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Possible involvement of inflammatory/reparative processes in the development of uterine fibroids

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Abstract

Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the “usual leiomyoma”, characterized by overexpression of ECM proteins, whereas the “cellular type” has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via α-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-15, GM-CSF and IFN-γ) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the “usual type”. Inside the fibroid tissue, we found cells positive for α-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the “usual type”, we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the “cellular type”, stromal fibroblasts were CD34-negative. Finally, we found that TNF-α increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth.

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References

  • Arici A, Sozen I (2000) Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 73(5):1006–1011

    Article  CAS  PubMed  Google Scholar 

  • Avritscher R, Iyer RB, Ro J, Whitman G (2001) Lipoleiomyoma of the uterus. Am J Roentgenol 177(4):856

    Article  CAS  Google Scholar 

  • Barth PJ, Ramaswamy A, Moll R (2002) CD34(+) fibrocytes in normal cervical stroma, cervical intraepithelial neoplasia III, and invasive squamous cell carcinoma of the cervix uteri. Virchows Arch 441(6):564–568

    Article  PubMed  Google Scholar 

  • Barth PJ, Westhoff CC (2007) CD34+ fibrocytes: morphology, histogenesis and function. Curr Stem Cell Res Ther 2(3):221–227

    Article  CAS  PubMed  Google Scholar 

  • Bloise E, Cassali GD, Ferreira MC, Ciarmela P, Petraglia F, Reis FM (2010) Activin-related proteins in bovine mammary gland: localization and differential expression during gestational development and differentiation. J Dairy Sci 93(10):4592–4601

    Article  CAS  PubMed  Google Scholar 

  • Buttram VC Jr, Reiter RC (1981) Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 36(4):433–445

    PubMed  Google Scholar 

  • Chegini N (2010) Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder. Semin Reprod Med 28(3):180–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chow MT, Moller A, Smyth MJ (2012) Inflammation and immune surveillance in cancer. Semin Cancer Biol 22(1):23–32

    Article  CAS  PubMed  Google Scholar 

  • Ciarmela P, Bloise E, Gray PC, Carrarelli P, Islam MS, De Pascalis F, Severi FM, Vale W, Castellucci M, Petraglia F (2011a) Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid. J Clin Endocrinol Metab 96(03):755–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarmela P, Carrarelli P, Islam MS, Janjusevic M, Zupi E, Tosti C, Castellucci M, Petraglia F (2014) Ulipristal acetate modulates the expression and functions of activin A in leiomyoma cells. Reprod Sci 21(9):1120–1125

    Article  PubMed  Google Scholar 

  • Ciarmela P, Islam MS, Lammana P, Tranquilli AL, Castellucci M (2012) Healthy and pathological changes of myometrium: pregnant myometrium, uterine fibroids and leiomyosarcoma. Rev Arg Anat Clin 1(4):7–13

    Google Scholar 

  • Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, Vale W, Castellucci M (2011b) Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update 17(6):772–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarmela P, Wiater E, Vale W (2008) Activin-A in myometrium: characterization of the actions on myometrial cells. Endocrinology 149(5):2506–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diaz-Flores L, Gutierrez R, Garcia MP, Saez FJ, Diaz-Flores L Jr, Valladares F, Madrid JF (2014) CD34+ stromal cells/fibroblasts/fibrocytes/telocytes as a tissue reserve and a principal source of mesenchymal cells. Location, morphology, function and role in pathology. Histol Histopathol 29(7):831–870

    CAS  PubMed  Google Scholar 

  • Eldar-Geva T, Meagher S, Healy DL, MacLachlan V, Breheny S, Wood C (1998) Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil Steril 70(4):687–691

    Article  CAS  PubMed  Google Scholar 

  • Erdag G, Qureshi HS, Patterson JW, Wick MR (2007) Solitary fibrous tumors of the skin: a clinicopathologic study of 10 cases and review of the literature. J Cutan Pathol 34(11):844–850

