Why Leiomyomas Are Called Fibroids: The Central Role of Extracellular Matrix in Symptomatic Women

Minnie Malik; John Norian; Desirée McCarthy-Keith; Joy Britten; William H Catherino

doi:10.1055/s-0030-1251475

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2010; 28(3): 169-179
DOI: 10.1055/s-0030-1251475

Published in 2010 by Thieme Medical Publishers

Why Leiomyomas Are Called Fibroids: The Central Role of Extracellular Matrix in Symptomatic Women

Minnie Malik¹ , John Norian¹ ^, ² , Desirée McCarthy-Keith¹ ^, ² , Joy Britten¹ , William H. Catherino¹ ^, ²

¹Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
²Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland

Abstract

ABSTRACT

Uterine leiomyomas are highly prevalent and symptomatic tumors of women in their reproductive years. The morbidity caused by these tumors is directly related to increasing size. Leiomyoma cells do not rapidly proliferate; instead, the tumors grow primarily due to excessive production of disorganized extracellular matrix (ECM). The aberrant ECM results from excessive production of collagen subtypes and proteoglycans, increased profibrotic cytokines including transforming growth factors β1 and β3, and decreased or disrupted matrix metalloproteinases. These alterations result in the development of an ECM that is exceptionally stable. As a result, therapeutic interventions must redirect leiomyoma cells toward extracellular matrix dissolution, rather than solely inhibiting cell proliferation. Gonadotropin-releasing hormone analogues and selective progesterone receptor modulators with demonstrated clinical efficacy provide such a change in abnormal extracellular matrix formation by leiomyoma cells, inhibiting and reversing the fibrotic process. Novel therapies using pathways distinct from gonadal hormones, including antifibrotics, retinoic acid, peroxisome-proliferator-activated receptor γ ligands, and curcumin, provide promise for a future with improved therapeutic options for women suffering from uterine leiomyomas.

KEYWORDS

Uterine leiomyoma - extracellular matrix - collagen - proteoglycan - transforming growth factor (TGF)

