Top

Published in:

01-01-2014 | Preclinical Study

Hyaluronan synthases (HAS1–3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival

Authors: Päivi Auvinen, Kirsi Rilla, Ritva Tumelius, Markku Tammi, Reijo Sironen, Ylermi Soini, Veli-Matti Kosma, Arto Mannermaa, Jukka Viikari, Raija Tammi

Published in: Breast Cancer Research and Treatment | Issue 2/2014

Abstract

Accumulation of hyaluronan (HA) in pericellular stroma and carcinoma cells is predictive of unfavorable patient prognosis in many epithelial cancers. However, it is not known whether the HA originates from carcinoma or stromal cells, or whether increased expression of hyaluronan synthase proteins (HAS1–3) contributes to HA accumulation. In this study, localization and expression of HAS1–3 were evaluated immunohistochemically in 278 cases of human breast cancer, and correlated with prognostic factors and patient outcome. Both carcinoma cells and stromal cells were HAS-positive. In carcinoma cells, HAS1 and HA stainings correlated with each other, and HAS1 associated with estrogen receptor negativity, HER2 positivity, high relapse rate, and short overall survival. In stromal cells, the staining levels of all HAS isoforms correlated with the stromal HA staining, stromal cell CD44, high relapse rate, and short overall survival of the patients. In addition, expression levels of stromal HAS1 and HAS2 were related to obesity, large tumor size, lymph node positivity, and estrogen receptor negativity. Thus, stromal HAS1 and HAS3 were independent prognostic factors in the multivariate analysis. The data suggest that increased levels of HAS enzymes contribute to the accumulation of HA in breast cancer, and that HA is synthesized in carcinoma cells and stromal cells. The study also indicates that HAS enzyme levels are related to tumor aggressiveness and poor patient outcome representing potential targets for therapy.

Available only for authorised users

Tammi R, Kultti A, Kosma VM, Pirinen R, Auvinen P, Tammi M (2008) Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 18:288–295PubMedCrossRef

Auvinen P, Tammi R, Parkkinen J, Tammi M, Ågren U, Johansson R, Hirvikoski P, Eskelinen M, Kosma VM (2000) Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156:529–536PubMedCrossRef

Weigel P, DeAngelis P (2007) Hyaluronan synthases: a decade-plus of novel glycosyltransferases. J Biol Chem 282:36777–36781PubMedCrossRef

Camenisch T, Spicer A, Brehm-Gibson T, Biesterfeldt J, Augustine M, Calabro A Jr, Kubalak S, Klewer S, McDonald J (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 106:349–360PubMedCentralPubMedCrossRef

Tammi R, Passi A, Rilla K, Karousou E, Vigetti D, Makkonen K, Tammi M (2011) Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J 278:1419–1428PubMedCrossRef

Tammi R, MacCallum D, Hascall V, Pienimäki J, Hyttinen M, Tammi M (1998) Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides. J Biol Chem 273:28878–28888PubMedCrossRef

Evanko S, Tammi M, Tammi R, Wight T (2007) Hyaluronan-dependent pericellular matrix. Adv Drug Deliv Rev 59:1351–1365PubMedCentralPubMedCrossRef

Rilla K, Siiskonen H, Spicer A, Hyttinen J, Tammi M, Tammi R (2005) Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity. J Biol Chem 280:31890–31897PubMedCrossRef

Kultti A, Pasonen-Seppänen S, Jauhiainen M, Rilla KJ, Kärnä R, Pyöriä E, Tammi R, Tammi M (2009) 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 315:1914–1923PubMedCrossRef

10.

Kramer M, Escudero D, Lokeshwar S, Golshani R, Ekwenna O, Acosta K, Merseburger A, Soloway M, Lokeshwar V (2011) Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis. Cancer 117:1197–1209PubMedCentralPubMedCrossRef

11.

Chi A, Shirodkar S, Escudero D, Ekwenna O, Yates T, Ayyathurai R, Garcia-Roig M, Gahan J, Manoharan M, Bird V, Lokeshwar V (2012) Molecular characterization of kidney cancer: association of hyaluronic acid family with histological subtypes and metastasis. Cancer 118:2394–2402PubMedCentralPubMedCrossRef

12.

Yamada Y, Itano N, Narimatsu H, Kudo T, Morozumi K, Hirohashi S, Ochiai A, Ueda M, Kimata K (2004) Elevated transcript level of hyaluronan synthase1 gene correlates with poor prognosis of human colon cancer. Clin Exp Metastasis 21:57–63PubMedCrossRef

13.

Yabushita H, Noguchi M, Kishida T, Fusano K, Noguchi Y, Itano N, Kimata K, Noguchi M (2004) Hyaluronan synthase expression in ovarian cancer. Oncol Rep 12:739–743PubMed

14.

Nykopp T, Rilla K, Tammi MI, Tammi RH, Sironen R, Hämäläinen K, Kosma VM, Heinonen S, Anttila M (2010) Hyaluronan synthases (HAS1–3) and hyaluronidases (HYAL1–2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma. BMC Cancer 10:512PubMedCentralPubMedCrossRef

15.

Udabage L, Brownlee G, Waltham M, Blick T, Walker E, Heldin P, Nilsson S, Thompson E, Brown T (2005) Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer. Cancer Res 65:6139–6150PubMedCrossRef

16.

Okuda H, Kobayashi A, Xia B, Watabe M, Pai SK, Hirota S, Xing F, Liu W, Pandey P, Fukuda K, Modur V, Ghosh A, Wilber A, Watabe K (2012) Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res 72:537–547PubMedCentralPubMedCrossRef

17.