    Article  PubMed  Google Scholar 

  • Eyden B (2008) The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J Cell Mol Med 12(1):22–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ezugwu EC, Iyoke CA, Ezugwu FO, Ugwu G (2014) Successful pregnancy following myomectomy for giant uterine fibroid in an infertile woman. J Reprod Infertil 15(4):233–236

    PubMed  PubMed Central  Google Scholar 

  • Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 178(8):5288–5295

    Article  CAS  PubMed  Google Scholar 

  • Ferreira MC, Cavallo IK, Florio P, Petraglia F, Reis FM (2008) Activin betaA subunit, follistatin and follistatin-like 3 are expressed in the endometrium of ovariectomized rats and regulated by estrogen replacement. J Mol Histol 39(5):535–541

    Article  CAS  PubMed  Google Scholar 

  • Flake GP, Moore AB, Sutton D, Kissling GE, Horton J, Wicker B, Walmer D, Robboy SJ, Dixon D (2013) The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation. Obstet Gynecol Int 2013:528376

    PubMed  PubMed Central  Google Scholar 

  • Friedman AJ, Harrison-Atlas D, Barbieri RL, Benacerraf B, Gleason R, Schiff I (1989) A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril 51(2):251–256

    CAS  PubMed  Google Scholar 

  • Fujita M (1985) Histological and biochemical studies of collagen in human uterine leiomyomas. Hokkaido Igaky Zasshi 60(4):602–615

    CAS  Google Scholar 

  • Gelse K, Poschl E, Aigner T (2003) Collagens--structure, function, and biosynthesis. Adv Drug Deliv Rev 55(12):1531–1546

    Article  CAS  PubMed  Google Scholar 

  • Haller ST, Kennedy DJ, Shidyak A, Budny GV, Malhotra D, Fedorova OV, Shapiro JI, Bagrov AY (2012) Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. Am J Hypertens 25(6):690–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinz B (2007) Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 127(3):526–537

    Article  CAS  PubMed  Google Scholar 

  • Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170(6):1807–1816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, De Wever O, Mareel M, Gabbiani G (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180(4):1340–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91

    Article  CAS  PubMed  Google Scholar 

  • Hubner G, Werner S (1996) Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes. Exp Cell Res 228(1):106–113

    Article  CAS  PubMed  Google Scholar 

  • Islam MS, Catherino WH, Protic O, Janjusevic M, Gray PC, Giannubilo SR, Ciavattini A, Lamanna P, Tranquilli AL, Petraglia F, Castellucci M, Ciarmela P (2014) Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. J Clin Endocrinol Metab:jc20132623

  • Islam MS, Protic O, Giannubilo SR, Toti P, Tranquilli AL, Petraglia F, Castellucci M, Ciarmela P (2013a) Uterine leiomyoma: available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab 98(3):921–934

    Article  CAS  PubMed  Google Scholar 

  • Islam MS, Protic O, Stortoni P, Grechi G, Lamanna P, Petraglia F, Castellucci M, Ciarmela P (2013b) Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil Steril 100(1):178–193

    Article  CAS  PubMed  Google Scholar 

  • Karmon AE, Cardozo ER, Rueda BR, Styer AK (2014) MicroRNAs in the development and pathobiology of uterine leiomyomata: does evidence support future strategies for clinical intervention? Hum Reprod Update 20(5):670–687

    Article  CAS  PubMed  Google Scholar 

  • Kisseleva T, Brenner DA (2008) Mechanisms of fibrogenesis. Exp Biol Med (Maywood) 233(2):109–122

    Article  CAS  Google Scholar 

  • Leppert PC, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH (2004) Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril 82(Suppl 3):1182–1187

    Article  PubMed  PubMed Central  Google Scholar 

  • Leppert PC, Catherino WH, Segars JH (2006) A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays. Am J Obstet Gynecol 195(2):415–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ligon AH, Morton CC (2000) Genetics of uterine leiomyomata. Gene Chromosomes Cancer 28(3):235–245

    Article  CAS  Google Scholar 

  • Lindenmayer AE, Miettinen M (1995) Immunophenotypic features of uterine stromal cells. CD34 expression in endocervical stroma. Virchows Arch 426(5):457–460

