Extracellular Matrix of Ovarian Tumors

ABSTRACT

Tumor cells interfere with the normal programming of extracellular matrix (ECM) biosynthesis and can extensively modify the structure and composition of the matrix. The role of ECM components is becoming increasingly recognized as an important determinant for the growth and progression of solid tumors. The extensive remodeling of the normal ECM in tumors can proceed through the degradation of pre-existing ECM molecules and/or by the neosynthesis of ECM components, which in many cases are not present in the ECM of normal tissues. In the ovary the ECM comprises a variety of molecules including the collagen superfamily and noncollagenous proteins such as glycoproteins, proteoglycans, and hyaluronan. Elevated levels of laminin-γ2, collagen types I and III, fibronectin, syndecan-1, glypican-1, versican, and hyaluronan and its receptors CD44 have all been associated with a poor prognosis of ovarian cancers. Generally, there is a differential expression of laminin chains α1, α4, and β2 among serous (α1, β2), mucinous (α4), and endometrioid (α1) tumors. This review focuses on these and other ECM molecules in ovarian tumors.

KEYWORDS

Ovary - tumor - cancer - metastasis - extracellular matrix - basal lamina - laminin - collagen type IV - tenascin C - hyaluronan - CD44 - decorin - versican - glypican - perlecan - syndecan - fibulin-1

REFERENCES

• 1 Scully R E. World Health Organization classification and nomenclature of ovarian cancer.  Natl Cancer Inst Monogr. 1975;  42 5-7
• 2 Scully R EY,  R H, Clements P B. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. In: Fascile 22 Atlas of Tumor Pathology. Third series ed. Washington, DC; Armed Forces Institute of Pathology 1998
• 3 Johns Hopkins Pathology .Ovarian cancer. Diagnosis: types of tumors. Epithelial cancers. Available at: http://ovariancancer.jhmi.edu/malignantepithelial.cfm Accessed July 21, 2006
• 4 Kaku T, Ogawa S, Kawano Y et al.. Histological classification of ovarian cancer.  Med Electron Microsc. 2003;  36 9-17
• 5 International Federation of Gynecology and Obstetrics . Changes in definitions of clinical staging for carcinoma of the cervix and ovary.  Am J Obstet Gynecol. 1987;  156 263-264
• 6 Sugiyama T, Kamura T, Kigawa J et al.. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy.  Cancer. 2000;  88 2584-2589
• 7 Timpl R, Dziadek M. Structure, development, and molecular pathology of basement membranes.  Int Rev Exp Pathol. 1986;  29 1-112
• 8 Hagios C, Lochter A, Bissell M J. Tissue architecture: the ultimate regulator of epithelial function?.  Philos Trans R Soc Lond B Biol Sci. 1998;  353 857-870
• 9 Auersperg N, Wong A S, Choi K C, Kang S K, Leung P C. Ovarian surface epithelium: biology, endocrinology, and pathology.  Endocr Rev. 2001;  22 255-288
• 10 Auersperg N, Maclaren I A, Kruk P A. Ovarian surface epithelium: autonomous production of connective tissue-type extracellular matrix.  Biol Reprod. 1991;  44 717-724
• 11 Rodgers R J, Lavranos T C, van Wezel I L, Irving-Rodgers H F. Development of the ovarian follicular epithelium.  Mol Cell Endocrinol. 1999;  151 171-179
• 12 Stenback F, Wasenius V M. Basement membrane structures in tumors of the ovary.  Eur J Obstet Gynecol Reprod Biol. 1985;  20 357-371
• 13 Paulsson M. Basement membrane proteins: structure, assembly, and cellular interactions.  Crit Rev Biochem Mol Biol. 1992;  27 93-127
