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PMID: 20535745 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Oxidative stress promotes myofibroblast differentiation and tumour spreading.

EMBO molecular medicine ·Vol. 2 ·No. 6 ·2010-06-00 ·Pages 211-30

Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C, Bellanger D, Stern MH, Dubois T, Sastre-Garau X, Delattre O, Vincent-Salomon A, Mechta-Grigoriou F

Abstract

JunD regulates genes involved in antioxidant defence. We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour development. In a model of mammary carcinogenesis, junD inactivation increased tumour incidence and revealed an associated reactive stroma. junD-inactivation in the stroma was sufficient to shorten tumour-free survival rate and enhance metastatic spread. ROS promoted conversion of fibroblasts into highly migrating myofibroblasts through accumulation of the hypoxia-inducible factor (HIF)-1alpha transcription factor and the CXCL12 chemokine. Accordingly, treatment with an antioxidant reduced the levels of HIF and CXCL12 and numerous myofibroblast features. CXCL12 accumulated in the stroma of HER2-human breast adenocarcinomas. Moreover, HER2 tumours exhibited a high proportion of myofibroblasts, which was significantly correlated to nodal metastases. Interestingly, this subset of tumours exhibited a significant nuclear exclusion of JunD and revealed an associated oxido-reduction signature, further demonstrating the relevance of our findings in human cancers. Collectively, our data uncover a new mechanism by which oxidative stress increases the migratory properties of stromal fibroblasts, which in turn potentiate tumour dissemination.