    Article  CAS  PubMed  Google Scholar 

  • Luna LG (1968) Manual of Histologic staining methods of the Armed Forces Institute of Pathology: Blakiston Division. McGraw-Hill, New York

  • Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino WH (2010) Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women. Semin Reprod Med 28(3):169–179

    Article  PubMed  Google Scholar 

  • Malik M, Webb J, Catherino WH (2008) Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells. Clin Endocrinol (Oxf) 69(3):462–470

    Article  CAS  Google Scholar 

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686

    Article  CAS  PubMed  Google Scholar 

  • Mashal RD, Fejzo ML, Friedman AJ, Mitchner N, Nowak RA, Rein MS, Morton CC, Sklar J (1994) Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata. Gene Chromosomes Cancer 11(1):1–6

    Article  CAS  Google Scholar 

  • Nielsen JS, McNagny KM (2008) Novel functions of the CD34 family. J Cell Sci 121(Pt 22):3683–3692

    Article  CAS  PubMed  Google Scholar 

  • Norian JM, Malik M, Parker CY, Joseph D, Leppert PC, Segars JH, Catherino WH (2009) Transforming growth factor beta3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reprod Sci 16(12):1153–1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okolo S (2008) Incidence, aetiology and epidemiology of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 22(4):571–588

    Article  PubMed  Google Scholar 

  • Petraglia F, Woodruff TK, Botticelli G, Botticelli A, Genazzani AR, Mayo KE, Vale W (1992) Gonadotropin-releasing hormone, inhibin, and activin in human placenta: evidence for a common cellular localization. J Clin Endocrinol Metab 74(5):1184–1188

    CAS  PubMed  Google Scholar 

  • Rosai (2011) Rosai and Ackerman’s Surgical Pathology, 10th edn. Mosby, Edinburgh, pp 1508–1513

  • Sarrazy V, Billet F, Micallef L, Coulomb B, Desmoulière A (2011) Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair Regen 19(s1):s10–s15

    Article  PubMed  Google Scholar 

  • Shao L, Frigon NL Jr, Sehy DW, Yu AL, Lofgren J, Schwall R, Yu J (1992) Regulation of production of activin A in human marrow stromal cells and monocytes. Exp Hematol 20(10):1235–1242

    CAS  PubMed  Google Scholar 

  • Shao LE, Frigon NL Jr, Yu A, Palyash J, Yu J (1998) Contrasting effects of inflammatory cytokines and glucocorticoids on the production of activin A in human marrow stromal cells and their implications. Cytokine 10(3):227–235

    Article  CAS  PubMed  Google Scholar 

  • Sierra-Filardi E, Puig-Kroger A, Blanco FJ, Nieto C, Bragado R, Palomero MI, Bernabeu C, Vega MA, Corbi AL (2011) Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood 117(19):5092–5101

    Article  CAS  PubMed  Google Scholar 

  • Skalli O, Ropraz P, Trzeciak A, Benzonana G, Gillessen D, Gabbiani G (1986) A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol 103(6):2787–2796

    Article  CAS  PubMed  Google Scholar 

  • Stewart EA, Friedman AJ, Peck K, Nowak RA (1994) Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab 79(3):900–906

    CAS  PubMed  Google Scholar 

  • Strauss LC, Skubitz KM, August JT, Civin CI (1984) Antigenic analysis of hematopoiesis: II. Expression of human neutrophil antigens on normal and leukemic marrow cells. Blood 63(3):574–578

    CAS  PubMed  Google Scholar 

  • Takahashi S, Uchimaru K, Harigaya K, Asano S, Yamashita T (1992) Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line. Biochem Biophys Res Commun 188(1):310–317

    Article  CAS  PubMed  Google Scholar 

  • Tavassoli FADP (2003) Pathology and Genetics of Tumors of the Breast and female Genital Organs. IARC, Lyon

  • Toledo G, Oliva E (2008) Smooth muscle tumors of the uterus: a practical approach. Arch Pathol Lab Med 132(4):595–605

