mt.2008.3.
[18]
Ren, C.; Kumar, S.; Chanda, D.; Chen, J.; Mountz, J.D.; Ponnazhagan, S. Therapeutic Potential of Mesenchymal Stem Cells Producing Interferon-α in a Mouse Melanoma Lung Metastasis Model. Stem Cells 2008, 26, 2332–2338, doi:10.1634/stemcells.2008-0084.
[19]
Tang, C.; Russell, P.J.; Martiniello-Wilks, R.; Rasko, J.E.; Khatri, A. Concise review: Nanoparticles and cellular carriers-allies in cancer imaging and cellular gene therapy? Stem Cells 2010, 28, 1686–1702, doi:10.1002/stem.473.
[20]
Bacus, S.S.; Kiguchi, K.; Chin, D.; King, C.R.; Huberman, E. Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen. Mol. Carcinogen. 1990, 3, 350–362, doi:10.1002/mc.2940030607.
Chung, B.G.; Choo, J. Microfluidic gradient platforms for controlling cellular behavior. Electrophoresis 2010, 31, 3014–3027, doi:10.1002/elps.201000137.
[23]
Kabiri, M.; Kul, B.; Lott, W.; Futrega, K.; Ghanavia, P.; Upton, Z.; Doran, M. 3D mesenchymal stem/stromal cell osteogenesis and autocrine signalling. Biochem. Biophys. Res. Commun. 2012, 419, 142–147, doi:10.1016/j.bbrc.2012.01.017.
[24]
Markway, B.D.; Tan, G.K.; Brooke, G.; Hudson, J.E.; Cooper-White, J.J.; Doran, M.R. Enhanced chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells in low oxygen environment micropellet cultures. Cell Transplant. 2010, 19, 29–42, doi:10.3727/096368909X478560.
[25]
Doran, M.R.; Mills, R.J.; Parker, A.J.; Landman, K.A.; Cooper-White, J.J. A cell migration device that maintains a defined surface with no cellular damage during wound edge generation. Lab Chip. 2009, 9, 2364–2369, doi:10.1039/b900791a.
[26]
Bodas, D.; Khan-Malek, C. Hydrophilization and hydrophobic recovery of PDMS by oxygen plasma and chemical treatment—An SEM investigation. Sens. Actuators B 2007, 123, 368–373, doi:10.1016/j.snb.2006.08.037.
[27]
Egeblad, M.; Jaattela, J. Cell death induced by TNF or serum starvation is independent of ErbB receptor signaling in MCF-7 breast carcinoma cells. Int. J. Cancer 2000, 86, 617–625, doi:10.1002/(SICI)1097-0215(20000601)86:5<617::AID-IJC3>3.0.CO;2-Z.
[28]
Chen, S.-H.; Hung, W.-C.; Wang, P.; Paul, C.; Konstantopoulos, K. Mesothelin Binding to CA125/MUC16 Promotes Pancreatic Cancer Cell Motility and Invasion via MMP-7 Activation. Sci. Rep. 2013, 3, doi:10.1038/srep01870.
[29]
Irimia, D.; Toner, M. Spontaneous migration of cancer cells under conditions of mechanical confinement. Integrat. Biol. 2009, 1, 506–512, doi:10.1039/b908595e.
[30]
Sordi, V.; Malosio, M.L.; Marchesi, F.; Mercalli, A.; Melzi, R.; Giordano, T.; Belmonte, N.; Ferrari, G.; Leone, B.E.; Bertuzzi, F.; et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 2005, 106, 419–427, doi:10.1182/blood-2004-09-3507.
[31]
Ryu, C.H.; Park, S.A.; Kim, S.M.; Lim, J.Y.; Jeong, C.H.; Jun, J.A.; Oh, J.H.; Park, S.H.; Oh, W.I.; Jeun, S.S. Migration of human umbilical cord blood mesenchymal stem cells mediated by stromal cell-derived factor-1/CXCR4 axis via Akt, ERK, and p38 signal transduction pathways. Biochem. Biophys. Res. Commun. 2010, 398, 105–110, doi:10.1016/j.bbrc.2010.06.043.
[32]
Bachelder, R.E.; Wendt, M.A.; Mercurio, A.M. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res. 2002, 62, 7203–7206.
[33]
Lee, B.C.; Lee, T.H.; Avraham, S.; Avraham, H.K. Involvement of the Chemokine Receptor CXCR4 and Its Ligand Stromal Cell-Derived Factor 1α in Breast Cancer Cell Migration Through Human Brain Microvascular Endothelial Cells. Mol. Cancer Res. 2004, 2, 327–338.
[34]
Hall, J.M.; Korach, K.S. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol. Endocrinol. 2003, 17, 792–803, doi:10.1210/me.2002-0438.
[35]
Müller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M.E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S.N.; et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410, 50–56, doi:10.1038/35065016.
[36]
Spaeth, E.L.; Dembinski, J.L.; Sasser, A.K.; Watson, K.; Klopp, A.; Hall, B.; Andreeff, M.; Marini, F. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 2009, 4, e4992, doi:10.1371/journal.pone.0004992.
[37]
Stoicov, C.; Li, H.; Carlson, J.; Houghton, J.M. Bone marrow cells as the origin of stomach cancer. Future Oncol. 2005, 1, 851–862, doi:10.2217/14796694.1.6.851.
[38]
Corsten, M.F.; Shah, K. Therapeutic stem-cells for cancer treatment: Hopes and hurdles in tactical warfare. Lancet Oncol. 2008, 9, 376–384, doi:10.1016/S1470-2045(08)70099-8.
[39]
Hall, B.; Dembinski, J.; Sasser, A.K.; Studeny, M.; Andreeff, M.; Marini, F. Mesenchymal stem cells in cancer: Tumor-associated fibroblasts and cell-based delivery vehicles. Int. J. Hematol. 2007, 86, 8–16, doi:10.1532/IJH97.06230.
[40]
Kim, S.M.; Kim, D.S.; Jeong, C.H.; Kim, D.H.; Kim, J.H.; Jeon, H.B.; Kwon, S.J.; Jeun, S.S.; Yang, Y.S.; Oh, W.; et al. CXC chemokine receptor 1 enhances the ability of human umbilical cord blood-derived mesenchymal stem cells to migrate toward gliomas. Biochem. Biophys. Res. Commun. 2011, 407, 741–746, doi:10.1016/j.bbrc.2011.03.093.
[41]
Gehmert, S.; Prantl, L.; Vykoukal, J.; Alt, E.; Song, Y.H. Breast cancer cells attract the migration of adipose tissue-derived stem cells via the PDGF-BB/PDGFR-β signaling pathway. Biochem. Biophys. Res. Commun. 2010, 398, 601–605, doi:10.1016/j.bbrc.2010.06.132.
[42]
Ben-Baruch, A. The tumor-promoting flow of cells into, within and out of the tumor site: Regulation by the inflammatory axis of TNFα and chemokines. Cancer Microenviron. 2012, 1–14.
