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PMID: 21670198 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer.

Journal of cell science ·Vol. 124 ·No. Pt 13 ·2011-07-01 ·Pages 2120-31

Roussos ET, Balsamo M, Alford SK, Wyckoff JB, Gligorijevic B, Wang Y, Pozzuto M, Stobezki R, Goswami S, Segall JE, Lauffenburger DA, Bresnick AR, Gertler FB, Condeelis JS

Abstract

We have shown previously that distinct Mena isoforms are expressed in invasive and migratory tumor cells in vivo and that the invasion isoform (Mena(INV)) potentiates carcinoma cell metastasis in murine models of breast cancer. However, the specific step of metastatic progression affected by this isoform and the effects on metastasis of the Mena11a isoform, expressed in primary tumor cells, are largely unknown. Here, we provide evidence that elevated Mena(INV) increases coordinated streaming motility, and enhances transendothelial migration and intravasation of tumor cells. We demonstrate that promotion of these early stages of metastasis by Mena(INV) is dependent on a macrophage-tumor cell paracrine loop. Our studies also show that increased Mena11a expression correlates with decreased expression of colony-stimulating factor 1 and a dramatically decreased ability to participate in paracrine-mediated invasion and intravasation. Our results illustrate the importance of paracrine-mediated cell streaming and intravasation on tumor cell dissemination, and demonstrate that the relative abundance of Mena(INV) and Mena11a helps to regulate these key stages of metastatic progression in breast cancer cells.