MeSH Terms
Animals Breast Neoplasms/pathology,secondary Cell Differentiation Cell Line Chemokine CXCL12/metabolism Female Fibroblasts/drug effects Histocytochemistry Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Immunohistochemistry Incidence Locomotion Mammary Neoplasms, Animal/pathology,secondary Mice Mice, Knockout Microscopy Microscopy, Fluorescence Models, Biological Neoplasm Metastasis/pathology Oxidative Stress Proto-Oncogene Proteins/deficiency,physiology Proto-Oncogene Proteins c-jun Reactive Oxygen Species/toxicity Survival Analysis
Chemicals
Chemokine CXCL12 Cxcl12 protein, mouse Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit Proto-Oncogene Proteins Proto-Oncogene Proteins c-jun Reactive Oxygen Species junD protein, mouse
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Toullec Aurore
Laboratory of "Stress and Cancer", Inserm U830, Institut Curie, 75248 Paris Cedex 05, France.
Gerald Damien
Despouy Gilles
Bourachot Brigitte
Cardon Melissa
Lefort Sylvain
Richardson Marion
Rigaill Guillem
Parrini Maria-Carla
Lucchesi Carlo
Bellanger Dorine
Stern Marc-Henri
Dubois Thierry
Sastre-Garau Xavier
Delattre Olivier
Vincent-Salomon Anne
Mechta-Grigoriou Fatima
References (89)
89 references, click to expand
  1. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.
    Nat Cell Biol. 2009 Aug;11(8):973-9 PMID: 19597488
  2. The biology of chemokines and their receptors.
    Annu Rev Immunol. 2000;18:217-42 PMID: 10837058
  3. Genomic alterations in tumor stroma.
    Cancer Res. 2009 Sep 1;69(17):6759-64 PMID: 19706759
  4. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)
    J Exp Med. 1996 Sep 1;184(3):1101-9 PMID: 9064327
  5. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1.
    Nat Med. 2004 Aug;10(8):858-64 PMID: 15235597
  6. Oxidants in receptor tyrosine kinase signal transduction pathways.
    Antioxid Redox Signal. 2003 Dec;5(6):781-8 PMID: 14588151
  7. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation.
    J Cell Sci. 2005 Feb 1;118(Pt 3):485-96 PMID: 15657080
  8. Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling.
    Cell Metab. 2008 Feb;7(2):113-24 PMID: 18249171
  9. Friends or foes - bipolar effects of the tumour stroma in cancer.
    Nat Rev Cancer. 2004 Nov;4(11):839-49 PMID: 15516957
  10. Origin of carcinoma associated fibroblasts.
    Cell Cycle. 2009 Feb 15;8(4):589-95 PMID: 19182519
  11. Tumor stroma and regulation of cancer development.
    Annu Rev Pathol. 2006;1:119-50 PMID: 18039110
  12. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
    Cell. 2005 May 6;121(3):335-48 PMID: 15882617
  13. Inflammation and oncogenesis: a vicious connection.
    Curr Opin Genet Dev. 2010 Feb;20(1):65-71 PMID: 20036794
  14. Regulation of HGF and SDF-1 expression by oral fibroblasts--implications for invasion of oral cancer.
    Oral Oncol. 2008 Jul;44(7):646-51 PMID: 17996483
  15. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts.
    Cancer Res. 2004 Dec 1;64(23):8492-5 PMID: 15574751
  16. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3738-43 PMID: 15701700
  17. New insights on the role of CXCR4 in cancer metastasis.
    J Pathol. 2008 Jul;215(3):211-3 PMID: 18523970
  18. The basics of epithelial-mesenchymal transition.
    J Clin Invest. 2009 Jun;119(6):1420-8 PMID: 19487818
  19. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow.
    Exp Cell Res. 2005 Mar 10;304(1):81-90 PMID: 15707576
  20. Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner.
    Cancer Cell. 2010 Feb 17;17(2):135-47 PMID: 20138012
  21. Inflammation, proteases and cancer.
    Eur J Cancer. 2006 Apr;42(6):728-34 PMID: 16524717
  22. Redox regulation of the hypoxia-inducible factor.
    Biol Chem. 2006 Oct-Nov;387(10-11):1337-46 PMID: 17081104
  23. Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway.
    Biochem Biophys Res Commun. 2005 Jan 14;326(2):282-9 PMID: 15582575
  24. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer.
    Breast Cancer Res Treat. 2008 Aug;110(3):465-75 PMID: 17805961
  25. Cancer-associated stromal fibroblasts promote pancreatic tumor progression.
    Cancer Res. 2008 Feb 1;68(3):918-26 PMID: 18245495
  26. Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast.
    Tumour Biol. 2004 Sep-Dec;25(5-6):290-5 PMID: 15627894
  27. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT?
    J Cell Biochem. 2007 Jul 1;101(4):830-9 PMID: 17211838
  28. Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis.
    Am J Physiol Cell Physiol. 2007 Mar;292(3):C987-95 PMID: 16943240
  29. 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
  30. The myofibroblast and its tumours.
    J Clin Pathol. 2009 Mar;62(3):236-49 PMID: 18930983
  31. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells.
    J Clin Invest. 1995 Feb;95(2):859-73 PMID: 7532191
  32. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac.
    FASEB J. 2004 Jun;18(9):1016-8 PMID: 15059978
  33. Molecular characterization of the tumor microenvironment in breast cancer.
    Cancer Cell. 2004 Jul;6(1):17-32 PMID: 15261139
  34. Fibroblasts in cancer.
    Nat Rev Cancer. 2006 May;6(5):392-401 PMID: 16572188
  35. Transformation by ras modifies AP1 composition and activity.
    Oncogene. 1997 Feb 20;14(7):837-47 PMID: 9047391
  36. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis.
    Cancer Cell. 2004 Nov;6(5):459-69 PMID: 15542430
  37. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.
    J Natl Cancer Inst. 2004 Nov 3;96(21):1593-603 PMID: 15523088
  38. Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential.
    BMC Genomics. 2007 Mar 14;8:73 PMID: 17359542
  39. Stromal cell-derived factor-1alpha promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities.
    Cancer Res. 2004 Apr 1;64(7):2534-43 PMID: 15059909
  40. Stromal gene expression predicts clinical outcome in breast cancer.
    Nat Med. 2008 May;14(5):518-27 PMID: 18438415
  41. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells.
    Cancer Res. 2008 Jun 1;68(11):4331-9 PMID: 18519693
  42. Stromal fibroblasts in cancer initiation and progression.
    Nature. 2004 Nov 18;432(7015):332-7 PMID: 15549095
  43. Pten in stromal fibroblasts suppresses mammary epithelial tumours.
    Nature. 2009 Oct 22;461(7267):1084-91 PMID: 19847259
