Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Review Article

Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells

Gene Therapy volume 15, pages 730–738 (2008)Cite this article

Abstract

Mesenchymal stem cells (MSC) exhibit tropism for sites of tissue damage as well as the tumor microenvironment. Many of the same inflammatory mediators that are secreted by wounds are found in the tumor microenvironment and are thought to be involved in attracting MSC to these sites. Cell migration is dependent on a multitude of signals ranging from growth factors to chemokines secreted by injured cells and/or respondent immune cells. MSC are likely to have chemotactic properties similar to other immune cells that respond to injury and sites of inflammation. Thus, the well-described model of leukocyte migration can serve as a reasonable example to facilitate the identification of factors involved in MSC migration.Understanding the factors involved in regulating MSC migration to tumors is essential to ultimately develop novel clinical strategies aimed at using MSC as vehicles to deliver antitumor proteins or suppress MSC migration to reduce tumor growth. For example, radiation enhances inflammatory signaling in the tumor microenvironment and may be used to potentiate site-specific MSC migration. Alternatively, restricting the migration of the MSC to the tumor microenvironment may prevent competent tumor-stroma formation, thereby hindering the growth of the tumor. In this review, we will discuss the role of inflammatory signaling in attracting MSC to tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Prockop DJ . Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71–74.

    Article  CAS  Google Scholar 

  2. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106: 1755–1761.

    Article  CAS  Google Scholar 

  3. Lopez Ponte A, Marais E, Gallay N, Langonné A, Delorme B, Hérault O et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 2007; 25: 1737–1745.

    Article  Google Scholar 

  4. Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M . Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of parkinson's disease. Neurosci Lett 2001; 316: 67–70.

    Article  CAS  Google Scholar 

  5. Niedzwiedzki T, Dabrowski Z, Miszta H, Pawlikowski M . Bone healing after bone marrow stromal cell transplantation to the bone defect. Biomaterials 1993; 14: 115–121.

    Article  CAS  Google Scholar 

  6. Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H et al. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 2004; 104: 3581–3587.

    Article  CAS  Google Scholar 

  7. Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, Takeda S et al. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 2005; 309: 314–317.

    Article  CAS  Google Scholar 

  8. Dvorak HF . Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650–1659.

    Article  CAS  Google Scholar 

  9. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    Article  CAS  Google Scholar 

  10. Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T et al. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther 2007; 14: 894–903.

    Article  CAS  Google Scholar 

  11. Hall B, Dembinski J, Sasser AK, 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.

    Article  CAS  Google Scholar 

  12. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.

    Article  CAS  Google Scholar 

  13. Balkwill F . Cancer and the chemokine network. Nat Rev Cancer 2004; 4: 540–550.

    Article  CAS  Google Scholar 

  14. Zernecke A, Weber KSC, Erwig LP, Kluth DC, Schröppel B, Rees AJ et al. Combinatorial model of chemokine involvement in glomerular monocyte recruitment: role of CXC chemokine receptor 2 in infiltration during nephrotoxic nephritis. J Immunol 2001; 166: 5755–5762.

    Article  CAS  Google Scholar 

  15. Malek S, Kaplan E, Wang JF, Ke Q, Rana JS, Chen Y et al. Successful implantation of intravenously administered stem cells correlates with severity of inflammation in murine myocarditis. Pflug Arch Eur J Physiol 2006; 452: 268–275.

    Article  CAS  Google Scholar 

  16. Winner M, Koong AC, Rendon BE, Zundel W, Mitchell RA . Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res 2007; 67: 186–193.

    Article  CAS  Google Scholar 

  17. Ye J, Gao Z, Yin J, He Q . Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293: E1118–E1128.

    Article  CAS  Google Scholar 

  18. Pold M, Zhu LX, Sharma S, Burdick MD, Lin Y, Lee PP et al. Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. Cancer Res 2004; 64: 1853–1860.

    Article  CAS  Google Scholar 

  19. Ubogu EE, Callahan MK, Tucky BH, Ransohoff RM . Determinants of CCL5-driven mononuclear cell migration across the blood-brain barrier. Implications for therapeutically modulating neuroinflammation. J Neuroimmunol 2006; 179: 132–144.

    Article  CAS  Google Scholar 

  20. Gregory JL, Morand EF, McKeown SJ, Ralph JA, Hall P, Yang YH et al. Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2. J Immunol 2006; 177: 8072–8079.

    Article  CAS  Google Scholar 

  21. Montecucco F, Bianchi G, Bertolotto M, Viviani G, Dallegri F, Ottonello L . Insulin primes human neutrophils for CCL3-induced migration: crucial role for JNK 1/2. Ann N Y Acad Sci 2006; 1090: 399–407.

