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Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

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Cancer Microenvironment

Abstract

Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a ‘wound that never heals’. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

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References

  1. Lopez-Novoa JM, Nieto MA (2009) Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 1:303–314. doi:10.1002/emmm.200900043

    Article  PubMed  CAS  Google Scholar 

  2. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444. doi:10.1038/nature07205

    Article  PubMed  CAS  Google Scholar 

  3. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26:711–724. doi:10.1038/sj.onc.1209808

    Article  PubMed  CAS  Google Scholar 

  4. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F et al (2007) Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26:7445–7456. doi:10.1038/sj.onc.1210546

    Article  PubMed  CAS  Google Scholar 

  5. Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101:816–829. doi:10.1002/jcb.21215

    Article  PubMed  CAS  Google Scholar 

  6. Dvorakova K, Payne CM, Ramsey L, Holubec H, Sampliner R, Dominguez J et al (2004) Increased expression and secretion of interleukin-6 in patients with Barrett’s esophagus. Clin Cancer Res 10:2020–2028

    Article  PubMed  CAS  Google Scholar 

  7. Ekbom A, Helmick C, Zack M, Adami HO (1990) Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet 336:357–359

    Article  PubMed  CAS  Google Scholar 

  8. Kai H, Kitadai Y, Kodama M, Cho S, Kuroda T, Ito M et al (2005) Involvement of proinflammatory cytokines IL-1beta and IL-6 in progression of human gastric carcinoma. Anticancer Res 25:709–713

    PubMed  CAS  Google Scholar 

  9. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG et al (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140:197–208. doi:10.1016/j.cell.2009.12.052

    Article  PubMed  CAS  Google Scholar 

  10. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659. doi:10.1056/NEJM198612253152606

    Article  PubMed  CAS  Google Scholar 

  11. Hibi M, Nakajima K, Hirano T (1996) IL-6 cytokine family and signal transduction: a model of the cytokine system. J Mol Med 74:1–12

    Article  PubMed  CAS  Google Scholar 

  12. Jazayeri JA, Carroll GJ, Vernallis AB (2010) Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists. Int Immunopharmacol 10:1–8. doi:10.1016/j.intimp.2009.09.019

    Article  PubMed  CAS  Google Scholar 

  13. Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9:351–369. doi:10.1016/j.coph.2009.06.020

    Article  PubMed  CAS  Google Scholar 

  14. Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD (2009) IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 183:3170–3176. doi:10.4049/jimmunol.0803721

    Article  PubMed  CAS  Google Scholar 

  15. Lebret SC, Newgreen DF, Thompson EW, Ackland ML (2007) Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors. Breast Cancer Res 9:R19. doi:10.1186/bcr1656

    Article  PubMed  Google Scholar 

  16. Lebret SC, Newgreen DF, Waltham MC, Price JT, Thompson EW, Ackland ML (2006) Myoepithelial molecular markers in human breast carcinoma PMC42-LA cells are induced by extracellular matrix and stromal cells. In Vitro Cell Dev Biol Anim 42:298–307. doi:10.1290/0601004.1

    PubMed  CAS  Google Scholar 

  17. Thompson EW, Paik S, Brunner N, Sommers CL, Zugmaier G, Clarke R et al (1992) Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 150:534–544. doi:10.1002/jcp.1041500314

    Article  PubMed  CAS  Google Scholar 

  18. McAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28:4022–4028. doi:10.1200/JCO.2010.28.4257

    Article  PubMed  Google Scholar 

  19. Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ (2003) Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst 48:82–84

    PubMed  CAS  Google Scholar 

  20. Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E et al (2003) Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 103:642–646. doi:10.1002/ijc.10833

    Article  PubMed  CAS  Google Scholar 

  21. Zhang GJ, Adachi I (1999) Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 19:1427–1432

    PubMed  CAS  Google Scholar 

  22. Asgeirsson KS, Olafsdottir K, Jonasson JG, Ogmundsdottir HM (1998) The effects of IL-6 on cell adhesion and e-cadherin expression in breast cancer. Cytokine 10:720–728. doi:10.1006/cyto.1998.0349

    Article  PubMed  CAS  Google Scholar 

  23. Hussein MZ, Al Fikky A, Abdel Bar I, Attia O (2004) Serum IL-6 and IL-12 levels in breast cancer patients. Egypt J Immunol 11:165–170

    PubMed  Google Scholar 

  24. Arihiro K, Oda H, Kaneko M, Inai K (2000) Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer 7:221–230

    Article  PubMed  CAS  Google Scholar 

  25. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28:2940–2947. doi:10.1038/onc.2009.180

