Cellular and Molecular Life Sciences

, Volume 74, Issue 10, pp 1871–1881 | Cite as

Reverse transendothelial cell migration in inflammation: to help or to hinder?

  • Thomas Burn
  • Jorge Ivan AlvarezEmail author


The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support “reverse” transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation.


Reverse migration rTEM Reverse interstitial migration Intravasation Transmigration Endothelial cell Neutrophil T cell Monocyte 



The authors want to thank Dr. Carolina Lopez and the immunology graduate program at the University of Pennsylvania for supporting this work. Special thanks to Lara Cheslow for helpful discussions to build this manuscript. J.I.A. holds The David L Torrey career developmental award from the Multiple Sclerosis Society of Canada (MSSC).


  1. 1.
    Nourshargh S, Alon R (2014) Leukocyte migration into inflamed tissues. Immunity 41(5):694–707. doi: 10.1016/j.immuni.2014.10.008 CrossRefPubMedGoogle Scholar
  2. 2.
    Muller WA (2016) Localized signals that regulate transendothelial migration. Curr Opin Immunol 38:24–29. doi: 10.1016/j.coi.2015.10.006 CrossRefPubMedGoogle Scholar
  3. 3.
    Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev Immunol 15(11):692–704. doi: 10.1038/nri3908 CrossRefPubMedGoogle Scholar
  4. 4.
    Shen B, Delaney MK, Du X (2012) Inside-out, outside-in, and inside-outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr Opin Cell Biol 24(5):600–606. doi: 10.1016/ CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs Hans D, Dvorak HF, Dvorak AM, Springer TA (2007) Transcellular diapedesis is initiated by invasive podosomes. Immunity 26(6):784–797. doi: 10.1016/j.immuni.2007.04.015 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wolburg H, Wolburg-Buchholz K, Engelhardt B (2004) Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol 109(2):181–190. doi: 10.1007/s00401-004-0928-x CrossRefPubMedGoogle Scholar
  7. 7.
    Schenkel Jason M, Masopust D (2014) Tissue-resident memory T cells. Immunity 41(6):886–897. doi: 10.1016/j.immuni.2014.12.007 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ehrhardt GRA, Hsu JT, Gartland L, Leu C-M, Zhang S, Davis RS, Cooper MD (2005) Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. J Exp Med 202(6):783–791. doi: 10.1084/jem.20050879 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Walsh GM (2013) Eosinophil apoptosis and clearance in asthma. J Cell Death 6:17–25. doi: 10.4137/JCD.S10818 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kennedy AD, DeLeo FR (2009) Neutrophil apoptosis and the resolution of infection. Immunol Res 43(1):25–61. doi: 10.1007/s12026-008-8049-6 CrossRefPubMedGoogle Scholar
  11. 11.
    Leitch AE, Duffin R, Haslett C, Rossi AG (2008) Relevance of granulocyte apoptosis to resolution of inflammation at the respiratory mucosa. Mucosal Immunol 1(5):350–363CrossRefPubMedGoogle Scholar
  12. 12.
    Roufaiel M, Gracey E, Siu A, Zhu S-N, Lau A, Ibrahim H, Althagafi M, Tai K, Hyduk SJ, Cybulsky KO, Ensan S, Li A, Besla R, Becker HM, Xiao H, Luther SA, Inman RD, Robbins CS, Jongstra-Bilen J, Cybulsky MI (2016) CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima. Nat Immunol 17(11):1263–1272. doi:10.1038/ni.3564. (supplementary information) Google Scholar
  13. 13.
    Starnes TW, Huttenlocher A (2012) Neutrophil reverse migration becomes transparent with zebrafish. Adv Hematol 2012:398640. doi: 10.1155/2012/398640 PubMedPubMedCentralGoogle Scholar
  14. 14.
    Mechnikov II (1988) Immunity in infective diseases. Clin Infect Dis 10(1):223–227. doi: 10.1093/clinids/10.1.223 CrossRefGoogle Scholar
  15. 15.
