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Studies on Tissue Factor with Focus on Cell Signaling and Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis have explored the functions of the protein Tissue Factor (TF), which together with its ligand coagulation factor VII/VIIa (FVII/FVIIa) forms a proteolytic complex that functions in initiation of blood coagulation and activation of cell signaling.

In paper I, the mechanisms behind the observation that TF/FVIIa signaling protects cells from apoptosis were further investigated. Using cell culture models, we found that antiapoptotic signaling by TF/FVIIa requires signaling by the Insulin-like growth factor I receptor (IGF-1R), as synthetic IGF-1R inhibitors and IGF1-R siRNA knock-down abolished the antiapoptotic effect of FVIIa. Furthermore, the IGF-1R translocated to the cell nucleus after FVIIa stimulation, implying a role in regulation of gene expression.

Papers II and III describe the discovery that the Eph tyrosine kinase receptors EphB2 and EphA2 are proteolytically cleaved directly by TF/FVIIa. By using mass spectrometry and N-terminal Edman sequencing, the exact cleavage site was identified after a conserved arginine residue in the EphA2/EphB2 ligand binding domains, in agreement with the cleavage preferences of FVIIa. TF and EphA2/EphB2 co-localized in cancer cell lines and FVIIa potentiated ligand-dependent Eph signaling by increasing cytoskeletal remodeling and cell repulsion, demonstrating a novel proteolytical event that modulates Eph receptor signaling.

In paper IV, expression of TF was investigated in colorectal cancer in both the stromal and tumor cell compartments by immunohistochemistry using an anti-TF-antibody developed and validated by the Human Protein Atlas project. In normal large intestine, TF was strongly expressed in the innermost pericryptal sheath cell layer lining the epithelium, in a cell population distinct from intestinal pericryptal myofibroblasts. We evaluated TF expression in two colorectal cancer materials, and found that TF was variably present in both the stromal and tumor cell compartments. TF expressed by pericryptal sheath cells was progressively lost after the adenoma-to-carcinoma transition and was a strong predictor of survival in rectal but not colon cancer patients independently of disease stage, histological tumor grade and age.

In summary, this thesis demonstrates novel signaling mechanisms for the TF/FVIIa complex, and provides evidence of a hitherto unknown role of TF expressed by a specific population of stromal cells in colorectal cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1075
Keyword [en]
Tissue Factor, blood coagulation, cell signaling, protease, mass spectrometry, immunohistochemistry, colorectal cancer, apoptosis, Eph receptor
National Category
Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Clinical Chemistry; Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-245807ISBN: 978-91-554-9180-2 (print)OAI: oai:DiVA.org:uu-245807DiVA: diva2:792061
Public defence
2015-04-22, Gunnesalen, Psykiatrins hus, Ing. 10, Akademiska Sjukhuset, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-04-01 Created: 2015-03-01 Last updated: 2015-04-17
List of papers
1. Tissue factor/factor VIIa induces cell survival and gene transcription by transactivation of the insulin-like growth factor 1 receptor
Open this publication in new window or tab >>Tissue factor/factor VIIa induces cell survival and gene transcription by transactivation of the insulin-like growth factor 1 receptor
2014 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 111, no 4, 748-760 p.Article in journal (Refereed) Published
Abstract [en]

The insulin-like growth factor 1 receptor (IGF-1R) is known to promote survival and has also been implicated in the pathogenesis of several disease states, including cardiovascular disorders and cancer. Recently, we showed that binding of coagulation factor VIIa (FVIIa) to its receptor tissue factor (TF) protects cancer cells from TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Here we present evidence that this biological function of TF/FVIIa is dependent on the IGF-1R. IGF-1R inhibitors AG1024 and PPP as well as siRNA-mediated downregulation of IGF-1R, abolished the TF/FVIIa-mediated protection against TRAIL-induced apoptosis. Moreover, FVIIa rapidly induced a time- and concentration-dependent tyrosine phosphorylation of the IGF-1R in MDA-MB-231 breast cancer cells and in primary human monocytes, an event that was accompanied by IGF-1R chromatin binding and gene transcription. We hereby present novel evidence of a cross-talk between the coagulation and IGF-1R signalling systems, and propose that the IGF-1R is a key player in mediating TF/FVIIa-induced cell survival.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-223990 (URN)10.1160/TH13-07-0593 (DOI)000334152900024 ()24336871 (PubMedID)
Available from: 2014-04-29 Created: 2014-04-29 Last updated: 2017-12-05Bibliographically approved
2. The Eph Tyrosine Kinase Receptors EphB2 and EphA2 Are Novel Proteolytic Substrates of Tissue Factor/Coagulation Factor VIIa
Open this publication in new window or tab >>The Eph Tyrosine Kinase Receptors EphB2 and EphA2 Are Novel Proteolytic Substrates of Tissue Factor/Coagulation Factor VIIa
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2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 47Article in journal (Refereed) Published
Abstract [en]

Tissue factor (TF) binds the serine protease factor VIIa (FVIIa) to form a proteolytically active complex that can trigger coagulation or activate cell signaling. Here we addressed the involvement of tyrosine kinase receptors (RTKs) in TF/FVIIa signaling by antibody array analysis and subsequently found that EphB2 and EphA2 of the Eph RTK family were cleaved in their ectodomains by TF/FVIIa. We used N-terminal Edman sequencing and LC-MS/MS analysis to characterize the cleaved Eph isoforms and identified a key arginine residue at the cleavage site, in agreement with the tryptic serine protease activity of FVIIa. Protease-activated receptor 2 (PAR2) signaling and downstream coagulation activity was non-essential in this context, in further support of a direct cleavage by TF/FVIIa. EphB2 was cleaved by FVIIa concentrations in the subnanomolar range in a number of TF expressing cell types, indicating that the active cellular pool of TF was involved. FVIIa caused potentiation of cell repulsion by the EphB2 ligand ephrin-B1, demonstrating a novel proteolytical event to control Eph-mediated cell segregation. These results define Eph RTKs as novel proteolytical targets of TF/FVIIa and provide new insights into how TF/FVIIa regulates cellular functions independently of PAR2.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-240089 (URN)10.1074/jbc.M114.599332 (DOI)000345335000001 ()25281742 (PubMedID)
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2017-12-05Bibliographically approved
3. Tissue Factor/coagulation factor VIIa potentiates ligand-dependent EphA2 signaling in cancer cells
Open this publication in new window or tab >>Tissue Factor/coagulation factor VIIa potentiates ligand-dependent EphA2 signaling in cancer cells
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-245804 (URN)
Available from: 2015-03-01 Created: 2015-03-01 Last updated: 2015-04-17
4. Tissue Factor in pericryptal sheath cells identifies a specific intestinal cell population and constitutes a candidate prognostic biomarker for rectal cancer
Open this publication in new window or tab >>Tissue Factor in pericryptal sheath cells identifies a specific intestinal cell population and constitutes a candidate prognostic biomarker for rectal cancer
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-245803 (URN)
Available from: 2015-03-01 Created: 2015-03-01 Last updated: 2015-04-17

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