    Article  PubMed  CAS  Google Scholar 

  26. Hugo HJ, Kokkinos MI, Blick T, Ackland ML, Thompson EW, Newgreen DF (2010) Defining the E-cadherin repressor interactome in epithelial-mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs 193:23–40. doi:10.1159/000320174

    Article  PubMed  Google Scholar 

  27. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED et al (2007) Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383. doi:10.1002/jcp.21223

    Article  PubMed  CAS  Google Scholar 

  28. Groppo R, Richter JD (2011) CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence. Mol Cell Biol 31:2707–2714. doi:10.1128/MCB.05133-11

    Article  PubMed  CAS  Google Scholar 

  29. Neveu WA, Bernardo E, Allard JL, Nagaleekar V, Wargo MJ, Davis RJ et al (2011) Fungal Allergen {beta}-glucans Trigger p38 MAPK-mediated IL-6 Translation in Lung Epithelial Cells. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2011-0054OC

  30. Van Camp B, Van Riet I (1998) Homing mechanisms in the biology of multiple myeloma. Verh K Acad Geneeskd Belg 60:163–194

    PubMed  Google Scholar 

  31. Ribatti D, Crivellato E (2009) The controversial role of mast cells in tumor growth. Int Rev Cell Mol Biol 275:89–131. doi:10.1016/S1937-6448(09)75004-X

    Article  PubMed  CAS  Google Scholar 

  32. Amini RM, Aaltonen K, Nevanlinna H, Carvalho R, Salonen L, Heikkila P et al (2007) Mast cells and eosinophils in invasive breast carcinoma. BMC Cancer 7:165. doi:10.1186/1471-2407-7-165

    Article  PubMed  Google Scholar 

  33. Dabiri S, Huntsman D, Makretsov N, Cheang M, Gilks B, Bajdik C et al (2004) The presence of stromal mast cells identifies a subset of invasive breast cancers with a favorable prognosis. Mod Pathol 17:690–695. doi:10.1038/modpathol.3800094

    Article  PubMed  Google Scholar 

  34. Samoszuk M, Kanakubo E, Chan JK (2005) Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts. BMC Cancer 5:121. doi:10.1186/1471-2407-5-121

    Article  PubMed  Google Scholar 

  35. Maltby S, Khazaie K, McNagny KM (2009) Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 1796:19–26. doi:10.1016/j.bbcan.2009.02.001

    PubMed  CAS  Google Scholar 

  36. Burd PR, Rogers HW, Gordon JR, Martin CA, Jayaraman S, Wilson SD et al (1989) Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med 170:245–257

    Article  PubMed  CAS  Google Scholar 

  37. Hultner L, Szots H, Welle M, Van Snick J, Moeller J, Dormer P (1989) Mouse bone marrow-derived IL-3-dependent mast cells and autonomous sublines produce IL-6. Immunology 67:408–413

    PubMed  CAS  Google Scholar 

  38. Gyotoku E, Morita E, Kameyoshi Y, Hiragun T, Yamamoto S, Hide M (2001) The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice. Arch Dermatol Res 293:508–514

    Article  PubMed  CAS  Google Scholar 

  39. Fitzgerald SM, Lee SA, Hall HK, Chi DS, Krishnaswamy G (2004) Human lung fibroblasts express interleukin-6 in response to signaling after mast cell contact. Am J Respir Cell Mol Biol 30:585–593. doi:10.1165/rcmb.2003-0282OC

    Article  PubMed  CAS  Google Scholar 

  40. Hu ZQ, Zhao WH, Shimamura T (2007) Regulation of mast cell development by inflammatory factors. Curr Med Chem 14:3044–3050

    Article  PubMed  CAS  Google Scholar 

  41. Dabbous MK, North SM, Haney L, Tipton DA, Nicolson GL (1995) Effects of mast cell-macrophage interactions on the production of collagenolytic enzymes by metastatic tumor cells and tumor-derived and stromal fibroblasts. Clin Exp Metastasis 13:33–41

    Article  PubMed  CAS  Google Scholar 

  42. Ch’ng S, Wallis RA, Yuan L, Davis PF, Tan ST (2006) Mast cells and cutaneous malignancies. Mod Pathol 19:149–159. doi:10.1038/modpathol.3800474

    Article  PubMed  Google Scholar 

  43. Harvima IT, Nilsson G, Naukkarinen A (2010) Role of mast cells and sensory nerves in skin inflammation. G Ital Dermatol Venereol 145:195–204

    PubMed  CAS  Google Scholar 

  44. Boersma BJ, Reimers M, Yi M, Ludwig JA, Luke BT, Stephens RM et al (2008) A stromal gene signature associated with inflammatory breast cancer. Int J Cancer 122:1324–1332. doi:10.1002/ijc.23237