MeSH Terms
Animals Breast Neoplasms/metabolism,pathology Cell Line, Tumor Cell Movement Cytoskeletal Proteins/metabolism Female Macrophage Colony-Stimulating Factor/biosynthesis Macrophages/metabolism Mice Mice, SCID Microfilament Proteins Neoplasm Invasiveness Neoplasm Metastasis Protein Isoforms/metabolism Rats Transendothelial and Transepithelial Migration
Chemicals
Cytoskeletal Proteins Enah protein, mouse Microfilament Proteins Protein Isoforms Macrophage Colony-Stimulating Factor
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Roussos Evanthia T
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. [email protected]
Balsamo Michele
Alford Shannon K
Wyckoff Jeffrey B
Gligorijevic Bojana
Wang Yarong
Pozzuto Maria
Stobezki Robert
Goswami Sumanta
Segall Jeffrey E
Lauffenburger Douglas A
Bresnick Anne R
Gertler Frank B
Condeelis John S
References (74)
74 references, click to expand
  1. Characterization of cytokeratins expressed in metastatic rat mammary adenocarcinoma cells.
    Cancer Res. 1989 Jan 1;49(1):104-11 PMID: 2461796
  2. Role of Ena/VASP proteins in homeostasis and disease.
    Handb Exp Pharmacol. 2008;(186):39-65 PMID: 18491048
  3. Epidermal growth factor: effects of androgens and adrenergic agents.
    Endocrinology. 1974 Sep;95(3):776-82 PMID: 4368688
  4. The immunohistochemical aspects of protein Mena in cervical lesions.
    Rom J Morphol Embryol. 2009;50(2):213-6 PMID: 19434313
  5. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop.
    Cancer Res. 2005 Jun 15;65(12):5278-83 PMID: 15958574
  6. Tes, a specific Mena interacting partner, breaks the rules for EVH1 binding.
    Mol Cell. 2007 Dec 28;28(6):1071-82 PMID: 18158903
  7. An improved model to study tumor cell autonomous metastasis programs using MTLn3 cells and the Rag2(-/-) gammac (-/-) mouse.
    Clin Exp Metastasis. 2009;26(7):673-84 PMID: 19466569
  8. Plasticity of cell migration: a multiscale tuning model.
    J Cell Biol. 2010 Jan 11;188(1):11-9 PMID: 19951899
  9. VASP is a processive actin polymerase that requires monomeric actin for barbed end association.
    J Cell Biol. 2010 Nov 1;191(3):571-84 PMID: 21041447
  10. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility.
    Nat Cell Biol. 2009 Nov;11(11):1287-96 PMID: 19838175
  11. Two-photon intravital multicolor imaging combined with inducible gene expression to distinguish metastatic behavior of breast cancer cells in vivo.
    Mol Imaging Biol. 2011 Feb;13(1):67-77 PMID: 20396956
  12. Cell motility and cytoskeletal regulation in invasion and metastasis.
    J Mammary Gland Biol Neoplasia. 2007 Sep;12(2-3):143-52 PMID: 17557195
  13. FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro.
    Oncogene. 1991 Jun;6(6):941-52 PMID: 1829808
  14. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling.
    Cancer Res. 2002 Nov 1;62(21):6278-88 PMID: 12414658
  15. Intravital imaging of metastatic behavior through a mammary imaging window.
    Nat Methods. 2008 Dec;5(12):1019-21 PMID: 18997781
  16. ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation.
    Clin Cancer Res. 2009 Jun 1;15(11):3733-9 PMID: 19458057
  17. Circulating colony stimulating factor-1 and breast cancer risk.
    Cancer Res. 2008 Jan 1;68(1):18-21 PMID: 18172291
  18. The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors.
    J Cell Biol. 2006 May 8;173(3):395-404 PMID: 16651380
  19. The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors.
    Clin Cancer Res. 2006 Mar 1;12(5):1470-8 PMID: 16533770
  20. The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12.
    Cancer Res. 2009 Apr 1;69(7):3221-7 PMID: 19293185
  21. Comparison of 'spontaneous' and 'experimental' metastasis using rat 13762 mammary adenocarcinoma metastatic cell clones.
    Invasion Metastasis. 1983;3(2):65-80 PMID: 6677622
  22. Inhibition by erlotinib of primary lung adenocarcinoma at an early stage in male mice.
    Cancer Chemother Pharmacol. 2008 Sep;62(4):605-20 PMID: 18030469
  23. Critical roles of phosphorylation and actin binding motifs, but not the central proline-rich region, for Ena/vasodilator-stimulated phosphoprotein (VASP) function during cell migration.
    Mol Biol Cell. 2002 Jul;13(7):2533-46 PMID: 12134088
  24. Ligand-induced activation of epidermal growth factor receptor in intact rat mammary adenocarcinoma cells without detectable receptor phosphorylation.
    J Biol Chem. 1992 Jun 15;267(17):11872-80 PMID: 1318304
  25. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor.
    Cancer Res. 2000 May 1;60(9):2504-11 PMID: 10811132
  26. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells.
    Nat Cell Biol. 2007 Dec;9(12):1392-400 PMID: 18037882
  27. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo.
    Clin Exp Metastasis. 2009;26(2):153-9 PMID: 18985426
  28. Breast cancer cells isolated by chemotaxis from primary tumors show increased survival and resistance to chemotherapy.
    Cancer Res. 2004 Nov 1;64(21):7664-7 PMID: 15520165
  29. Invadopodia and podosomes in tumor invasion.
    Eur J Cell Biol. 2006 Apr;85(3-4):213-8 PMID: 16546563
  30. Development and biologic properties of malignant cell sublines and clones of a spontaneously metastasizing rat mammary adenocarcinoma.
    J Natl Cancer Inst. 1982 Mar;68(3):507-17 PMID: 6950180
  31. PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer.
    Breast Cancer Res Treat. 2000 Nov;64(2):221-8 PMID: 11194458
  32. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis.
    J Natl Cancer Inst. 1994 Jan 19;86(2):120-6 PMID: 8271294
  33. Mena invasive (Mena(INV)) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM.
    Clin Exp Metastasis. 2011 Aug;28(6):515-27 PMID: 21484349
  34. Ena/VASP: towards resolving a pointed controversy at the barbed end.
    J Cell Sci. 2009 Jun 15;122(Pt 12):1947-53 PMID: 19494122
  35. Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors.
    Cancer Res. 2007 Apr 15;67(8):3505-11 PMID: 17440055
  36. Coexpression of cytokeratins characteristic for myoepithelial and luminal cell lineages in rat 13762NF mammary adenocarcinoma tumors and their spontaneous metastases.
    Cancer Res. 1991 Nov 1;51(21):5943-50 PMID: 1718590
  37. CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract.
    Mol Reprod Dev. 1997 Jan;46(1):71-4 PMID: 8981366
  38. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.
    Cell. 2006 Jan 27;124(2):263-6 PMID: 16439202
  39. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors.
    Cancer Res. 2007 Mar 15;67(6):2649-56 PMID: 17363585
  40. EGF stimulates lamellipod extension in metastatic mammary adenocarcinoma cells by an actin-dependent mechanism.
    Clin Exp Metastasis. 1996 Jan;14(1):61-72 PMID: 8521618
  41. Ena/VASP proteins capture actin filament barbed ends.
    J Biol Chem. 2008 Apr 11;283(15):9814-9 PMID: 18283104
  42. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination.
    Clin Cancer Res. 2009 Apr 1;15(7):2433-41 PMID: 19318480
  43. Infrared multiphoton microscopy: subcellular-resolved deep tissue imaging.
    Curr Opin Biotechnol. 2009 Feb;20(1):54-62 PMID: 19324541
  44. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors.
    Breast Cancer Res. 2010;12(6):R101 PMID: 21108830
  45. Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.
    Clin Cancer Res. 2008 Aug 1;14(15):4943-50 PMID: 18676769
  46. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors.
    Cancer Res. 2004 Dec 1;64(23):8585-94 PMID: 15574765
  47. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.
    J Cell Biol. 2003 Jan 20;160(2):267-77 PMID: 12527751
  48. Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis.
    Cancer Res. 2006 Jan 1;66(1):192-7 PMID: 16397232
  49. Structural basis for the recruitment of profilin-actin complexes during filament elongation by Ena/VASP.
    EMBO J. 2007 Oct 31;26(21):4597-606 PMID: 17914456
  50. Ena/VASP proteins have an anti-capping independent function in filopodia formation.
    Mol Biol Cell. 2007 Jul;18(7):2579-91 PMID: 17475772
  51. A new chemotaxis device for cell migration studies.
    Integr Biol (Camb). 2010 Nov;2(11-12):696-706 PMID: 20938544
  52. Regulation of colony-stimulating factor 1 during pregnancy.
    J Exp Med. 1986 Sep 1;164(3):956-61 PMID: 3489064
  53. Mechanisms of cancer cell invasion.
    Curr Opin Genet Dev. 2005 Feb;15(1):87-96 PMID: 15661538
  54. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis.
    Dev Cell. 2008 Dec;15(6):813-28 PMID: 19081071
  55. Characterization of human Enah gene.
    Biochim Biophys Acta. 2006 Jan-Feb;1759(1-2):99-107 PMID: 16494957
  56. Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility.
    Cell. 2002 May 17;109(4):509-21 PMID: 12086607
  57. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics.
    Cell. 1996 Oct 18;87(2):227-39 PMID: 8861907
  58. Simultaneous imaging of GFP, CFP and collagen in tumors in vivo using multiphoton microscopy.
    BMC Biotechnol. 2005 May 23;5:14 PMID: 15910685
  59. In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts.
    Nat Methods. 2009 Feb;6(2):143-5 PMID: 19151720
  60. A novel proline-rich motif present in ActA of Listeria monocytogenes and cytoskeletal proteins is the ligand for the EVH1 domain, a protein module present in the Ena/VASP family.
    EMBO J. 1997 Sep 1;16(17):5433-44 PMID: 9312002
  61. The expression of cytoskeleton regulatory protein Mena in colorectal lesions.
    Rom J Morphol Embryol. 2008;49(3):345-9 PMID: 18758639
  62. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors.
    Cancer Res. 2004 Oct 1;64(19):7022-9 PMID: 15466195
  63. The collection of the motile population of cells from a living tumor.
    Cancer Res. 2000 Oct 1;60(19):5401-4 PMID: 11034079
  64. Epidermal growth factor receptor distribution during chemotactic responses.
    Mol Biol Cell. 2000 Nov;11(11):3873-83 PMID: 11071913
  65. Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins.
    J Biol Chem. 2005 Aug 5;280(31):28653-62 PMID: 15939738
  66. Intravital imaging of cell movement in tumours.
    Nat Rev Cancer. 2003 Dec;3(12):921-30 PMID: 14737122
  67. Negative regulation of fibroblast motility by Ena/VASP proteins.
    Cell. 2000 Jun 23;101(7):717-28 PMID: 10892743
  68. The macrophage colony-stimulating factor 1 response signature in breast carcinoma.
    Clin Cancer Res. 2009 Feb 1;15(3):778-87 PMID: 19188147
  69. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy.
    Dis Model Mech. 2008 Sep-Oct;1(2-3):155-67; discussion 165 PMID: 19048079
  70. "In vivo" depletion of macrophages by liposome-mediated "suicide".
    Methods Enzymol. 2003;373:3-16 PMID: 14714393
  71. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor.
    Cancer Res. 2009 Dec 15;69(24):9498-506 PMID: 19934330
  72. Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines.
    Cancer Res. 2007 Mar 15;67(6):2657-65 PMID: 17363586
  73. Ligand mediated activation of ectopic EGF receptor promotes matrix protein adhesion and lung colonization of rat mammary adenocarcinoma cells.
    Oncogene. 1995 May 4;10(9):1823-32 PMID: 7753557
  74. Mechanisms of collective cell migration at a glance.
    J Cell Sci. 2009 Sep 15;122(Pt 18):3203-8 PMID: 19726629
Article Info
Journal
Journal of cell science
Abbr.
J Cell Sci
ISSN
1477-9137
DOI
10.1242/jcs.086231
Email
[email protected]
Published
2011-07-01
Pages
2120-31
Language
English
Region
England
NLM ID
0052457
PMCID
PMC3113666
Subset
IM
Grants
NCI NIH HHS · P01 CA100324 · United States
NCI NIH HHS · CA100324 · United States
NIGMS NIH HHS · GM58801 · United States
NCI NIH HHS · U54 CA112967 · United States
NIGMS NIH HHS · R01 GM058801 · United States
NCI NIH HHS · U01 CA105490 · United States
NCI NIH HHS · CA150344 · United States
NCI NIH HHS · R01 CA150344 · United States
NCI NIH HHS · CA77522 · United States
NCI NIH HHS · U54 CA126511 · United States
NCI NIH HHS · CA126511 · United States
NIGMS NIH HHS · R01 GM058801-12 · United States
NCI NIH HHS · R01 CA077522 · United States
External Links
PubMed source DOI: 10.1242/jcs.086231 PMC Full Text View journal details
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