• 14 Timpl R, Brown J C. Supramolecular assembly of basement membranes.  Bioessays. 1996;  18 123-132
• 15 Yurchenco P D, Schittny J C. Molecular architecture of basement membranes.  FASEB J. 1990;  4 1577-1590
• 16 Weber M. Basement membrane proteins.  Kidney Int. 1992;  41 620-628
• 17 Hay E. Cell Biology of Extracellular Matrix. New York; Plenum Press 1991
• 18 Rodgers H F, Irvine C M, van Wezel I L et al.. Distribution of the alpha1 to alpha6 chains of type IV collagen in bovine follicles.  Biol Reprod. 1998;  59 1334-1341
• 19 Capo-Chichi C D, Smith E R, Yang D H et al.. Dynamic alterations of the extracellular environment of ovarian surface epithelial cells in premalignant transformation, tumorigenicity, and metastasis.  Cancer. 2002;  95 1802-1815
• 20 Yang D H, Smith E R, Cohen C et al.. Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity.  Cancer. 2002;  94 2380-2392
• 21 Bar J K, Grelewski P, Popiela A, Noga L, Rabczynski J. Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki-67 and p53 immunoreactivity.  Gynecol Oncol. 2004;  95 23-31
• 22 Aumailley M, Bruckner-Tuderman L, Carter W G et al.. A simplified laminin nomenclature.  Matrix Biol. 2005;  24 326-332
• 23 Byers L J, Osborne J L, Carson L F et al.. Increased levels of laminin in ascitic fluid of patients with ovarian cancer.  Cancer Lett. 1995;  88 67-72
• 24 Kohlberger P, Muller-Klingspor V, Heinzl H, Obermair A, Breitenecker G, Leodolter S. Prognostic value of laminin-5 in serous adenocarcinomas of the ovary.  Anticancer Res. 2002;  22 3541-3544
• 25 Maatta M, Butzow R, Luostarinen J et al.. Differential expression of laminin isoforms in ovarian epithelial carcinomas suggesting different origin and providing tools for differential diagnosis.  J Histochem Cytochem. 2005;  53 1293-1300
• 26 Mizushima H, Koshikawa N, Moriyama K et al.. Wide distribution of laminin-5 gamma 2 chain in basement membranes of various human tissues.  Horm Res. 1998;  50(suppl 2) 7-14
• 27 Virtanen I, Gullberg D, Rissanen J et al.. Laminin alpha1-chain shows a restricted distribution in epithelial basement membranes of fetal and adult human tissues.  Exp Cell Res. 2000;  257 298-309
• 28 Zhu G G, Stenback F, Risteli L, Risteli J, Kauppila A. Organization of type III collagen in benign and malignant ovarian tumors. An immunohistochemical study.  Cancer. 1993;  72 1679-1684
• 29 Wolanska M, Sobolewski K, Bankowski E, Drozdzewicz M. Accumulation of collagen in ovarian benign tumours.  Acta Biochim Pol. 1999;  46 941-947
• 30 Kauppila S, Bode M K, Stenback F, Risteli L, Risteli J. Cross-linked telopeptides of type I and III collagens in malignant ovarian tumours in vivo.  Br J Cancer. 1999;  81 654-661
• 31 Stenback F. Collagen type III in ovarian tumors. Histological, immunohistochemical and ultrastructural findings.  Eur J Obstet Gynecol Reprod Biol. 1989;  30 73-88
• 32 Risteli L, Risteli J, Puistola U, Tomas C, Zhu G G, Kauppila A. Aminoterminal propeptide of type III procollagen in ovarian cancer. A review.  Acta Obstet Gynecol Scand. 1992;  155(suppl) 99-103
• 33 Abdel Aziz M T, Abdel Aziz Wassef M, Kamel M, el Zein M, el Hassan H. Clinical evaluation of serum aminoterminal propeptide of type III procollagen as tumor marker in gynecologic malignancies.  Tumori. 1993;  79 219-223
• 34 Zhu G G, Risteli J, Puistola U, Kauppila A, Risteli L. Progressive ovarian carcinoma induces synthesis of type I and type III procollagens in the tumor tissue and peritoneal cavity.  Cancer Res. 1993;  53 5028-5032
