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Collagen of the Extracellular Matrix. Functional and Structural Studies Collagen of the extracellular matrix. Functional and structural studies. Olsson, Olof 2017 Document Version: Publisher's PDF, also known as Version of record Link to publication Citation for published version (APA): Olsson, O. (2017). Collagen of the extracellular matrix. Functional and structural studies. Lund University: Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 PER OL O F OLSS O N Collagen the of extracellular matrix in carcinoma Collagen of the extracellular matrix in carcinoma Functional and structural studies PER OLOF OLSSON DEPARTMENT OF LABORATORY MEDICINE | LUND UNIVERSITY 2017 Functional and structural studies structural and Functional Lund University, Faculty of Medicine 193907 Doctoral Dissertation Series 2017:9 ISBN 978-91-7619-390-7 ISSN 1652-8220 789176 9 9 Collagen of the extracellular matrix in carcinoma Functional and structural studies 1 2 Collagen of the extracellular matrix in carcinoma Functional and structural studies Per Olof Olsson DOCTORAL DISSERTATION By due permission of the Facultry of Medicine, Lund University, Sweden. To be defended at Segerfalksalen, BMC, Lund on the 20th January 2017 at 13.00. Faculty opponent: Prof. Stefan Johansson Department of Medical Biochemistry and Microbiology Uppsala University, Sweden 3 Organization Document name LUND UNIVERSITY Doctoral Thesis Faculty of Medicine Date of issue Translational Cancer Research Center 20 January 2017 Deparment of Laboratory Medicine Author(s) P. Olof Olsson Sponsoring organization Title and subtitle: Collagen of the extracellular matrix in carcinoma Functional and structural studies Abstract The cancer microenvironment has been attracting increasing attention as the realization of its importance for both disease treatment and malignant progression. Here the aim was to elucidate some of the effects and mechanisms of the tumor microenvironment related to the extracellular matrix (ECM). We hypothesized that collagen fibril assembly is an instrumental component in the formation of the barriers for transport of small molecules into carcinoma that have been seen in the treatment of carcinoma. To investigate this hypothesis we have utilized human xenograft and syngeneic generated tumors in mice, cellular and biochemical analyses. We found that fluid flow through carcinoma interstitium can be increased through STI571 treatment, and that this flow corresponds with a decreasing collagen fibril diameter. Additionally STI571 was found to increase blood flow and tumor oxygenation in a manner that correlates to matrix composition. Collagen fibril diameter was decreased via inhibition of the TGF-β activating integrin αvβ6 which corresponded to a clear trend toward a decreased interstitial fluid pressure, in all but the most fibrotic tumors. This illustrates the diversity of actable agents involved in stromal change. It points to a central role of collagen in the maintenance and regulation of fluid and solute exchange in tumors. Based on these results it may be possible to beneficially augment tumor treatment by altering one or more of the regulatory elements in the stroma of carcinoma. Key words. Collagen, Extra cellular matrix. TGF-beta, integrin αvβ6 Classification system and/or index terms (if any) Supplementary bibliographical information Language English ISSN and key title 1652-8220 ISBN 978-91-7619-390-7 Recipient’s notes Number of pages 80 Price Security classification I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation. Signature Date 4 Collagen of the extracellular matrix in carcinoma Functional and structural studies Per Olof Olsson 5 Cover: Collagen of the extracellular matrix Functional and structural studies Copyright. P. Olof Olsson Faculty of Medicine, Translational Cancer Research Center. Departments of Experimental Medical Science and Laboratory Medicine. ISSN 1652-8220 ISBN 978-91-7619-390-7 Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:9 Printed in Sweden by Media-Tryck, Lund University Lund 2017 6 A special thanks to: My family. For their sacrifice and encouragement through time and distance Citation. Psalm 139:14 I will praise thee; for I am fearfully and wonderfully made: marvellous are thy works; and that my soul knoweth right well. 7 Content Overview ................................................................................................................ 11 Scientific Question ....................................................................................... 11 Introduction .................................................................................................. 11 Hypotheses ................................................................................................... 12 List of Papers ................................................................................................ 13 Abstract ........................................................................................................ 14 Terms and Abbreviations: ............................................................................ 15 I Introduction .......................................................................................................... 17 II Stroma ................................................................................................................. 18 i. Loose Connective Tissue .......................................................................... 18 ii. Vessels ..................................................................................................... 19 iii. Basement membrane ............................................................................... 20 iv. Exchange between blood and interstitium .............................................. 21 v. Cellular components in stroma ................................................................. 22 III ECM components .............................................................................................. 24 i. Collagen and Collagen Assembly ............................................................. 24 ii. Non collagenous components of the ECM ............................................... 26 iv. Glycosaminoglycan and Proteoglycans .................................................. 29 IV Stroma and the Microenvironment .................................................................... 31 V Epithelial-to-mesenchymal transition (EMT). .................................................... 34 VI Physiology of carcinoma ................................................................................... 35 i. Loose connective tissue in carcinoma. ...................................................... 35 ii. Producers of stromal ECM in Carcinoma ................................................ 35 iii. Blood vessels and the exchange of fluid and solutes in carcinoma. ....... 36 VII Carcinoma and the Immune system ................................................................. 38 i. Inflammation profiles ................................................................................ 38 8 ii. Neutrophil cytosolic factor 1 (Ncf-1) a down-regulation of autoimmunity. .......................................................................................... 39 VIII Barriers to transport ........................................................................................ 40 i. Interstitial Fluid Pressure (PIF) ................................................................. 40 IX ECM and growth factor signaling ..................................................................... 42 i TGF-β: TGF-β activation and biological significance. .............................. 43 X Aims of the thesis ............................................................................................... 45 i. Ambition of the studies. ............................................................................ 45 XI Methods and Models ......................................................................................... 47 i. Model System ........................................................................................... 47 ii. Cell and Mouse lines ................................................................................ 47 iii. Hexosaminidase Assay to determine cell numbers ................................. 49 iv. TGF-β Luciferase Assay ......................................................................... 49 v. PIF measurement .....................................................................................
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