interacted with inflammatory cells and stimulated by enriched milieu of pro-inflammatory mediators, specifically IL-6, and then acquired a benign tumor-like stem cell phenotype characterized by moderately increased telomerase activity, and consequently, an increased proliferative capacity, whereby the increased IL-17 continuously drives this process by augmenting the production of IL-6 by KPCs, thus leading to the overgrowth of keloid benign tumor. References 1. Niessen FB, Spauwen PHM, Schalkwijk J, Moshe K (1999) On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg 104: 1435–1458. 2. Kelly AP (2004) Medical and surgical therapies for keloids. Dermatol Ther 17: 212–218. 3. Ketchum LD, Robinson DW, Masters FW (1971) Follow-up on treatment of hypertrophic scars and keloids with triamcinolone. Plast Reconstr Surg 48: 256–259. 4. Lee JY, Yang CC, Chao SC, Wong TW (2004) Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol 26: 379–384. 5. Xue H, McCauley RL, Zhang W (2000) Elevated interleukin-6 expression in keloid fibroblasts. J Surg Res 89: 74–77. 6. Ghazizadeh M, Tosa M, Shimizu H, Hyakusoku H, Kawanami O (2007) Functional implications of the IL-6 signaling pathway in keloid pathogenesis. J Invest Dermatol 127: 98–105. 7. Akino K, Akita S, Yakabe A, Mineda T, Hayashi T, et al. (2008) Human mesenchymal stem cells may be involved in keloid pathogenesis. Int J Dermatol 47: 1112–1117. 8. Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21: 605–631. 9. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4: 7–25. 10. Kolf CM, Cho E, Tuan RS (2007) Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 9: 204. 11. Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441: 1075–1079. 12. Li LH, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66: 4553–4557. 13. Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311: 1880–1885. 14. Xie T, Li LH (2007) Stem cells and their niche: an inseparable relationship. Development 134: 2001–2006. 15. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H (1987) Interferon b2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 84: 7251–7255. 16. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, et al. (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368: 339–342. 17. Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C (2003) IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 24: 25–29. 18. Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8: 1–6. 19. Tan P, Farmiloe S, Yeoman S, Watson J (1990) Expresssion of IL-6 gene in rheumatoid synovial fibroblasts. J Rheumatol 17: 1608–1612. 20. Feghali CA, Bost KL, Bouware DW, Levy LS (1994) Control of IL-6 expression and response in fibroblasts from patients with systemic sclerosis. Autoimmunity 17: 309–318. 21. Xu G, Zhang Y, Zhang L, Ren G, Shi Y (2007) The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. Biochem Biophys Res Commun 361: 745–750. 22. Kovacevic´-Filipovic´ M, Petakov M, Hermitte F, Debeissat C, Krstic´ A, et al. (2007) Interleukin-6 (IL-6) and low O2 concentration (1%) synergize to improve the maintenance of hematopoietic stem cells (Pre-CFC). J Cell Physiol 212: 68–75. 23. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, et al. (2009) gp130-mediated stat-3 activation in enterocytes regulates cell survival and cell- cycle progression during colitis-associated tumorigenesis. Cancer Cell 15: 91–102. 24. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, et al. (2009) Il-6 and Stat- 3 are required for survival of intestinal epithelial cells and development of colitis- associated cancer. Cancer Cell 15: 103–113. 25. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, et al. (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117: 3988–4002. 26. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, et al. (2002) Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res 62: 3876–3882. Niche-Driven Overgrowth of KPC Found at: doi:10.1371/journal.pone.0007798.s011 (0.87 DOC) MB Author Contributions Conceived and designed the experiments: QZ TY SS AL. Performed the experiments: QZ TY SS LW. Analyzed the data: QZ TY SWF SS AL. Contributed reagents/materials/analysis tools: APK SW JB. Wrote the paper: QZ SS AL. Provide patient samples: AK. 27. Yamagiwa Y, Meng FY, Patel T (2006) Interleutin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci 78: 2494–2502. 28. Lee HW, Blasco MA, Gottlieb GJ, Horner JW 2nd, Greider CW, et al. (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392: 569–574. 29. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, et al. (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701–712. 30. Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309: 1253–1256. 31. Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, et al. (2005) Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436: 1048–1052. 32. Harrinton LE, Hatton RD, Mangan PR, Turner H, Murphy TL, et al. (2005) Interleukin-17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6: 1123–1132. 33. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441: 235–238. 34. Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T (H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9: 641–649. 35. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of TH17 cells. Nature 453: 1051–1057. 36. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, et al. (2008) IL-21 and TGF-beta are required for differentiation of human T (H)17 cells. Nature 454: 350–352. 37. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe´ P, et al. (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflamma- tory cytokines in driving and modulating human T (H)-17 responses. Nat Immunol 9: 650–657. 38. Nakae S, Saijo S, Horai R, Sudo K, Mori S, et al. (2003) IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA 100: 5986–5990. 39. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, et al. (2003) Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198: 1951–1957. 40. Lubberts E, Koenders MI, van den Berg WB (2005) The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 7: 29–37. 41. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, et al. (2003) Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52: 65–70. 42. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, et al. (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. J Immunol 155: 811–821. 43. Aggarwal S, Gurney AL (2002) IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71: 1–8. 44. Hwang S-Y, Kim JY, Kim KW, Park MK, Moon Y, et al. (2004) IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NKkB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther 6: R120–R128. 45. Ruddy MJ, Wong GC, Liu XK, Yamamoto H, Kasayama S, et al. (2004) Functional cooperation between interleukin-17 and tumor necrosis factor-a is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 279: 2559–2567. 46. Huang F, Kao C-Y, Wachi S, Thai P, Ryu J, et al. (2007) Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. J Immunol 179: 6504–6513. 47. Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam K, et al. (2007) Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NKkB and C/ EBP b activation. J Biol Chem 282: 27229–27238. 48. Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, et al. (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160: 3513–3521. PLoS ONE | www.plosone.org 15 November 2009 | Volume 4 | Issue 11 | e7798