• 35 Zhu G G, Risteli L, Makinen M, Risteli J, Kauppila A, Stenback F. Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms.  Cancer. 1995;  75 1010-1017
• 36 Kauppila S, Saarela J, Stenback F, Risteli J, Kauppila A, Risteli L. Expression of mRNAs for type I and type III procollagens in serous ovarian cystadenomas and cystadenocarcinomas.  Am J Pathol. 1996;  148 539-548
• 37 Cracchiolo B M, Hanauske-Abel H M, Schwartz P E, Chambers J T, Holland B, Chambers S K. Procollagen-derived biomarkers in malignant ascites of ovarian cancer. Independent prognosticators for progression-free interval and survival.  Gynecol Oncol. 2002;  87 24-33
• 38 Simojoki M, Santala M, Risteli J, Kauppila A. Discrepant expression of carboxy- and aminoterminal propeptides of type I procollagen predicts poor clinical outcome in epithelial ovarian cancer.  Gynecol Oncol. 2003;  88 358-362
• 39 Santala M, Simojoki M, Risteli J, Risteli L, Kauppila A. Type I and III collagen metabolites as predictors of clinical outcome in epithelial ovarian cancer.  Clin Cancer Res. 1999;  5 4091-4096
• 40 Simojoki M, Santala M, Risteli J, Risteli L, Kauppila A. Serial determinations of aminoterminal propeptide of type III procollagen (PIIINP) and prognosis in ovarian cancer; comparison to CA125.  Anticancer Res. 2000;  20 4655-4660
• 41 Simojoki M, Santala M, Risteli J, Kauppila A. Carboxyterminal telopeptide of type I collagen (ICTP) in predicting prognosis in epithelial ovarian cancer.  Gynecol Oncol. 2001;  82 110-115
• 42 Hassager C, Risteli J, Risteli L, Jensen S B, Christiansen C. Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women.  J Bone Miner Res. 1992;  7 1307-1311
• 43 Wolthers O D, Heuck C, Heickendorff L. Diurnal variations in serum and urine markers of type I and type III collagen turnover in children.  Clin Chem. 2001;  47 1721-1722
• 44 Qvist P, Christgau S, Pedersen B J, Schlemmer A, Christiansen C. Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting.  Bone. 2002;  31 57-61
• 45 Pfaff M, Aumailley M, Specks U, Knolle J, Zerwes H G, Timpl R. Integrin and Arg-Gly-Asp dependence of cell adhesion to the native and unfolded triple helix of collagen type VI.  Exp Cell Res. 1993;  206 167-176
• 46 Sherman-Baust C A, Weeraratna A T, Rangel L B et al.. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells.  Cancer Cell. 2003;  3 377-386
• 47 Varma R R, Hector S M, Clark K, Greco W R, Hawthorn L, Pendyala L. Gene expression profiling of a clonal isolate of oxaliplatin-resistant ovarian carcinoma cell line A2780/C10.  Oncol Rep. 2005;  14 925-932
• 48 Wiberg C, Hedbom E, Khairullina A et al.. Biglycan and decorin bind close to the n-terminal region of the collagen VI triple helix.  J Biol Chem. 2001;  276 18947-18952
• 49 Dean D C, Birkenmeier T M, Rosen G D, Weintraub S J. Glycoprotein synthesis and secretion. Expression of fibronectin and its cell surface receptors.  Am Rev Respir Dis. 1991;  144 S25-S28
• 50 Labat-Robert J. Fibronectin in malignancy.  Semin Cancer Biol. 2002;  12 187-195
• 51 Barlati S, Columbi M, DePetro G. Differential expression of fibronectin and its degradation products in malignant tumors. In: Adony R Tumor Matrix Biology. Boca Raton; CRC Press 1995: 81-100
• 52 De Candia L M, Rodgers R J. Characterization of the expression of the alternative splicing of the ED-A, ED-B and V regions of fibronectin mRNA in bovine ovarian follicles and corpora lutea.  Reprod Fertil Dev. 1999;  11 367-377