    Article  CAS  Google Scholar 

  22. Lehman N, Di Fulvio M, McCray N, Campos I, Tabatabaian F, Gomez-Cambronero J . Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2. Blood 2006; 108: 3564–3572.

    Article  CAS  Google Scholar 

  23. Laconi E . The evolving concept of tumor microenvironments. BioEssays 2007; 29: 738–744.

    Article  CAS  Google Scholar 

  24. Guo HT, Cai CQ, Schroeder RA, Kuo PC . Nitric oxide is necessary for CC-class chemokine expression in endotoxin-stimulated ANA-1 murine macrophages. Immunol Lett 2002; 80: 21–26.

    Article  CAS  Google Scholar 

  25. Takahashi F, Takahashi K, Maeda K, Tominaga S, Fukuchi Y . Osteopontin is induced by nitric oxide in RAW 264.7 cells. IUBMB Life 2000; 49: 217–221.

    Article  CAS  Google Scholar 

  26. Chamberlain G, Fox J, Ashton B, Middleton J . Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25: 2739–2749.

    Article  CAS  Google Scholar 

  27. Ringe J, Strassburg S, Neumann K, Endres M, Notter M, Burmester G-R . Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem 2007; 101: 135–146.

    Article  CAS  Google Scholar 

  28. Allen SJ, Crown SE, Handel TM . Chemokine: Receptor structure, interactions, and antagonism. Annu Rev Immunol 2007; 25: 787–820.

    Article  CAS  Google Scholar 

  29. Viola A, Luster AD . Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 2008; 48: 171–197.

    Article  CAS  Google Scholar 

  30. Luster AD, Alon R, von Andrian UH . Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005; 6: 1182–1190.

    Article  CAS  Google Scholar 

  31. Becker MD, O'Rourke LM, Blackman WS, Planck SR, Rosenbaum JT . Reduced leukocyte migration, but normal rolling and arrest, in interleukin-8 receptor homologue knockout mice. Invest Ophthalmol Vis Sci 2000; 41: 1812–1817.

    CAS  PubMed  Google Scholar 

  32. Sekido N, Mukaida N, Harada A, Nakanishi I, Watanabe Y, Matsushima K . Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 1993; 365: 654–657.

    Article  CAS  Google Scholar 

  33. Leemans JC, te Velde AA, Florquin S, Bennink RJ, de Bruin K, van Lier RA et al. The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense. J Immunol 2004; 172: 1125–1131.

    Article  CAS  Google Scholar 

  34. Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M et al. Individual cell-based models of tumor-environment interactions: multiple effects of CD97 on tumor invasion. Am J Pathol 2006; 169: 1802–1811.

    Article  CAS  Google Scholar 

  35. Zabel BA, Zuniga L, Ohyama T, Allen SJ, Cichy J, Handel TM et al. Chemoattractants, extracellular proteases, and the integrated host defense response. Exp Hematol 2006; 34: 1021–1032.

    Article  CAS  Google Scholar 

  36. Pisterna GV, Siragusa M . CD44 presence in inflamed pulp tissue. J Endodontics 2007; 33: 1203–1207.

    Article  Google Scholar 

  37. Chaulet H, Desgranges C, Renault MA, Dupuch F, Ezan G, Peiretti F et al. Extracellular nucleotides induce arterial smooth muscle cell migration via osteopontin. Circ Res 2001; 89: 772–778.

    Article  CAS  Google Scholar 

  38. Jiang D, Liang J, Noble PW . Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007; 23: 435–461.

    Article  CAS  Google Scholar 

  39. Simpson MA, Wilson CM, McCarthy JB . Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice. Am J Pathol 2002; 161: 849–857.

    Article  CAS  Google Scholar 

  40. Herrera MB, Bussolati B, Bruno S, Morando L, Mauriello-Romanazzi G, Sanavio F et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int 2007; 72: 430–441.

    Article  CAS  Google Scholar 

  41. Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL . Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 2002; 195: 1145–1154.

    Article  CAS  Google Scholar 

  42. Sutton A, Friand V, Brule-Donneger S, Chaigneau T, Ziol M, Sainte-Catherine O et al. Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res 2007; 5: 21–33.

    Article  CAS  Google Scholar 

  43. Ip JE, Wu Y, Huang J, Zhang L, Pratt RE, Dzau VJ . Mesenchymal stem cells use integrin beta1 not CXC chemokine receptor 4 for myocardial migration and engraftment. Mol Biol Cell 2007; 18: 2873–2882.

    Article  CAS  Google Scholar 

  44. Schwabe RF, Bataller R, Brenner DA . Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 2003; 285: G949–G958.

    Article  CAS  Google Scholar 

  45. Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007; 170: 1942–1953.

    Article  CAS  Google Scholar 

  46. Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ . Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by gcsf or cyclophosphamide. J Clin Invest 2003; 111: 187–196.