    Mathias JR, Perrin BJ, Liu TX, Kanki J, Look AT, Huttenlocher A (2006) Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J Leukoc Biol 80(6):1281–1288. doi: 10.1189/jlb.0506346 CrossRefPubMedGoogle Scholar
  16. 16.
    Bratton DL, Henson PM (2011) Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol 32(8):350–357. doi: 10.1016/ CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yoo SK, Huttenlocher A (2011) Spatiotemporal photolabeling of neutrophil trafficking during inflammation in live zebrafish. J Leukoc Biol 89(5):661–667. doi: 10.1189/jlb.1010567 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Elks PM, van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MK, Walmsley SR, Renshaw SA (2011) Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood 118(3):712–722. doi: 10.1182/blood-2010-12-324186 CrossRefPubMedGoogle Scholar
  19. 19.
    Yoo SK, Starnes TW, Deng Q, Huttenlocher A (2011) Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480 (7375):109–112. doi:10.1038/ni.3564. (supplementary information)Google Scholar
  20. 20.
    Tauzin S, Starnes TW, Becker FB, P-y Lam, Huttenlocher A (2014) Redox and Src family kinase signaling control leukocyte wound attraction and neutrophil reverse migration. J Cell Biol 207(5):589CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Nourshargh S, Renshaw SA, Imhof BA (2016) Reverse migration of neutrophils: where, when, how, and why? Trends Immunol 37(5):273–286. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  22. 22.
    Buckley CD, Ross EA, McGettrick HM, Osborne CE, Haworth O, Schmutz C, Stone PC, Salmon M, Matharu NM, Vohra RK, Nash GB, Rainger GE (2005) Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration. J Leukoc Biol 79(2):303–311. doi: 10.1189/jlb.0905496 CrossRefPubMedGoogle Scholar
  23. 23.
    Woodfin A, Voisin M-B, Beyrau M, Colom B, Caille D, Diapouli F-M, Nash GB, Chavakis T, Albelda SM, Rainger GE, Meda P, Imhof BA, Nourshargh S (2011) The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol 12(8):761–769. doi: 10.1038/ni.2062 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Joly E, Hudrisier D (2003) What is trogocytosis and what is its purpose? Nat Immunol 4(9):815. doi: 10.1038/ni0903-815 CrossRefPubMedGoogle Scholar
  25. 25.
    Hamza B, Irimia D (2015) Whole blood human neutrophil trafficking in a microfluidic model of infection and inflammation. Lab Chip 15(12):2625–2633. doi: 10.1039/c5lc00245a CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hellwig-Bürgel T, Stiehl DP, Wagner AE, Metzen E, Jelkmann W (2005) Review: Hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res 25(6):297–310. doi: 10.1089/jir.2005.25.297 CrossRefPubMedGoogle Scholar
  27. 27.
    Podjaski C, Alvarez JI, Bourbonniere L, Larouche S, Terouz S, Bin JM, Lécuyer M-A, Saint-Laurent O, Larochelle C, Darlington PJ, Arbour N, Antel JP, Kennedy TE, Prat A (2015) Netrin 1 regulates blood–brain barrier function and neuroinflammation. Brain 138(6):1598–1612. doi: 10.1093/brain/awv092 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ly NP, Komatsuzaki K, Fraser IP, Tseng AA, Prodhan P, Moore KJ, Kinane TB (2005) Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci 102(41):14729–14734. doi: 10.1073/pnas.0506233102 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rosenberger P, Schwab JM, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia JC, Unertl K, Eltzschig HK (2009) Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 10(2):195–202. doi: 10.1038/ni.1683 CrossRefPubMedGoogle Scholar
  30. 30.
    Akhtar S, Hartmann P, Karshovska E, Rinderknecht F-A, Subramanian P, Gremse F, Grommes J, Jacobs M, Kiessling F, Weber C, Steffens S, Schober A (2015) Endothelial hypoxia-inducible factor-1α promotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a. Hypertension 66(6):1220PubMedGoogle Scholar
  31. 31.