    Article  PubMed  CAS  Google Scholar 

  45. Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM et al (2008) Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis 25:629–642. doi:10.1007/s10585-008-9170-6

    Article  PubMed  CAS  Google Scholar 

  46. D’Anello L, Sansone P, Storci G, Mitrugno V, D'Uva G, Chieco P et al (2010) Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells. Mol Cancer 9:300. doi:10.1186/1476-4598-9-300

    Article  PubMed  Google Scholar 

  47. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL et al (2007) Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117:3846–3856. doi:10.1172/JCI31871

    Article  PubMed  CAS  Google Scholar 

  48. Schlaepfer DD, Hou S, Lim ST, Tomar A, Yu H, Lim Y et al (2007) Tumor necrosis factor-alpha stimulates focal adhesion kinase activity required for mitogen-activated kinase-associated interleukin 6 expression. J Biol Chem 282:17450–17459. doi:10.1074/jbc.M610672200

    Article  PubMed  CAS  Google Scholar 

  49. Edwards ST, Cruz AC, Donnelly S, Dazin PF, Schulman ES, Jones KD et al (2005) c-Kit immunophenotyping and metalloproteinase expression profiles of mast cells in interstitial lung diseases. J Pathol 206:279–290. doi:10.1002/path.1780

    Article  PubMed  CAS  Google Scholar 

  50. Hirabayashi Y, Ishii T, Harigae H (2010) Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice. Rheumatol Int 30:1041–1048. doi:10.1007/s00296-009-1095-0

    Article  PubMed  CAS  Google Scholar 

  51. Singh JA, Beg S, Lopez-Olivo MA (2010) Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev 7:CD008331. doi:10.1002/14651858.CD008331.pub2

    PubMed  Google Scholar 

  52. Brietzke E, Scheinberg M, Lafer B (2010) Therapeutic potential of interleukin-6 antagonism in bipolar disorder. Med Hypotheses. doi:10.1016/j.mehy.2010.08.021

  53. Nishimoto N (2010) Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther 87:483–487. doi:10.1038/clpt.2009.313

    Article  PubMed  CAS  Google Scholar 

  54. Fulciniti M, Hideshima T, Vermot-Desroches C, Pozzi S, Nanjappa P, Shen Z et al (2009) A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res 15:7144–7152. doi:10.1158/1078-0432.CCR-09-1483

    Article  PubMed  CAS  Google Scholar 

  55. Karkera J, Steiner H, Li W, Skradski V, Moser PL, Riethdorf S et al (2011) The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate. doi:10.1002/pros.21362

  56. Rossi JF, Negrier S, James ND, Kocak I, Hawkins R, Davis H et al (2011) A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer 103:1154–1162. doi:10.1038/sj.bjc.6605872

    Article  Google Scholar 

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Acknowledgements

The research efforts associated with this article were funded in part by the U.S. Army Medical Research and Materiel Command (BC0213201 and BC084667), the Victorian Breast Cancer Research Consortium, and the National Breast Cancer Foundation (Australia). We thank Dr. Geoff Lindeman (Walter and Eliza Hall Institute, Melbourne, Australia) for supplying us with the additional NMF populations (B6RA1H and F127H), and Geraldine Mitchell and Keren Abberton (O’Brien Institute, Melbourne, Australia) for help with mast cell identification.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. St Vincent’s Institute of Medical Research, Fitzroy, Australia

    Honor J. Hugo, Eva Tomaskovic-Crook, Tony Blick & Erik W. Thompson

  2. Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood Campus, Burwood, Australia

    Stephanie Lebret & M. Leigh Ackland

  3. Women’s Cancer Research Centre, Royal Women’s Hospital, Parkville, Australia

    Nuzhat Ahmed

  4. Department of Obstetrics & Gynaecology, University of Melbourne, Parkville, Australia

    Nuzhat Ahmed

  5. Department of Surgery, St Vincent’s Hospital, University of Melbourne, Fitzroy, Australia

    Erik W. Thompson

  6. Embryology Laboratory, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Australia

    Donald F. Newgreen

  7. VBCRC Invasion and Metastasis Unit, St Vincent’s Institute, 9 Princes St, Fitzroy, 3065, Victoria, Australia

    Honor J. Hugo

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  1. Honor J. Hugo
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  2. Stephanie Lebret
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  3. Eva Tomaskovic-Crook
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  8. M. Leigh Ackland
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Correspondence to Honor J. Hugo.

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Erik W. Thompson and M. Leigh Ackland contributed equally

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Hugo, H.J., Lebret, S., Tomaskovic-Crook, E. et al. Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment. Cancer Microenvironment 5, 83–93 (2012). https://doi.org/10.1007/s12307-012-0098-7

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