Activation of Signal Transducers and Activators of Transcription 3 and Focal Adhesion Kinase by Stromal Cell-Derived Factor 1 Is Required for Migration of Human Mesenchymal Stem Cells in Response to Tumor Cell-Conditioned Medium

Stem Cells - Tập 27 Số 4 - Trang 857-865 - 2009
Hui Gao1, Waldemar Priebe2, John Glod3,1, Debabrata Banerjee1
1Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA
2Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
3Department of Pediatrics, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA

Tóm tắt

Abstract Mesenchymal stem cells (MSCs) migrate to tumors both in vitro and in vivo. Gene expression profiling analysis reveals that stromal cell-derived factor 1 (SDF-1) is significantly upregulated in MSCs exposed to tumor cell-conditioned medium, when compared with cells treated with control medium, suggesting that SDF-1 signaling is important in mediating MSC migration. This study investigates downstream signaling during MSC migration in response to tumor cell-conditioned medium and recombinant SDF-1 protein treatments. We observed that both recombinant SDF-1 and tumor cell-conditioned medium were able to activate downstream signaling via signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) as revealed by increased phosphorylation of STAT3 and ERK1/2 in human MSCs (hMSCs). Significant impairment of in vitro migration was observed in the presence of MAPK/ERK kinase (MEK) inhibitor PD98059, whereas two Janus kinase 2 (Jak2) inhibitors completely abolished migration induced by tumor cell-conditioned medium. Impaired MSC migration correlated with decreased levels of phosphorylated STAT3 and ERK1/2, suggesting that SDF-1 stimulation activates Jak2/STAT3 as well as MEK/ERK1/2 signaling, which in turn promotes migration of MSCs toward tumor cells. Furthermore, stimulation of hMSCs with recombinant SDF-1 and tumor cell-conditioned medium also significantly activated the focal adhesion kinases (FAKs) and paxillin, which correlated with reorganization of F-actin filaments in hMSCs. Decreased phosphorylation of FAK and paxillin as well as disruption of cytoskeleton organization was observed following Jak2 and MEK inhibitor treatment. Taken together, our results provide insight into the molecular pathways responsible for MSC migration toward the tumor microenvironment and may provide the molecular basis for modifying MSCs for therapeutic purposes. Disclosure of potential conflicts of interest is found at the end of this article.

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Tài liệu tham khảo

Pittenger, 1999, Multilineage potential of adult human mesenchymal stem cells, Science, 284, 143, 10.1126/science.284.5411.143

Studeny, 2002, Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors, Cancer Res, 62, 3603

Studeny, 2004, Mesenchymal stem cells: Potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents, J Natl Cancer Inst, 96, 1593, 10.1093/jnci/djh299

Menon, 2007, Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells, Stem Cells, 25, 520, 10.1634/stemcells.2006-0257

Satake, 2004, Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue, Spine, 29, 1971, 10.1097/01.brs.0000138273.02820.0a

Ji, 2004, Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury, Stem Cells, 22, 415, 10.1634/stemcells.22-3-415

Wynn, 2004, A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow, Blood, 104, 2643, 10.1182/blood-2004-02-0526

Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature, 449, 557, 10.1038/nature06188

Mishra, 2008, Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells, Cancer Res, 68, 4331, 10.1158/0008-5472.CAN-08-0943

Kucia, 2005, Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: Pivotal role of the SDF-1-CXCR4 axis, Stem Cells, 23, 879, 10.1634/stemcells.2004-0342

Son, 2006, Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases, Stem Cells, 24, 1254, 10.1634/stemcells.2005-0271

Dwyer, 2007, Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells, Clin Cancer Res, 13, 5020, 10.1158/1078-0432.CCR-07-0731

Balabanian, 2005, The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes, J Biol Chem, 280, 35760, 10.1074/jbc.M508234200

Heesen, 1998, Cloning and chromosomal mapping of an orphan chemokine receptor: Mouse RDC1, Immunogenetics, 47, 364, 10.1007/s002510050371

Vallee, 1996, Targeting of motor proteins, Science, 271, 1539, 10.1126/science.271.5255.1539

Ilić, 1995, Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice, Nature, 377, 539, 10.1038/377539a0

Palazzo, 2004, Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling, Science, 303, 836, 10.1126/science.1091325

Bernardo, 2007, Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms, Cancer Res, 67, 9142, 10.1158/0008-5472.CAN-06-4690

Galiè, 2008, Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice, Oncogene, 27, 2542, 10.1038/sj.onc.1210920

Tolar, 2007, Sarcoma derived from cultured mesenchymal stem cells, Stem Cells, 25, 371, 10.1634/stemcells.2005-0620

Li, 2007, Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: A model of age-related tumorigenesis in mice, Cancer Res, 67, 10889, 10.1158/0008-5472.CAN-07-2665

Horuk, 1996, Chemokines: Molecular double agents, Curr Biol, 6, 1581, 10.1016/S0960-9822(02)70777-X

Bleul, 1996, The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry, Nature, 382, 829, 10.1038/382829a0

Zou, 1998, Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development, Nature, 393, 595, 10.1038/31269

Nagasawa, 1996, Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1, Nature, 382, 635, 10.1038/382635a0

Ma, 1998, Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice, Proc Natl Acad Sci USA, 95, 9448, 10.1073/pnas.95.16.9448

Valentin, 2007, The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b, Curr Biol, 17, 1026, 10.1016/j.cub.2007.05.020

Dambly-Chaudiere, 2007, Control of cell migration in the development of the posterior lateral line: Antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1, BMC Dev Biol, 7, 23, 10.1186/1471-213X-7-23

Aaronson, 2002, A road map for those who don't know JAK-STAT, Science, 296, 1653, 10.1126/science.1071545

Kerr, 2003, Of JAKs, STATs, blind watchmakers, jeeps and trains, FEBS Lett, 546, 1, 10.1016/S0014-5793(03)00411-3

Platanias, 2005, Mechanisms of type-I- and type-II-interferon-mediated signalling, Nat Rev Immunol, 5, 375, 10.1038/nri1604

Schindler, 2007, JAK-STAT signaling: From interferons to cytokines, J Biol Chem, 282, 20059, 10.1074/jbc.R700016200

Haura, 2005, Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer, Nat Clin Pract Oncol, 2, 315, 10.1038/ncponc0195

Lacronique, 1997, A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia, Science, 278, 1309, 10.1126/science.278.5341.1309

Takemoto, 1997, Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins, Proc Natl Acad Sci USA, 94, 13897, 10.1073/pnas.94.25.13897

van der Plas, 1996, Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain, Leukemia, 10, 1317

Motté, 2007, Mutations in JAK2V617F homologous domain of JAK genes are uncommon in solid tumors, Int J Cancer, 121, 2113, 10.1002/ijc.22939

Nagpal, 2002, Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis, Cancer, 94, 2393, 10.1002/cncr.10499

Annabi, 2003, Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation, Stem Cells, 21, 337, 10.1634/stemcells.21-3-337

Silver, 2005, Requirement for JAK/STAT signaling throughout border cell migration in Drosophila, Development, 132, 3483, 10.1242/dev.01910

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Stem Cells

Tập 27 Số 4

857-865

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