    Engelhardt S, Huang S-F, Patkar S, Gassmann M, Ogunshola OO (2015) Differential responses of blood–brain barrier associated cells to hypoxia and ischemia: a comparative study. Fluids Barriers CNS 12:4. doi: 10.1186/2045-8118-12-4 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Enzmann G, Mysiorek C, Gorina R, Cheng Y-J, Ghavampour S, Hannocks M-J, Prinz V, Dirnagl U, Endres M, Prinz M, Beschorner R, Harter PN, Mittelbronn M, Engelhardt B, Sorokin L (2013) The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol 125(3):395–412. doi: 10.1007/s00401-012-1076-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Ullrich N, Strecker J-K, Minnerup J, Schilling M (2014) The temporo-spatial localization of polymorphonuclear cells related to the neurovascular unit after transient focal cerebral ischemia. Brain Res 1586:184–192. doi: 10.1016/j.brainres.2014.08.037 CrossRefPubMedGoogle Scholar
  34. 34.
    Barletta KE, Ley K, Mehrad B (2012) Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 32(4):856–864. doi: 10.1161/ATVBAHA.111.226845 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Robertson AL, Holmes GR, Bojarczuk AN, Burgon J, Loynes CA, Chimen M, Sawtell AK, Hamza B, Willson J, Walmsley SR, Anderson SR, Coles MC, Farrow SN, Solari R, Jones S, Prince LR, Irimia D, Rainger GE, Kadirkamanathan V, Whyte MKB, Renshaw SA (2014) A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism. Sci Transl Med 6(225):225ra229–225ra229. doi:10.1126/scitranslmed.3007672Google Scholar
  36. 36.
    Tang C, H-l Xue, Bai C-l FuR (2010) Regulation of adhesion molecules expression in TNF-α-stimulated brain microvascular endothelial cells by tanshinone IIA: involvement of NF-κB and ROS generation. Phytother Res. doi: 10.1002/ptr.3278 Google Scholar
  37. 37.
    Kogut MH, Genovese KJ, Haiqi H, Kaiser P (2008) Flagellin and lipopolysaccharide up-regulation of IL-6 and CXCLi2 gene expression in chicken heterophils is mediated by ERK1/2-dependent activation of AP-1 and NF-B signaling pathways. Innate Immunity 14(4):213–222. doi: 10.1177/1753425908094416 CrossRefPubMedGoogle Scholar
  38. 38.
    Xu Y, Feng D, Wang Y, Lin S, Xu L (2008) Sodium tanshinone IIA sulfonate protects mice from ConA-induced hepatitis via inhibiting NF-κB and IFN-γ/STAT1 pathways. J Clin Immunol 28(5):512–519. doi: 10.1007/s10875-008-9206-3 CrossRefPubMedGoogle Scholar
  39. 39.
    Bradfield PF, Scheiermann C, Nourshargh S, Ody C, Luscinskas FW, Rainger GE, Nash GB, Miljkovic-Licina M, Aurrand-Lions M, Imhof BA (2007) JAM-C regulates unidirectional monocyte transendothelial migration in inflammation. Blood 110(7):2545–2555. doi: 10.1182/blood-2007-03-078733 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Colom B, Bodkin JV, Beyrau M, Woodfin A, Ody C, Rourke C, Chavakis T, Brohi K, Imhof BA, Nourshargh S (2015) Leukotriene B4-neutrophil elastase axis drives neutrophil reverse transendothelial cell migration in vivo. Immunity 42(6):1075–1086. doi: 10.1016/j.immuni.2015.05.010 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Crooks SW, Stockley RA (1998) Leukotriene B4. Int J Biochem Cell Biol 30(2):173–178. doi: 10.1016/s1357-2725(97)00123-4 CrossRefPubMedGoogle Scholar
  42. 42.
    Wu D, Zeng Y, Fan Y, Wu J, Mulatibieke T, Ni J, Yu G, Wan R, Wang X, Hu G (2016) Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury. Sci Rep 6:20545. doi: 10.1038/srep20545 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    ErnstrÖm U, Gyllensten L, Larsson B (1965) Venous output of lymphocytes from the thymus. Nature 207(4996):540–541. doi: 10.1038/207540b0 CrossRefPubMedGoogle Scholar
  44. 44.
    Weinreich MA, Hogquist KA (2008) Thymic emigration: when and how T cells leave home. J Immunol 181(4):2265–2270. doi: 10.4049/jimmunol.181.4.2265 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kotani M, Yamashita A, Rai F, Seiki K, Miyamoto M, Matsunaga N, Okada K, Horii I (1967) Absorption from intestinal lumen into blood and lymph of DNA and DNA degradation products from H3-thymidine labeled lymphocytes. Jpn Circ J 31(11):1745–1750. doi: 10.1253/jcj.31.1745 CrossRefPubMedGoogle Scholar
  46. 46.
    Lee JY, Buzney CD, Poznansky MC, Sackstein R (2009) Dynamic alterations in chemokine gradients induce transendothelial shuttling of human T cells under physiologic shear conditions. J Leukoc Biol 86(6):1285–1294. doi: 10.1189/jlb.0309214 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14(6):392–404. doi: 10.1038/nri3671 CrossRefPubMedGoogle Scholar
  48. 48.
    Randolph GJ, Furie MB (1996) Mononuclear phagocytes egress from an in vitro model of the vascular wall by migrating across endothelium in the basal to apical direction: role of intercellular adhesion molecule 1 and the CD11/CD18 integrins. J Exp Med 183(2):451–462. doi: 10.1084/jem.183.2.451 CrossRefPubMedGoogle Scholar
  49. 49.
    Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA (1998) Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science 282(5388):480–483. doi: 10.1126/science.282.5388.480 CrossRefPubMedGoogle Scholar
  50. 50.
    Ifergan I, Kebir H, Bernard M, Wosik K, Dodelet-Devillers A, Cayrol R, Arbour N, Prat A (2008) The blood–brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 131(3):785–799. doi: 10.1093/brain/awm295 CrossRefPubMedGoogle Scholar
  51. 51.
    Alvarez JI, Kebir H, Cheslow L, Chabarati M, Larochelle C, Prat A (2015) JAML mediates monocyte and CD8 T cell migration across the brain endothelium. Ann Clin Transl Neurol 2(11):1032–1037. doi: 10.1002/acn3.255 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Guo Y-L, Bai R, Chen CXJ, Liu D-Q, Liu Y, Zhang C-Y, Zen K (2008) Role of junctional adhesion molecule-like protein in mediating monocyte transendothelial migration. Arterioscler Thromb Vasc Biol 29(1):75CrossRefPubMedGoogle Scholar
  53. 53.
    Zen K, Liu Y, McCall IC, Wu T, Lee W, Babbin BA, Nusrat A, Parkos CA (2005) Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophils. Mol Biol Cell 16(6):2694–2703. doi: 10.1091/mbc.E05-01-0036 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Zimmermann HW, Bruns T, Weston CJ, Curbishley SM, Liaskou E, Li K-K, Resheq YJ, Badenhorst PW, Adams DH (2015) Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver. Hepatology 63(1):233–246. doi: 10.1002/hep.28285 CrossRefPubMedGoogle Scholar
  55. 55.
    Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci 101(32):11779–11784. doi: 10.1073/pnas.0403259101 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Reymond N, d’Agua BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13(12):858–870. doi: 10.1038/nrc3628 CrossRefPubMedGoogle Scholar
  57. 57.
    Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029. doi: 10.1158/0008-5472.can-04-1449 CrossRefPubMedGoogle Scholar
  58. 58.
    Wyckoff JB, Wang Y, Lin EY, Jf Li, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67(6):2649–2656. doi: 10.1158/0008-5472.can-06-1823 CrossRefPubMedGoogle Scholar
  59. 59.
    Qian B-Z, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi: 10.1016/j.cell.2010.03.014 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Smirnova T, Zhou ZN, Flinn RJ, Wyckoff J, Boimel PJ, Pozzuto M, Coniglio SJ, Backer JM, Bresnick AR, Condeelis JS, Hynes NE, Segall JE (2011) Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene 31(6):706–715. doi: 10.1038/onc.2011.275 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gligorijevic B, Wyckoff J, Yamaguchi H, Wang Y, Roussos ET, Condeelis J (2012) N-WASP-mediated invadopodium formation is involved in intravasation and lung metastasis of mammary tumors. J Cell Sci 125(3):724–734. doi: 10.1242/jcs.092726 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Roh-Johnson M, Bravo-Cordero JJ, Patsialou A, Sharma VP, Guo P, Liu H, Hodgson L, Condeelis J (2013) Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene 33(33):4203–4212. doi: 10.1038/onc.2013.377 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Chan G, Nogalski MT, Yurochko AD (2009) Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility. Proc Natl Acad Sci 106(52):22369–22374. doi: 10.1073/pnas.0908787106 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Escribese MM, Conde E, Saenz-Morales D, Hordijk PL, Garcia-Bermejo ML (2007) Mononuclear cell extravasation in an inflammatory response is abrogated by all-trans-retinoic acid through inhibiting the acquisition of an appropriate migratory phenotype. J Pharmacol Exp Ther 324(2):454–462. doi: 10.1124/jpet.107.127225 CrossRefPubMedGoogle Scholar
  65. 65.
    Chabottaux V, Ricaud S, Host L, Blacher S, Paye A, Thiry M, Garofalakis A, Pestourie C, Gombert K, Bruyere F, Lewandowsky D, Tavitian B, Foidart J-M, Duconge F, Noel A (2009) Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumour vascular architecture. J Cell Mol Med 13(9b):4002–4013. doi: 10.1111/j.1582-4934.2009.00764.x CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Fröhlich C, Klitgaard M, Noer Julie B, Kotzsch A, Nehammer C, Kronqvist P, Berthelsen J, Blobel C, Kveiborg M, Albrechtsen R, Wewer Ulla M (2013) ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins. Biochem J 452(1):97–109. doi: 10.1042/bj20121558 CrossRefPubMedGoogle Scholar
  67. 67.
    Host L, Paye A, Detry B, Blacher S, Munaut C, Foidart JM, Seiki M, Sounni NE, Noel A (2012) The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic promoting effects. Int J Cancer 131(7):1537–1548. doi: 10.1002/ijc.27436 CrossRefPubMedGoogle Scholar
  68. 68.
    Kveiborg M, Albrechtsen R, Couchman JR, Wewer UM (2008) Cellular roles of ADAM12 in health and disease. Int J Biochem Cell Biol 40(9):1685–1702. doi: 10.1016/j.biocel.2008.01.025 CrossRefPubMedGoogle Scholar
  69. 69.
    Fröhlich C, Nehammer C, Albrechtsen R, Kronqvist P, Kveiborg M, Sehara-Fujisawa A, Mercurio AM, Wewer UM (2011) ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression. Mol Cancer Res 9(11):1449–1461. doi: 10.1158/1541-7786.MCR-11-0100 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Chiang SPH, Cabrera RM, Segall JE (2016) Tumor cell intravasation. A review in the theme: cell and molecular processes in cancer metastasis. Am J Physiol Cell Physiol. doi:10.1152/ajpcell.00238.2015Google Scholar
  71. 71.
    Weis SM, Cheresh DA (2011) αv integrins in angiogenesis and cancer. Cold Spring Harbor Perspect Med 1(1):a006478–a006478. doi: 10.1101/cshperspect.a006478 CrossRefGoogle Scholar
  72. 72.
    Dudley AC (2012) Tumor endothelial cells. Cold Spring Harbor Perspect Med 2(3):a006536. doi: 10.1101/cshperspect.a006536 CrossRefGoogle Scholar
  73. 73.
    Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789. doi: 10.1189/jlb.1109766 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R (1989) Neutrophil function in ischemic heart disease. Circulation 79(3):549–556. doi: 10.1161/01.cir.79.3.549 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Institute of Immunology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathobiology, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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