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Heparanase expression soils the microenvironment for tumor growth by enhancing Notch signaling and suppressing antitumor immunity.: Heparanase effects on immune response in tumor microenvironment.
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(English)In: Article in journal (Other academic) Submitted
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-363257OAI: oai:DiVA.org:uu-363257DiVA, id: diva2:1256046
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15
In thesis
1. Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis
Open this publication in new window or tab >>Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate proteoglycans (HSPGs) consist of a protein core to which several linear, negatively charged heparan sulfate (HS) chains are covalently attached. HSPGs are expressed on the cell surface and in the extra-cellular matrix (ECM) where they have diverse biological functions, for example co-receptor functions. The diverse functions of HS are linked to structural variability of the polysaccharide. In this thesis, I investigated HS structure-function relationship by using different cell and animal models of one HS-biosynthetic enzyme, glucuronyl C5-epimerase (Hsepi) and one enzyme responsible for post synthetic modification, heparanase.

Deletion of Hsepi in mice resulted in neonatal lethality, with multiple organ defects, indicating the importance of HS in embryogenesis. Up-regulated expression of heparanase is found in most human tumor tissues, correlating with increased metastatic potential and decreased survival of cancer patients.

In the first project, I focused on the effects of HS on cancer associated cell signaling and found that heparanase overexpression attenuated TGF-β1 stimulated Smad phosphorylation in tumor cells because of increased sulfation degree and turnover rate of HS.

Heparanase role in cancer progression has led to clinical trials where inhibition of heparanase activity is currently being evaluated as a potential cancer treatment. Heparin, a HS-related polysaccharide, is being used to inhibit heparanase activity. In my second project, we studied the effect of low molecular weight heparin (LMWH) on cisplatin resistance of ovarian cancer cells (A2780cis). LMWH treatment of A2780cis cells reduced Wnt-activity in these cells and consequently reduce the drug resistance.

In paper III, we continued exploring the HS/heparanase role in cancer by using heparanase overexpressing mice (Hpa-tg). We found Lewis Lung Carcinoma (LLC2) cells showed faster growth, bigger tumors and more metastasis in the Hpa-tg mice as compared to wild-type (WT) mice, because of suppressed antitumor immunity in the Hpa-tg mice.

In paper IV and V, we studied the structure-function relationship of HS by using Hsepi-/- mice model. Hsepi-/- results in HS-chains lacking IdoA, which makes the chain rigid and consequently affects its co-receptor function. Skeletal malformation in Hsepi-/- mice, led us in paper IV to investigate bone morphogenic protein (BMP), an important signal molecule during embryogenesis and known to interact with HS. We found upregulation of a number of BMPs and expression of P-smad1/5/8, but reduced expression of inhibitory Smads and Gremlin1 in the Hsepi-/- MEF cells. The study indicated that the developmental defects in Hsepi mice could be contributed by a higher BMP signaling. In paper V we investigated the lung of the Hsepi-/- mice. The distal lung of 17.5 days old embryos remained populated by epithelial tubules, because of impaired differentiation of type I cells of the lungs. Potential mechanisms behind the failure of type I cell formation was identified to be reduced vascularization and a sustained signaling of Smad pathways.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1506
Keywords
Heparanase, Glucuronyl-C5 epimerase, Heparan Sulfate, Heparin, Lung Cancer, Cancer cell Singling, TGF-Beta, BMP, VEGF, Notch Signaling, Tumor growth, Metastasis, embryonic development
National Category
Cell and Molecular Biology Cancer and Oncology Physiology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-363258 (URN)978-91-513-0478-6 (ISBN)
Public defence
2018-12-06, 13:15 (English)
Opponent
Supervisors
Funder
Swedish Cancer Society
Note

Tahira Batool 's  PhD was funded  for three years (2014-2017) by Erasmus Mundus "Experts4Asia " programm coordinated by  University of Göttingen, Germany.

Available from: 2018-11-15 Created: 2018-10-15 Last updated: 2018-11-30

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