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Importance of Hyaluronan-CD44 Signaling in Tumor Progression: Crosstalk with TGFβ and PDGF-BB Signaling
Uppsala University, Science for Life Laboratory, SciLifeLab. 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]

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 [en]
extracellular matrix, growth factor, hyaluronan synthase, hyaluronidase, epithelial-mesenchymal transition
National Category
Medical and Health Sciences
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-198165ISBN: 978-91-554-8649-5 (print)OAI: oai:DiVA.org:uu-198165DiVA: diva2:615345
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
List of papers
1. 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
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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
2. 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
3. The receptors for transforming growth factor β (TGFβ) and platelet derived growth factor-BB (PDGF-BB) interact physically and functionally with CD44
Open this publication in new window or tab >>The receptors for transforming growth factor β (TGFβ) and platelet derived growth factor-BB (PDGF-BB) interact physically and functionally with CD44
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

Keyword
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:nbn:se:uu:diva-198164 (URN)
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2013-04-29
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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