Auvinen P, Tammi R, Kosma VM, Sironen R, Soini Y, Mannermaa A, Tumelius R, Uljas E, Tammi M (2013) Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer. Int J Cancer 132:531–539PubMedCrossRef

18.

Törrönen K, Nikunen K, Kärnä R, Tammi M, Tammi R, Rilla K (2013) Tissue distribution and subcellular localization of hyaluronan synthase isoenzymes. Histochem Cell Biol. doi:10.1007/s00418-013-1143-4

19.

Tammi R, Ågren U, Tuhkanen A, Tammi M (1994) Hyaluronan metabolism in skin. Prog Histochem Cytochem 29:1–81PubMedCrossRef

20.

McShane L, Altman D, Sauerbrei W, Taube S, Gion M, Clark G, Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics (2006) Reporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235PubMedCrossRef

21.

Bharadwaj A, Kovar J, Loughman E, Elowsky C, Oakley G, Simpson M (2009) Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing. Am J Pathol 174:1027–1036PubMedCrossRef

22.

Itano N, Kimata K (2008) Altered hyaluronan biosynthesis in cancer progression. Semin Cancer Biol 18:268–274PubMedCrossRef

23.

Itano N, Sawai T, Atsumi F, Miyaishi O, Taniguchi S, Kannagi R, Hamaguchi M, Kimata K (2004) Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic malignant transformation. J Biol Chem 279:18679–18687PubMedCrossRef

24.

Ichikawa T, Itano N, Sawai T, Kimata K, Koganehira Y, Saida T, Taniguchi S (1999) Increased synthesis of hyaluronate enhances motility of human melanoma cells. J Invest Dermatol 113:935–939PubMedCrossRef

25.

Karousou E, Kamiryo M, Skandalis SS, Ruusala A, Asteriou T, Passi A, Yamashita H, Hellman U, Heldin CH, Heldin P (2010) The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J Biol Chem 285:23647–23654PubMedCrossRef

26.

Petersen O, Nielsen H, Gudjonsson T, Villadsen R, Rank F, Niebuhr E, Bissell M, Ronnov-Jessen L (2003) Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 162:391–402PubMedCrossRef

27.

Zoltan-Jones A, Huang L, Ghatak S, Toole B (2003) Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem 278:45801–45810PubMedCrossRef

28.

Porsch H, Bernert B, Mehic M, Theocharis A, Heldin C, Heldin P (2012) Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene 32(37):4355–4365PubMedCentralPubMedCrossRef

29.

Koyama H, Hibi T, Isogai Z, Yoneda M, Fujimori M, Amano J, Kawakubo M, Kannagi R, Kimata K, Taniguchi S, Itano N (2007) Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. Am J Pathol 170:1086–1099PubMedCrossRef

30.

Rilla K, Oikari S, Jokela TA, Hyttinen J, Kärnä R, Tammi R, Tammi M (2013) Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3. J Biol Chem 288:5973–5983PubMedCrossRef

31.

Vigetti D, Deleonibus S, Moretto P, Karousou E, Viola M, Bartolini B, Hascall V, Tammi M, De Luca G, Passi A (2012) Role of UDP-N-acetylglucosamine (GlcNAc) and O-GlcNAcylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis. J Biol Chem 287:35544–35555PubMedCrossRef

32.

van den Brandt P, Spiegelman D, Yaun S, Adami H, Beeson L, Folsom A, Fraser G, Goldbohm R, Graham S, Kushi L, Marshall J, Miller A, Rohan T, Smith-Warner S, Speizer F, Willett W, Wolk A, Hunter D (2000) Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 152:514–527PubMedCrossRef

33.

Contiero P, Berrino F, Tagliabue G, Mastroianni A, Di Mauro M, Fabiano S, Annulli M, Muti P (2013) Fasting blood glucose and long-term prognosis of non-metastatic breast cancer: a cohort study. Breast Cancer Res Treat 138:951–959PubMedCrossRef

34.

Varadi T, Mersich T, Auvinen P, Tammi R, Tammi M, Salamon F, Besznyak I Jr, Jakab F, Baranyai Z, Szollosi J, Nagy P (2012) Binding of trastuzumab to ErbB2 is inhibited by a high pericellular density of hyaluronan. J Histochem Cytochem 60:567–575PubMedCrossRef

35.

Hascall V, Majors A, De La Motte C, Evanko S, Wang A, Drazba JA, Strong S, Wight T (2004) Intracellular hyaluronan: a new frontier for inflammation? Biochim Biophys Acta 1673:3–12PubMedCrossRef

36.

Toole B (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539PubMedCrossRef

37.

Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444PubMedCrossRef

38.

Baek J, Jin Q, Ensor J, Boulbes D, Esteva F (2011) Serum CD44 levels and overall survival in patients with HER2-positive breast cancer. Breast Cancer Res Treat 130:1029–1036PubMedCrossRef

39.

Urakawa H, Nishida Y, Wasa J, Arai E, Zhuo L, Kimata K, Kozawa E, Futamura N, Ishiguro N (2012) Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo. Int J Cancer 130:454–466PubMedCrossRef

Title: Hyaluronan synthases (HAS1–3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival
Authors: Päivi Auvinen
Kirsi Rilla
Ritva Tumelius
Markku Tammi
Reijo Sironen
Ylermi Soini
Veli-Matti Kosma
Arto Mannermaa
Jukka Viikari
Raija Tammi
Publication date: 01-01-2014
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2014
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2804-7

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2014

CXCL13–CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis

Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers

Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal carcinoma in situ (DCIS)

Inhibition of LINE-1 retrotransposon-encoded reverse transcriptase modulates the expression of cell differentiation genes in breast cancer cells

Spinal IFN-γ-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models

Prospective associations of depression with survival: a population-based cohort study in patients with newly diagnosed breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer