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The receptors for transforming growth factor β (TGFβ) and platelet derived growth factor-BB (PDGF-BB) interact physically and functionally with CD44
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.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

Keyword [en]
extracellular matrix, growth factor, hyaluronan, Smad, receptor tyrosine kinase
National Category
Medical and Health Sciences Natural Sciences
Research subject
Biology with specialization in Molecular Cell Biology; Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-198164OAI: oai:DiVA.org:uu-198164DiVA: diva2:615343
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2013-04-29
In thesis
1. 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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