    PubMed  Google Scholar 

  • Truong LD, Rangdaeng S, Cagle P, Ro JY, Hawkins H, Font RL (1990) The diagnostic utility of desmin. A study of 584 cases and review of the literature. Am J Clin Pathol 93(3):305–314

    Article  CAS  PubMed  Google Scholar 

  • Wallach EE, Vlahos NF (2004) Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 104(2):393–406

    Article  PubMed  Google Scholar 

  • Werner S, Alzheimer C (2006) Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine Growth Factor Rev 17(3):157–171

    Article  CAS  PubMed  Google Scholar 

  • Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30(3):245–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaragosi LE, Wdziekonski B, Villageois P, Keophiphath M, Maumus M, Tchkonia T, Bourlier V, Mohsen-Kanson T, Ladoux A, Elabd C, Scheideler M, Trajanoski Z, Takashima Y, Amri EZ, Lacasa D, Sengenes C, Ailhaud G, Clement K, Bouloumie A, Kirkland JL, Dani C (2010) Activin a plays a critical role in proliferation and differentiation of human adipose progenitors. Diabetes 59(10):2513–2521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

O.P. and M.J. are recipients of a fellowship from the Polytechnic University of Marche, reserved for PhD students coming from universities of the UNIADRION, a network of universities established with the purpose of creating a permanent connection among universities and research centers from the Adriatic-Ionian Region (Italy). M.S.I. is recipient of a fellowship from the Polytechnic University of Marche, reserved for PhD students from non-EU countries. We thank Dr. Francesco Piva (Bio-engineer, Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, Italy) for his valuable help to perform statistical data analysis.

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Authors and Affiliations

  1. Department of Experimental and Clinical Medicine, Faculty of Medicine, Polytechnic University of Marche, via Tronto 10/a, 60020, Ancona, Italy

    Olga Protic, Md Soriful Islam, Saverio Cinti, Mario Castellucci & Pasquapina Ciarmela

  2. Department of Medical Biotechnology, University of Siena, 53100, Siena, Italy

    Paolo Toti & Rossella Occhini

  3. Biotechnology and Microbiology Laboratory, Department of Botany, University of Rajshahi, Rajshahi, 6205, Bangladesh

    Md Soriful Islam

  4. Department of Clinical Science, Polytechnic University of Marche, 60131, Ancona, Italy

    Stefano Raffaele Giannubilo & Andrea Ciavattini

  5. Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814, USA

    William H. Catherino

  6. Center of Obesity, Polytechnic University of Marche – United Hospitals, Ancona, Italy

    Saverio Cinti

  7. Department of Molecular and Developmental Medicine, Obstetrics, and Gynecology, University of Siena, 53100, Siena, Italy

    Felice Petraglia

  8. Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, M5S 3E2, Canada

    Boris Hinz

  9. Department of Information Engineering, Polytechnic University of Marche, Ancona, Italy

    Pasquapina Ciarmela

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  1. Olga Protic
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  2. Paolo Toti
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  3. Md Soriful Islam
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  4. Rossella Occhini
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  5. Stefano Raffaele Giannubilo
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  6. William H. Catherino
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  7. Saverio Cinti
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  8. Felice Petraglia
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  9. Andrea Ciavattini
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  10. Mario Castellucci
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  11. Boris Hinz
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  12. Pasquapina Ciarmela
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Corresponding authors

Correspondence to Mario Castellucci or Pasquapina Ciarmela.

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Funding

This work was supported by the “Fondazione Cassa di Risparmio di Fabriano e Cupramontana” (to M.C. and P.C.) and by the Italian Ministry of University and Research (PRIN 2010–2011, No. 20102CHST5_007, to S.R.G.). B.H is funded by grants from the Canadian Institutes of Health Research (#210820, #286720, #286920, #497202).

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Protic, O., Toti, P., Islam, M.S. et al. Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. Cell Tissue Res 364, 415–427 (2016). https://doi.org/10.1007/s00441-015-2324-3

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