    Article  Google Scholar 

  47. Shi M, Li J, Liao L, Chen B, Li B, Chen L et al. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: Role in homing efficiency in NOD/SCID mice. Haematologica 2007; 92: 897–904.

    Article  Google Scholar 

  48. Segers VFM, VanRiet I, Andries LJ, Lemmens K, Demolder MJ, De Becker AJ et al. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. Am J Physiol Heart Circ Physiol 2006; 290: H1370–H1377.

    Article  CAS  Google Scholar 

  49. Li Y, Yu X, Lin S, Li X, Zhang S, Song YH . Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells. Biochem Biophys Res Commun 2007; 356: 780–784.

    Article  CAS  Google Scholar 

  50. Mira E, Lacalle RA, González MA, Gómez-Moutón C, Abad JL, Bernad A et al. A role for chemokine receptor transactivation in growth factor signaling. EMBO Rep 2001; 2: 151–156.

    Article  CAS  Google Scholar 

  51. Schmidt A, Ladage D, Schinkothe T, Klausmann U, Ulrichs C, Klinz FJ et al. Basic fibroblast growth factor controls migration in human mesenchymal stem cells. Stem Cells 2006; 24: 1750–1758.

    Article  CAS  Google Scholar 

  52. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 2007; 13: 5020–5027.

    Article  CAS  Google Scholar 

  53. Wang L, Li Y, Chen J, Gautam SC, Zhang Z, Lu M et al. Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. Exp Hematol 2002; 30: 831–836.

    Article  CAS  Google Scholar 

  54. Ball SG, Shuttleworth CA, Kielty CM . Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol 2007; 177: 489–500.

    Article  CAS  Google Scholar 

  55. Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE . Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 2006; 24: 1030–1041.

    Article  CAS  Google Scholar 

  56. Boyd JH, Divangahi M, Yahiaoui L, Gvozdic D, Qureshi S, Petrof BJ . Toll-like receptors differentially regulate CC and CXC chemokines in skeletal muscle via NF-kappaB and calcineurin. Infect Immun 2006; 74: 6829–6838.

    Article  CAS  Google Scholar 

  57. West AP, Koblansky AA, Ghosh S . Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol 2006; 22: 409–437.

    Article  CAS  Google Scholar 

  58. Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 2007; 26: 99–107.

    Article  Google Scholar 

  59. Hamada H, Kobune M, Nakamura K, Kawano Y, Kato K, Honmou O et al. Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy. Cancer Sci 2005; 96: 149–156.

    Article  CAS  Google Scholar 

  60. Foxman EF, Kunkel EJ, Butcher EC . Integrating conflicting chemotactic signals: the role of memory in leukocyte navigation. J Cell Biol 1999; 147: 577–587.

    Article  CAS  Google Scholar 

  61. Tabatabai G, Frank B, Mohle R, Weller M, Wick W . Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain 2006; 129 (Pt 9): 2426–2435.

    Article  Google Scholar 

  62. Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y, Rafael T et al. Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 2005; 202: 739–750.

    Article  CAS  Google Scholar 

  63. Rabbany SY, Heissig B, Hattori K, Rafii S . Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends Mol Med 2003; 9: 109–117.

    Article  CAS  Google Scholar 

  64. Schichor C, Birnbaum T, Etminan N, Schnell O, Grau S, Miebach S et al. Vascular endothelial growth factor A contributes to glioma-induced migration of human marrow stromal cells (hMSC). Exp Neurol 2006; 199: 301–310.

    Article  CAS  Google Scholar 

  65. Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res 2006; 12: 5550–5556.

    Article  CAS  Google Scholar 

  66. Evans CH, Robbins PD, Ghivizzani SC, Wasko MC, Tomaino MM, Kang R et al. Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci USA 2005; 102: 8698–8703.

    Article  CAS  Google Scholar 

  67. Fiedler J, Röderer G, Günther KP, Brenner RE . BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells. J Cell Biochem 2002; 87: 305–312.

    Article  CAS  Google Scholar 

  68. Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells 2006; 24: 23–33.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the National Cancer Institute (CA-1094551 and CA-116199 for FCM, CA-55164, CA-16672, and CA-49639 for MA) and by the Paul and Mary Haas Chair in Genetics (MA). ES, AK and FCM are supported in part by grants from the Susan G Komen Breast Cancer Foundation.

Author information

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, Molecular Hematology and Therapy, UT-M.D. Anderson Cancer Center, Houston, TX, USA

    E Spaeth, A Klopp, J Dembinski, M Andreeff & F Marini

Authors
  1. E Spaeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Klopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Dembinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Andreeff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Marini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Marini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spaeth, E., Klopp, A., Dembinski, J. et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15, 730–738 (2008). https://doi.org/10.1038/gt.2008.39

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.39

Keywords

This article is cited by

Search

Advanced search

Quick links