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CD44 and Hyal2 affect capillary endothelial cell differentiation and breast cancer transmigration
Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab.
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-190704OAI: oai:DiVA.org:uu-190704DiVA: diva2:584024
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2013-04-29
In thesis
1. Importance of Hyaluronan Metabolism and Signalling in Tumour Progression
Open this publication in new window or tab >>Importance of Hyaluronan Metabolism and Signalling in Tumour Progression
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
Hyaluronan, CD44, cancer, growth factors
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-190715 (URN)978-91-554-8574-0 (ISBN)
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
2. Importance of Hyaluronan-CD44 Signaling in Tumor Progression: Crosstalk with TGFβ and PDGF-BB Signaling
Open this publication in new window or tab >>Importance of Hyaluronan-CD44 Signaling in Tumor Progression: Crosstalk with TGFβ and PDGF-BB Signaling
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In order for solid tumors to metastasize, tumor cells must acquire the ability to invade the surrounding tissue and intravasate into blood- or lymph vessels, survive in the circulation and then extravasate at a distant site to form a new tumor. Overexpression of the glycosaminoglycan hyaluronan, and its adhesion receptor CD44, correlate with breast cancer progression. This thesis focuses on the role of hyaluronan in tumor invasion and metastasis.

In paper I, we demonstrated that upregulation of the hyaluronan synthesizing enzyme hyaluronan synthase 2 (HAS2) was crucial for transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells. In paper II, we further demonstrated that silencing of HAS2 decreased the invasive behavior of bone-metastasizing breast cancer cells, via upregulation of tissue inhibitor for metalloproteinase 1 (TIMP1), and dephosphorylation of focal adhesion kinase (FAK).

During tumorigenesis, stromal cells, such as fibroblasts, play important roles and several growth factors are synthesized, promoting crosstalk between different cell surface receptors. In paper III, we investigated the crosstalk between the hyaluronan receptor CD44 and the receptors for TGFβ and platelet-derived growth factor BB (PDGF-BB) in dermal fibroblasts. We found that the receptors for the three molecules form a ternary complex, and that PDGF-BB can activate the Smad pathway downstream of TGFβRI. Importantly, CD44 negatively modulated the signaling of both PDGF-BB and TGFβ.

In paper IV, we studied the process by which breast cancer cells invade blood-vessels and the role of hyaluronan and CD44 in angiogenesis. Importantly, CD44, or the hyaluronan degrading enzyme hyaluronidase 2 (HYAL2), decreased the capacity of endothelial cells to form tubes in a 3D in vivo-like assay.  Collectively, our studies add to the understanding of the role of hyaluronan in tumor progression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 894
Keyword
extracellular matrix, growth factor, hyaluronan synthase, hyaluronidase, epithelial-mesenchymal transition
National Category
Medical and Health Sciences
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-198165 (URN)978-91-554-8649-5 (ISBN)
Public defence
2013-05-24, B42, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-04-10 Last updated: 2015-09-11Bibliographically approved

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