• 53 Wilhelm O, Hafter R, Coppenrath E et al.. Fibrin-fibronectin compounds in human ovarian tumor ascites and their possible relation to the tumor stroma.  Cancer Res. 1988;  48 3507-3514
• 54 Franke F E, Von Georgi R, Zygmunt M, Munstedt K. Association between fibronectin expression and prognosis in ovarian carcinoma.  Anticancer Res. 2003;  23 4261-4267
• 55 Demeter A, Sziller I, Csapo Z et al.. Molecular prognostic markers in recurrent and in non-recurrent epithelial ovarian cancer.  Anticancer Res. 2005;  25 2885-2889
• 56 Kaspar M, Zardi L, Neri D. Fibronectin as target for tumor therapy.  Int J Cancer. 2006;  118 1331-1339
• 57 Clinton G M, Rougeot C, Derancourt J et al.. Estrogens increase the expression of fibulin-1, an extracellular matrix protein secreted by human ovarian cancer cells.  Proc Natl Acad Sci USA. 1996;  93 316-320
• 58 Roger P, Pujol P, Lucas A, Baldet P, Rochefort H. Increased immunostaining of fibulin-1, an estrogen-regulated protein in the stroma of human ovarian epithelial tumors.  Am J Pathol. 1998;  153 1579-1588
• 59 Moll F, Katsaros D, Lazennec G et al.. Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells.  Oncogene. 2002;  21 1097-1107
• 60 Chiquet-Ehrismann R. Tenascin and other adhesion-modulating proteins in cancer.  Semin Cancer Biol. 1993;  4 301-310
• 61 Mackie E J, Chiquet-Ehrismann R, Pearson C A et al.. Tenascin is a stromal marker for epithelial malignancy in the mammary gland.  Proc Natl Acad Sci USA. 1987;  84 4621-4625
• 62 Wilson K E, Langdon S P, Lessells A M, Miller W R. Expression of the extracellular matrix protein tenascin in malignant and benign ovarian tumours.  Br J Cancer. 1996;  74 999-1004
• 63 Wilson K E, Bartlett J M, Miller E P et al.. Regulation and function of the extracellular matrix protein tenascin-C in ovarian cancer cell lines.  Br J Cancer. 1999;  80 685-692
• 64 Ishihara A, Yoshida T, Tamaki H, Sakakura T. Tenascin expression in cancer cells and stroma of human breast cancer and its prognostic significance.  Clin Cancer Res. 1995;  1 1035-1041
• 65 Suwiwat S, Ricciardelli C, Tammi R et al.. Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer.  Clin Cancer Res. 2004;  10 2491-2498
• 66 Timar J, Lapis K, Dudas J, Sebestyen A, Kopper L, Kovalszky I. Proteoglycans and tumor progression: Janus-faced molecules with contradictory functions in cancer.  Semin Cancer Biol. 2002;  12 173-186
• 67 Iozzo R V. Matrix proteoglycans: from molecular design to cellular function.  Annu Rev Biochem. 1998;  67 609-652
• 68 Blackhall F H, Merry C L, Davies E J, Jayson G C. Heparan sulfate proteoglycans and cancer.  Br J Cancer. 2001;  85 1094-1098
• 69 Beauvais D M, Rapraeger A C. Syndecans in tumor cell adhesion and signaling.  Reprod Biol Endocrinol. 2004;  2 3
• 70 Iozzo R V. Perlecan: a gem of a proteoglycan.  Matrix Biol. 1994;  14 203-208
• 71 McArthur M E, Irving-Rodgers H F, Byers S, Rodgers R J. Identification and immunolocalization of decorin, versican, perlecan, nidogen, and chondroitin sulfate proteoglycans in bovine small-antral ovarian follicles.  Biol Reprod. 2000;  63 913-924
• 72 Irving-Rodgers H F, Harland M L, Rodgers R J. A novel basal lamina matrix of the stratified epithelium of the ovarian follicle.  Matrix Biol. 2004;  23 207-217
• 73 Davies E J, Blackhall F H, Shanks J H et al.. Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.  Clin Cancer Res. 2004;  10 5178-5186