Full Text

References

REFERENCES

1 Selo-Ojeme D, Lawal O, Shah J et al.. The incidence of uterine leiomyoma and other pelvic ultrasonographic findings in 2,034 consecutive women in a north London hospital. J Obstet Gynaecol. 2008; 28(4) 421-423
2 Borgfeldt C, Andolf E. Transvaginal ultrasonographic findings in the uterus and the endometrium: low prevalence of leiomyoma in a random sample of women age 25–40 years. Acta Obstet Gynecol Scand. 2000; 79(3) 202-207
3 Marino J L, Eskenazi B, Warner M et al.. Uterine leiomyoma and menstrual cycle characteristics in a population-based cohort study. Hum Reprod. 2004; 19(10) 2350-2355
4 Eskenazi B, Warner M, Samuels S et al.. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study. Am J Epidemiol. 2007; 166(1) 79-87
5 Baird D D, Dunson D B, Hill M C, Cousins D, Schectman J M. Association of physical activity with development of uterine leiomyoma. Am J Epidemiol. 2007; 165(2) 157-163
6 Day Baird D, Dunson D B, Hill M C, Cousins D, Schectman J M. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003; 188(1) 100-107
7 Chen C R, Buck G M, Courey N G, Perez K M, Wactawski-Wende J. Risk factors for uterine fibroids among women undergoing tubal sterilization. Am J Epidemiol. 2001; 153(1) 20-26
8 Kjerulff K H, Langenberg P, Seidman J D, Stolley P D, Guzinski G M. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med. 1996; 41(7) 483-490
9 Peddada S D, Laughlin S K, Miner K et al.. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci U S A. 2008; 105(50) 19887-19892
10 Pron G, Cohen M, Soucie J et al.. The Ontario Uterine Fibroid Embolization Trial. Part 1. Baseline patient characteristics, fibroid burden, and impact on life. Fertil Steril. 2003; 79 112-119
11 Buttram Jr V C, Reiter R C. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981; 36(4) 433-445
12 Olufowobi O, Sharif K, Papaionnou S, Neelakantan D, Mohammed H, Afnan M. Are the anticipated benefits of myomectomy achieved in women of reproductive age? A 5-year review of the results at a UK tertiary hospital. J Obstet Gynaecol. 2004; 24(4) 434-440
13 Pritts E A, Parker W H, Olive D L. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009; 91 1215-1223
14 Bulletti C, DE Ziegler D, Levi Setti P, Cicinelli E, Polli V, Stefanetti M. Myomas, pregnancy outcome, and in vitro fertilization. Ann N Y Acad Sci. 2004; 1034 84-92
15 Qidwai G I, Caughey A B, Jacoby A F. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006; 107(2 Pt 1) 376-382
16 Sheiner E, Bashiri A, Levy A, Hershkovitz R, Katz M, Mazor M. Obstetric characteristics and perinatal outcome of pregnancies with uterine leiomyomas. J Reprod Med. 2004; 49(3) 182-186
17 Szamatowicz J, Laudanski T, Bulkszas B, Akerlund M. Fibromyomas and uterine contractions. Acta Obstet Gynecol Scand. 1997; 76(10) 973-976
18 Salvig J D, Petersen K R, Møller B R. Acute abdominal pain caused by torsion of an enlarged non-pregnant uterus. J Obstet Gynaecol. 2005; 25(1) 81-82
19 Ilbey O, Apaydin E, Gürsan A, Cikili N. Bladder leiomyoma: a rare cause of urinary stress incontinence. Arch Ital Urol Androl. 2000; 72(2) 85-87
20 Catherino W H, Leppert P C, Stenmark M H et al.. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes Chromosomes Cancer. 2004; 40(3) 204-217
21 Leppert P C, Baginski T, Prupas C, Catherino W H, Pletcher S, Segars J H. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril. 2004; 82(suppl 3) 1182-1187
22 Kramar C, Baud C A, Lagier R. Presumed calcified leiomyoma of the uterus. Morphologic and chemical studies of a calcified mass dating from the Neolithic period. Arch Pathol Lab Med. 1983; 107(2) 91-93
23 Wolańska M, Sobolewski K, Drozdzewicz M, Bańkowski E. Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth. Mol Cell Biochem. 1998; 189(1-2) 145-152
24 Berto A G, Oba S M, Michelacci Y M, Sampaio L O. Galactosaminoglycans from normal myometrium and leiomyoma. Braz J Med Biol Res. 2001; 34(5) 633-637
25 Berto A G, Sampaio L O, Franco C R, Cesar Jr R M, Michelacci Y M. A comparative analysis of structure and spatial distribution of decorin in human leiomyoma and normal myometrium. Biochim Biophys Acta. 2003; 1619(1) 98-112
26 Norian J M, Malik M, Parker C Y et al.. Transforming growth factor β3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reprod Sci. 2009; 16(12) 1153-1164
27 Bornstein P, Agah A, Kyriakides T R. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol. 2004; 36(6) 1115-1125
28 Behera M A, Feng L, Yonish B, Catherino W, Jung S H, Leppert P. Thrombospondin-1 and thrombospondin-2 mRNA and TSP-1 and TSP-2 protein expression in uterine fibroids and correlation to the genes COL1A1 and COL3A1 and to the collagen cross-link hydroxyproline. Reprod Sci. 2007; 14(8, suppl) 63-76
29 Vincenti M P. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol. 2001; 151 121-148
30 Inagaki N, Ung L, Otani T, Wilkinson D, Lopata A. Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp. Eur J Obstet Gynecol Reprod Biol. 2003; 111(2) 197-203
31 Bodner-Adler B, Bodner K, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K. Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma. J Soc Gynecol Investig. 2004; 11(3) 182-186
32 Wolańska M, Sobolewski K, Bańkowski E, Jaworski S. Matrix metalloproteinases of human leiomyoma in various stages of tumor growth. Gynecol Obstet Invest. 2004; 58(1) 14-18
33 Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk A J, Rechberger T. Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol. 2007; 23(9) 541-546
34 Willis B C, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol. 2007; 293(3) L525-L534
35 Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006; 69(2) 213-217
36 Yata Y, Gotwals P, Koteliansky V, Rockey D C. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy. Hepatology. 2002; 35(5) 1022-1030
37 Verrecchia F, Mauviel A, Farge D. Transforming growth factor-beta signaling through the Smad proteins: role in systemic sclerosis. Autoimmun Rev. 2006; 5(8) 563-569
38 Bonniaud P, Margetts P J, Ask K, Flanders K, Gauldie J, Kolb M. TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol. 2005; 175(8) 5390-5395
39 Ding L, Xu J, Luo X, Chegini N. Gonadotropin releasing hormone and transforming growth factor beta activate mitogen-activated protein kinase/extracellularly regulated kinase and differentially regulate fibronectin, type I collagen, and plasminogen activator inhibitor-1 expression in leiomyoma and myometrial smooth muscle cells. J Clin Endocrinol Metab. 2004; 89(11) 5549-5557
40 Lee B S, Nowak R A. Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta. J Clin Endocrinol Metab. 2001; 86(2) 913-920
41 Arici A, Sozen I. Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril. 2000; 73(5) 1006-1011
42 Derynck R, Lindquist P B, Lee A et al.. A new type of transforming growth factor-beta, TGF-beta 3. EMBO J. 1988; 7(12) 3737-3743
43 Joseph D S, Malik M, Nurudeen S, Catherino W H. Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta-3. Fertil Steril. 2009; , March 26 (Epub ahead of print)
44 Moench G L. The etiology of adenomyositis and uterine fibromyoma: an hypothesis. Am J Obstet Gynecol. 1929; 18 682-688
45 Friedman A J, Rein M S, Harrison-Atlas D, Garfield J M, Doubilet P M. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy. Fertil Steril. 1989; 52(5) 728-733
46 Maheux R, Lemay A, Blanchet P, Friede J, Pratt X. Maintained reduction of uterine leiomyoma following addition of hormonal replacement therapy to a monthly luteinizing hormone-releasing hormone agonist implant: a pilot study. Hum Reprod. 1991; 6(4) 500-505
47 Engel J B, Audebert A, Frydman R, Zivny J, Diedrich K. Presurgical short term treatment of uterine fibroids with different doses of cetrorelix acetate: a double-blind, placebo-controlled multicenter study. Eur J Obstet Gynecol Reprod Biol. 2007; 134(2) 225-232
48 Kawamura N, Ito F, Ichimura T, Shibata S, Umesaki N, Ogita S. Correlation between shrinkage of uterine leiomyoma treated with buserelin acetate and histopathologic findings of biopsy specimen before treatment. Fertil Steril. 1997; 68(4) 632-636
49 Zbucka M, Miltyk W, Bielawski T, Surazynski A, Palka J, Wolczynski S. Mechanism of collagen biosynthesis up-regulation in cultured leiomyoma cells. Folia Histochem Cytobiol. 2007; 45(Suppl 1) S181-S185
50 Hassan M H, Salama S A, Arafa H M, Hamada F M, Al-Hendy A. Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression. J Clin Endocrinol Metab. 2007; 92(10) 3949-3957
51 Chegini N, Ma C, Tang X M, Williams R S. Effects of GnRH analogues, ‘add-back’ steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. Mol Hum Reprod. 2002; 8(12) 1071-1078
52 Chegini N, Luo X, Ding L, Ripley D. The expression of Smads and transforming growth factor beta receptors in leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy. Mol Cell Endocrinol. 2003; 209(1–2) 9-16
53 Salama S A, Nasr A B, Dubey R K, Al-Hendy A. Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids. J Soc Gynecol Investig. 2006; 13(8) 542-550
54 Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel C A. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil Steril. 2007; 87(6) 1399-1412
55 Ohara N, Morikawa A, Chen W et al.. Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. Reprod Sci. 2007; 14(8, suppl) 20-27
56 Morikawa A, Ohara N, Xu Q et al.. Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer. Hum Reprod. 2008; 23(4) 944-951
57 Levens E D, Potlog-Nahari C, Armstrong A Y et al.. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstet Gynecol. 2008; 111(5) 1129-1136
58 Xu Q, Ohara N, Liu J et al.. Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. Mol Hum Reprod. 2008; 14(3) 181-191
59 Catherino W H, Malik M, Driggers P et al.. Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation and induces apoptosis without adversely affecting endometrium or myometrium. J Clin Endocrinol Metab. 2009; , in press
60 Azuma A, Nukiwa T, Tsuboi E et al.. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005; 171(9) 1040-1047
61 Cho M E, Smith D C, Branton M H, Penzak S R, Kopp J B. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007; 2(5) 906-913
62 Lee B S, Margolin S B, Nowak R A. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production. J Clin Endocrinol Metab. 1998; 83(1) 219-223
63 Grudzien M, Low P S, Manning P C et al.. The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells. Fertil Steril. 2009; , January 8 (Epub ahead of print)
64 Zhang C H, Wen Z Q, Li J F et al.. Inhibition of proliferation and transforming growth factor beta3 protein expression by peroxisome proliferators-activated receptor gamma ligands in human uterine leiomyoma cells. Chin Med J (Engl). 2008; 121(2) 166-171
65 Malik M, Webb J, Catherino W H. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells. Clin Endocrinol (Oxf). 2008; 69(3) 462-470
66 Kwon Y, Malik M, Magnuson B A. Inhibition of colonic aberrant crypt foci by curcumin in rats is affected by age. Nutr Cancer. 2004; 48(1) 37-43
67 Malik M, Mendoza M, Payson M, Catherino W H. Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression. Fertil Steril. 2009; 91(5, Suppl) 2177-2184
68 Malik M, Britten J, Mendoza M et al.. Symptomatic leiomyomas are a 3-dimensional disease: moving from two dimensions to tumor. Fertil Steril. 2009; 92(3, Suppl) S126-S127

William H CatherinoM.D. Ph.D.

Department of Obstetrics and Gynecology, Building A, Room 3078, Uniformed Services University of the Health Sciences

4301 Jones Bridge Road, Bethesda, MD 20814-4799

Email: wcatherino@usuhs.mil