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Importance of Hyaluronan Metabolism and Signalling in Tumour Progression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hyaluronan, an unbranched glycosaminoglycan of the extracellular matrix, has an amazingly simple structure. Initially thought to fulfil only hydrating and space-filling functions in tissues, evidence generated during the past decades shows that hyaluronan is involved in intriguingly complex signalling events in health and disease. In cancer, increased hyaluronan levels have been correlated with poor patient survival.

The research underlying this thesis sheds light on the interplay between hyaluronan, its producing and degrading enzymes as well as the triggered intracellular signalling in the metastatic cascade. Utilising breast cancer and normal mammary cells, paper I and II investigate the initial steps of tumour progression: proliferation, invasion and epithelial-mesenchymal transition. Hyaluronan synthase 2 plays a central role in all these processes. In paper III, the focus is shifted toward growth factor-induced hyaluronan production. Stimulation with PDGF-BB, which can be secreted by tumour cells, increased hyaluronan production via upregulation of HAS2 in fibroblast cultures. Finally, paper IV discusses the involvement of hyaluronidases and CD44 in angiogenesis and intravasation – events that are associated with advanced cancer stages.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 855
Keyword [en]
Hyaluronan, CD44, cancer, growth factors
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-190715ISBN: 978-91-554-8574-0 (print)OAI: oai:DiVA.org:uu-190715DiVA: diva2:584056
Public defence
2013-02-27, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-02-04 Created: 2013-01-08 Last updated: 2013-04-02Bibliographically approved
List of papers
1. Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1)
Open this publication in new window or tab >>Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1)
2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 49, 42349-42359 p.Article in journal (Refereed) Published
Abstract [en]

Invasion and metastasis are the primary causes of breast cancer mortality, and increased knowledge about the molecular mechanisms involved in these processes is highly desirable. High levels of hyaluronan in breast tumors have been correlated with poor patient survival. The involvement of hyaluronan in the early invasive phase of a clone of breast cancer cell line MDA-MB-231 that forms bone metastases was studied using an in vivo-like basement membrane model. The metastatic to bone tumor cells exhibited a 7-fold higher hyaluronan-synthesizing capacity compared with MDA-MB-231 cells predominately due to an increased expression of hyaluronan synthase 2 (HAS2). We found that knockdown of HAS2 completely suppressed the invasive capability of these cells by the induction of tissue metalloproteinase inhibitor 1 (TIMP-1) and dephosphorylation of focal adhesion kinase. HAS2 knockdown-mediated inhibition of basement membrane remodeling was rescued by HAS2 overexpression, transfection with TIMP-1 siRNA, or addition of TIMP-1-blocking antibodies. Moreover, knockdown of HAS2 suppressed the EGF-mediated induction of the focal adhesion kinase/PI3K/Akt signaling pathway. Thus, this study provides new insights into a possible mechanism whereby HAS2 enhances breast cancer invasion.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168725 (URN)10.1074/jbc.M111.278598 (DOI)000298180900044 ()22016393 (PubMedID)
Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2017-12-07Bibliographically approved
2. Efficient TGF beta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2
Open this publication in new window or tab >>Efficient TGF beta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2
Show others...
2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 37, 4355-4365 p.Article in journal (Refereed) Published
Abstract [en]

Epithelial-mesenchymal transition (EMT) is a developmental program, which can be adopted by cancer cells to increase their migration and ability to form metastases. Transforming growth factor β (TGFβ) is a well-studied inducer of EMT. We demonstrate that TGFβ potently stimulates hyaluronan synthesis via upregulation of hyaluronan synthase 2 (HAS2) in NMuMG mammary epithelial cells. This stimulatory effect requires the kinase active type I TGFβ receptor and is dependent on Smad signaling and activation of the p38 mitogen-activated protein kinase. Knockdown of HAS2 inhibited the TGFβ-induced EMT by about 50%, as determined by the phase contrast microscopy and immunostaining using the EMT marker ZO-1. Furthermore, real-time PCR analysis of the EMT markers fibronectin, Snail1 and Zeb1 revealed decreased expressions upon HAS2 suppression, using specific small interfering RNA (siRNA) for HAS2. Removal of the extracellular hyaluronan by Streptomyces hyaluronidase or inhibiting the binding to its cell surface receptor CD44 by blocking antibodies, did not inhibit TGFβ-induced EMT. Interestingly, HAS2 suppression completely abolished the TGFβ-induced cell migration, whereas CD44 knockdown did not. These observations suggest that TGFβ-dependent HAS2 expression, but not extracellular hyaluronan, has an important regulatory role in TGFβ-induced EMT.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-190691 (URN)10.1038/onc.2012.475 (DOI)000324404200004 ()23108409 (PubMedID)
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2017-12-06Bibliographically approved
3. Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB
Open this publication in new window or tab >>Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB
Show others...
2007 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 404, 327-336 p.Article in journal (Refereed) Published
Abstract [en]

The glycosaminoglycan hyaluronan is important in many tissue-repair processes. We have investigated the synthesis of hyaluronan in a panel of cell lines of fibroblastic and epithelial origin in response to PDGF (platelet-derived growth factor)-BB and other growth factors. Human dermal fibroblasts exhibited the highest hyaluronan-synthesizing activity in response to PDGF-BB. Analysis of HAS (hyaluronan synthase) and HYAL (hyaluronidase) mRNA expression showed that PDGF-BB treatment induced a 3-fold increase in the already high level of HAS2 mRNA, and increases in HAS1 and HYAL1 mRNA, whereas the levels of HAS3 and HYAL2 mRNA were not affected. Furthermore, PDGF-BB also increased the amount and activity of HAS2 protein, but not of HYAL1 and HYAL2 proteins. Using inhibitors for MEK 1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] (U0126) and for PI3K (phosphoinositide 3-kinase) (LY294002), as well as the SN50 inhibitor, which prevents translocation of the active NF-kappa B (nuclear factor KB) to the nucleus, we observed a complete inhibition of both HAS2 transcriptional activity and hyaluronan synthesis, whereas inhibitors of other signalling pathways were without any significant effect. TGF-beta 1 (transforming growth factor-beta 1) did not increase the activity of hyaluronan synthesis in dermal fibroblasts, but increased the activity of HYALs. Imponantly, inhibition of hyaluronan binding to its receptor CD44 by the monoclonal antibody Hennes-1, inhibited PDGF-BB-stimulated [H-3]thymidine incorporation of dermal fibroblasts. We conclude that the ERK MAPK and PI3K signalling pathways are necessary for the regulation of hyaluronan synthesis by PDGF-BB, and that prevention of its binding to CD44 inhibits PDGF-BB-induced cell growth.

Keyword
dermal fibroblast, growth factor, hyaluronan synthase (HAS), hyaluronidase, platelet-derived growth factor (PDGF), signal transduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-144329 (URN)10.1042/BJ20061757 (DOI)000247014700017 ()17324121 (PubMedID)
Available from: 2011-01-31 Created: 2011-01-28 Last updated: 2017-12-11Bibliographically approved
4. CD44 and Hyal2 affect capillary endothelial cell differentiation and breast cancer transmigration
Open this publication in new window or tab >>CD44 and Hyal2 affect capillary endothelial cell differentiation and breast cancer transmigration
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-190704 (URN)
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2013-04-29

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