• 74 Ishiguro K, Kojima T, Taguchi O, Saito H, Muramatsu T, Kadomatsu K. Syndecan-4 expression is associated with follicular atresia in mouse ovary.  Histochem Cell Biol. 1999;  112 25-33
• 75 Oksjoki S, Sallinen S, Vuorio E, Anttila L. Cyclic expression of mRNA transcripts for connective tissue components in the mouse ovary.  Mol Hum Reprod. 1999;  5 803-808
• 76 Princivalle M, Hasan S, Hosseini G, de Agostini A I. Anticoagulant heparan sulfate proteoglycans expression in the rat ovary peaks in preovulatory granulosa cells.  Glycobiology. 2001;  11 183-194
• 77 Kokenyesi R. Ovarian carcinoma cells synthesize both chondroitin sulfate and heparan sulfate cell surface proteoglycans that mediate cell adhesion to interstitial matrix.  J Cell Biochem. 2001;  83 259-270
• 78 Casey R C, Oegema Jr T R, Skubitz K M, Pambuccian S E, Grindle S M, Skubitz A P. Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells.  Clin Exp Metastasis. 2003;  20 143-152
• 79 Wiksten J P, Lundin J, Nordling S et al.. Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer.  Int J Cancer. 2001;  95 1-6
• 80 Barbareschi M, Maisonneuve P, Aldovini D et al.. High syndecan-1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis.  Cancer. 2003;  98 474-483
• 81 Tsanou E, Ioachim E, Briasoulis E et al.. Clinicopathological study of the expression of syndecan-1 in invasive breast carcinomas. Correlation with extracellular matrix components.  J Exp Clin Cancer Res. 2004;  23 641-650
• 82 Maeda T, Desouky J, Friedl A. Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis.  Oncogene. 2006;  25 1408-1412
• 83 Filmus J. Glypicans in growth control and cancer.  Glycobiology. 2001;  11 19R-23R
• 84 Veugelers M, Vermeesch J, Reekmans G, Steinfeld R, Marynen P, David G. Characterization of glypican-5 and chromosomal localization of human GPC5, a new member of the glypican gene family.  Genomics. 1997;  40 24-30
• 85 Veugelers M, De Cat B, Ceulemans H et al.. Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans.  J Biol Chem. 1999;  274 26968-26977
• 86 LeBaron R G. Versican.  Perspect Dev Neurobiol. 1996;  3 261-271
• 87 LeBaron R G, Zimmermann D R, Ruoslahti E. Hyaluronate binding properties of versican.  J Biol Chem. 1992;  267 10003-10010
• 88 Bode-Lesniewska B, Dours-Zimmermann M T, Odermatt B F, Briner J, Heitz P U, Zimmermann D R. Distribution of the large aggregating proteoglycan versican in adult human tissues.  J Histochem Cytochem. 1996;  44 303-312
• 89 Russell D L, Doyle K M, Ochsner S A, Sandy J D, Richards J S. Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation.  J Biol Chem. 2003;  278 42330-42339
• 90 Voutilainen K, Anttila M, Sillanpaa S et al.. Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis.  Int J Cancer. 2003;  107 359-364
• 91 Wight T N. Versican: a versatile extracellular matrix proteoglycan in cell biology.  Curr Opin Cell Biol. 2002;  14 617-623
• 92 Weber I T, Harrison R W, Iozzo R V. Model structure of decorin and implications for collagen fibrillogenesis.  J Biol Chem. 1996;  271 31767-31770
• 93 Adany R, Heimer R, Caterson B, Sorrell J M, Iozzo R V. Altered expression of chondroitin sulfate proteoglycan in the stroma of human colon carcinoma. Hypomethylation of PG-40 gene correlates with increased PG-40 content and mRNA levels.  J Biol Chem. 1990;  265 11389-11396
• 94 Ricciardelli C, Mayne K, Sykes P J et al.. Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer.  Clin Cancer Res. 1998;  4 963-971
• 95 Brown L F, Guidi A J, Schnitt S J et al.. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.  Clin Cancer Res. 1999;  5 1041-1056
• 96 Nash M A, Deavers M T, Freedman R S. The expression of decorin in human ovarian tumors.  Clin Cancer Res. 2002;  8 1754-1760
• 97 Nash M A, Loercher A E, Freedman R S. In vitro growth inhibition of ovarian cancer cells by decorin: synergism of action between decorin and carboplatin.  Cancer Res. 1999;  59 6192-6196
• 98 Santra M, Eichstetter I, Iozzo R V. An anti-oncogenic role for decorin. Down-regulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells.  J Biol Chem. 2000;  275 35153-35161
• 99 Merle B, Durussel L, Delmas P D, Clezardin P. Decorin inhibits cell migration through a process requiring its glycosaminoglycan side chain.  J Cell Biochem. 1999;  75 538-546
• 100 Shridhar V, Sen A, Chien J et al.. Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization.  Cancer Res. 2002;  62 262-270
• 101 Shridhar V, Lee J, Pandita A et al.. Genetic analysis of early- versus late-stage ovarian tumors.  Cancer Res. 2001;  61 5895-5904
• 102 Reed C C, Waterhouse A, Kirby S et al.. Decorin prevents metastatic spreading of breast cancer.  Oncogene. 2005;  24 1104-1110
• 103 Knudson C B, Knudson W. Hyaluronan-binding proteins in development, tissue homeostasis, and disease.  FASEB J. 1993;  7 1233-1241
• 104 Prehm P. Release of hyaluronate from eukaryotic cells.  Biochem J. 1990;  267 185-189
• 105 Spicer A P, McDonald J A. Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family.  J Biol Chem. 1998;  273 1923-1932
• 106 Day A J, Prestwich G D. Hyaluronan-binding proteins: tying up the giant.  J Biol Chem. 2002;  277 4585-4588
• 107 Salustri A, Yanagishita M, Underhill C B, Laurent T C, Hascall V C. Localization and synthesis of hyaluronic acid in the cumulus cells and mural granulosa cells of the preovulatory follicle.  Dev Biol. 1992;  151 541-551
• 108 Fulop C, Salustri A, Hascall V C. Coding sequence of a hyaluronan synthase homologue expressed during expansion of the mouse cumulus-oocyte complex.  Arch Biochem Biophys. 1997;  337 261-266
• 109 Rodgers R J, Irving-Rodgers H F, Russell D L. Extracellular matrix of the developing ovarian follicle.  Reproduction. 2003;  126 415-424
• 110 Schoenfelder M, Einspanier R. Expression of hyaluronan synthases and corresponding hyaluronan receptors is differentially regulated during oocyte maturation in cattle.  Biol Reprod. 2003;  69 269-277
• 111 Ulbrich S E, Schoenfelder M, Thoene S, Einspanier R. Hyaluronan in the bovine oviduct-modulation of synthases and receptors during the estrous cycle.  Mol Cell Endocrinol. 2004;  214 9-18
• 112 Tammi M I, Day A J, Turley E A. Hyaluronan and homeostasis: a balancing act.  J Biol Chem. 2002;  277 4581-4584
• 113 Boregowda R K, Appaiah H N, Siddaiah M et al.. Expression of Hyaluronan in human tumor progression.  J Carcinog. 2006;  5 2
• 114 Anttila M A, Tammi R H, Tammi M I, Syrjanen K J, Saarikoski S V, Kosma V M. High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer.  Cancer Res. 2000;  60 150-155
• 115 Hiltunen E L, Anttila M, Kultti A et al.. Elevated hyaluronan concentration without hyaluronidase activation in malignant epithelial ovarian tumors.  Cancer Res. 2002;  62 6410-6413
• 116 Jojovic M, Delpech B, Prehm P, Schumacher U. Expression of hyaluronate and hyaluronate synthase in human primary tumours and their metastases in scid mice.  Cancer Lett. 2002;  188 181-189