  44. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability.
    Nature. 2005 Jul 7;436(7047):123-7 PMID: 16001073
  45. NF-kappaB: linking inflammation and immunity to cancer development and progression.
    Nat Rev Immunol. 2005 Oct;5(10):749-59 PMID: 16175180
  46. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.
    Cell. 2006 Jan 27;124(2):263-6 PMID: 16439202
  47. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
    PLoS Biol. 2008 Dec 2;6(12):2853-68 PMID: 19053174
  48. Cancer associated fibroblasts stimulated by transforming growth factor beta1 (TGF-beta 1) increase invasion rate of tumor cells: a population study.
    Breast Cancer Res Treat. 2008 Jul;110(1):39-49 PMID: 17674196
  49. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3.
    Nat Rev Cancer. 2009 Jul;9(7):463-75 PMID: 19536107
  50. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.
    Cancer Res. 1999 Oct 1;59(19):5002-11 PMID: 10519415
  51. Determination of stromal signatures in breast carcinoma.
    PLoS Biol. 2005 Jun;3(6):e187 PMID: 15869330
  52. The myofibroblast: one function, multiple origins.
    Am J Pathol. 2007 Jun;170(6):1807-16 PMID: 17525249
  53. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo.
    Cell. 1987 May 22;49(4):465-75 PMID: 3032456
  54. Microenvironmental regulation of metastasis.
    Nat Rev Cancer. 2009 Apr;9(4):239-52 PMID: 19279573
  55. Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.
    Oncogene. 2005 Dec 15;24(56):8240-51 PMID: 16091733
  56. Stromal induction of breast cancer: inflammation and invasion.
    Rev Endocr Metab Disord. 2007 Sep;8(3):279-87 PMID: 17447144
  57. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
    Nature. 2007 Oct 4;449(7162):557-63 PMID: 17914389
  58. Coevolution of cancer and stromal cellular responses.
    Cancer Cell. 2005 Jun;7(6):499-500 PMID: 15950897
  59. Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy.
    J Clin Oncol. 2007 Oct 1;25(28):4423-30 PMID: 17906205
  60. Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?
    Breast Cancer Res. 2004;6(3):R191-8 PMID: 15084243
  61. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.
    Nat Med. 2009 Jan;15(1):68-74 PMID: 19122658
  62. c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.
    Clin Cancer Res. 2004 Dec 1;10(23):7972-7 PMID: 15585632
  63. Stromal myofibroblasts predict disease recurrence for colorectal cancer.
    Clin Cancer Res. 2007 Apr 1;13(7):2082-90 PMID: 17404090
  64. Hematopoietic origins of fibroblasts: I. In vivo studies of fibroblasts associated with solid tumors.
    Exp Hematol. 2006 Feb;34(2):208-18 PMID: 16459189
  65. Cancer-associated fibroblasts and tumor growth--bystanders turning into key players.
    Curr Opin Genet Dev. 2009 Feb;19(1):67-73 PMID: 19211240
  66. Cancer-related inflammation.
    Nature. 2008 Jul 24;454(7203):436-44 PMID: 18650914
  67. c-MET expression in myofibroblasts: role in autocrine activation and prognostic significance in lung adenocarcinoma.
    Am J Pathol. 2001 Apr;158(4):1451-63 PMID: 11290563
  68. Scavenging of extracellular H2O2 by catalase inhibits the proliferation of HER-2/Neu-transformed rat-1 fibroblasts through the induction of a stress response.
    J Biol Chem. 2001 Mar 23;276(12):9558-64 PMID: 11134000
  69. A global test for groups of genes: testing association with a clinical outcome.
    Bioinformatics. 2004 Jan 1;20(1):93-9 PMID: 14693814
  70. Inflammation and cancer.
    Nature. 2002 Dec 19-26;420(6917):860-7 PMID: 12490959
  71. Regulation of in situ to invasive breast carcinoma transition.
    Cancer Cell. 2008 May;13(5):394-406 PMID: 18455123
  72. Paradoxical roles of the immune system during cancer development.
    Nat Rev Cancer. 2006 Jan;6(1):24-37 PMID: 16397525
  73. JunD reduces tumor angiogenesis by protecting cells from oxidative stress.
    Cell. 2004 Sep 17;118(6):781-94 PMID: 15369676
  74. Collagen density promotes mammary tumor initiation and progression.
    BMC Med. 2008 Apr 28;6:11 PMID: 18442412
  75. The Galpha13-Rho signaling axis is required for SDF-1-induced migration through CXCR4.
    J Biol Chem. 2006 Dec 22;281(51):39542-9 PMID: 17056591
  76. Mechanisms of disease: Fibroblasts--a new look at an old problem.
    Nat Clin Pract Nephrol. 2006 Feb;2(2):101-8 PMID: 16932401
  77. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction.
    Biochem Biophys Res Commun. 2003 Sep 12;309(1):232-40 PMID: 12943687
  78. Epithelial-mesenchymal transition.
    Cancer Res. 2008 Dec 1;68(23):9574-7 PMID: 19047131
  79. The elevated level of CXCR4 is correlated with nodal metastasis of human breast cancer.
    Breast. 2005 Oct;14(5):360-7 PMID: 16216737
  80. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis.
    J Endocrinol Invest. 2008 Sep;31(9):809-19 PMID: 18997494
  81. Putting tumours in context.
    Nat Rev Cancer. 2001 Oct;1(1):46-54 PMID: 11900251
  82. The mammalian Jun proteins: redundancy and specificity.
    Oncogene. 2001 Apr 30;20(19):2378-89 PMID: 11402334
  83. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells.
    Br J Cancer. 2004 Feb 23;90(4):822-32 PMID: 14970860
  84. Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer.
    J Clin Pathol. 2005 Feb;58(2):172-7 PMID: 15677538
  85. Involvement of chemokine receptors in breast cancer metastasis.
    Nature. 2001 Mar 1;410(6824):50-6 PMID: 11242036
  86. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment.
    Am J Pathol. 2007 Nov;171(5):1608-18 PMID: 17916596
  87. A mouse stromal response to tumor invasion predicts prostate and breast cancer patient survival.
    PLoS One. 2006 Dec 20;1:e32 PMID: 17183660
  88. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.
    PLoS Biol. 2004 Feb;2(2):E7 PMID: 14737219
  89. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.
    Nat Genet. 2008 May;40(5):650-5 PMID: 18408720
Article Info
Journal
EMBO molecular medicine
Abbr.
EMBO Mol Med
ISSN
1757-4684
DOI
10.1002/emmm.201000073
Published
2010-06-00
Pages
211-30
Language
English
Region
England
NLM ID
101487380
PMCID
PMC3377319
Subset
IM
External Links
PubMed source DOI: 10.1002/emmm.201000073 PMC Full Text View journal details
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