• 117 Yabushita H, Noguchi M, Kishida T et al.. Hyaluronan synthase expression in ovarian cancer.  Oncol Rep. 2004;  12 739-743
• 118 Casey R C, Skubitz A P. CD44 and beta1 integrins mediate ovarian carcinoma cell migration toward extracellular matrix proteins.  Clin Exp Metastasis. 2000;  18 67-75
• 119 Lessan K, Aguiar D J, Oegema T, Siebenson L, Skubitz A P. CD44 and beta1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells.  Am J Pathol. 1999;  154 1525-1537
• 120 Strobel T, Swanson L, Cannistra S A. In vivo inhibition of CD44 limits intra-abdominal spread of a human ovarian cancer xenograft in nude mice: a novel role for CD44 in the process of peritoneal implantation.  Cancer Res. 1997;  57 1228-1232
• 121 Gardner M J, Catterall J B, Jones L M, Turner G A. Human ovarian tumour cells can bind hyaluronic acid via membrane CD44: a possible step in peritoneal metastasis.  Clin Exp Metastasis. 1996;  14 325-334
• 122 Yeo T K, Nagy J A, Yeo K T, Dvorak H F, Toole B P. Increased hyaluronan at sites of attachment to mesentery by CD44-positive mouse ovarian and breast tumor cells.  Am J Pathol. 1996;  148 1733-1740
• 123 Catterall J B, Gardner M J, Jones L M, Turner G A. Binding of ovarian cancer cells to immobilized hyaluronic acid.  Glycoconj J. 1997;  14 867-869
• 124 Bourguignon L Y, Gilad E, Rothman K, Peyrollier K. Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.  J Biol Chem. 2005;  280 11961-11972
• 125 Bourguignon L Y, Zhu H, Zhou B, Diedrich F, Singleton P A, Hung M C. Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth.  J Biol Chem. 2001;  276 48679-48692
• 126 Bourguignon L Y, Zhu H, Shao L, Chen Y W. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration.  J Biol Chem. 2001;  276 7327-7336
• 127 Uhl-Steidl M, Muller-Holzner E, Zeimet A G et al.. Prognostic value of CD44 splice variant expression in ovarian cancer.  Oncology. 1995;  52 400-406
• 128 Kayastha S, Freedman A N, Piver M S, Mukkamalla J, Romero-Guittierez M, Werness B A. Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival.  Clin Cancer Res. 1999;  5 1073-1076
• 129 Afify A M, Ferguson A W, Davila R M, Werness B A. Expression of CD44S and CD44v5 is more common in stage III than in stage I serous ovarian carcinomas.  Appl Immunohistochem Mol Morphol. 2001;  9 309-314
• 130 Ross J S, Sheehan C E, Williams S S, Malfetano J H, Szyfelbein W M, Kallakury B V. Decreased CD44 standard form expression correlates with prognostic variables in ovarian carcinomas.  Am J Clin Pathol. 2001;  116 122-128
• 131 Rodriguez-Rodriguez L, Sancho-Torres I, Mesonero C, Gibbon D G, Shih W J, Zotalis G. The CD44 receptor is a molecular predictor of survival in ovarian cancer.  Med Oncol. 2003;  20 255-263
• 132 Cannistra S A, Abu-Jawdeh G, Niloff J et al.. CD44 variant expression is a common feature of epithelial ovarian cancer: lack of association with standard prognostic factors.  J Clin Oncol. 1995;  13 1912-1921
• 133 Speiser P, Wanner C, Breitenecker G, Kohlberger P, Kainz C. CD-44 is not involved in the metastatic spread of ovarian cancer in vivo.  Anticancer Res. 1995;  15 2767-2769
• 134 Sanchez Lockhart M, Hajos S E, Basilio F M, Mongini C, Alvarez E. Splice variant expression of CD44 in patients with breast and ovarian cancer.  Oncol Rep. 2001;  8 145-151
• 135 Sillanpaa S, Anttila M A, Voutilainen K et al.. CD44 expression indicates favorable prognosis in epithelial ovarian cancer.  Clin Cancer Res. 2003;  9 5318-5324