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Cell-cell interactions in the gastrointestinal tumour-microenvironment

Hawinkels, L.J.A.C.

Citation

Hawinkels, L. J. A. C. (2009, January 27). Cell-cell interactions in the gastrointestinal tumour- microenvironment. Retrieved from https://hdl.handle.net/1887/13432

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/13432

Note: To cite this publication please use the final published version (if applicable).

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Cell-cell interactions in the gastrointestinal tumour-microenvironment

Lukas Hawinkels

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Cell-cell interactions in the gastrointestinal tumour-microenvironment

Lukas J.A.C. Hawinkels

Thesis, University of Leiden with references-with summary in Dutch and English

ISBN: 978-90-9023531-8

Cover design by Jordi van de Wall

Printing: Gildeprint drukkerijen, Enschede

© 2008 L.J.A.C. Hawinkels, Leiden, the Netherlands

All rights reserved. No part of this thesis may be reproduced or transmitted in any form, by any means, electronic or mechanical without prior written permission of the author.

Printing of this thesis was financially supported by the Stichting Nationaal Fonds Tegen Kanker, Section Experimental Gastroenterology (SEG) of the Netherlands Society of Gastroenterology (NVGE), Novartis Oncology, Calbiochem, Greiner Bio-one and Tebu-bio.

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Cell-cell interactions in the gastrointestinal tumour-microenvironment

PROEFSCHRIFT

ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof. mr. P.F. van der Heijden,

volgens besluit van het College voor Promoties te verdedigen op dinsdag 27 januari 2009

klokke 15.00 uur

door

Lukas Jacobus Antonius Christiaan Hawinkels

geboren te Heerlen in 1980

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Promotiecommissie:

Promotor:

Prof. dr. C.B.H.W. Lamers

Co-Promotores:

Dr. C.F.M. Sier Dr. ir. H.W. Verspaget

Referent:

Prof. dr. A. Noël, Université de Liège, Belgique

Overige leden:

Prof. dr. P. ten Dijke Prof. dr. D.W. Hommes

Prof. dr. E.A.L. Biessen, Universiteit Maastricht

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Aan pap, mam en opa

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Contents

Abbreviations 9 Chapter 1

General introduction 11 Chapter 2

Outline and aim of the thesis 45 Chapter 3

Tissue level, activation and cellular localisation of TGF-1 and 49 association with survival in gastric cancer patients

British Journal of Cancer 2007; 97, 398-404

Chapter 4

Active TGF-1 correlates with myofibroblasts and malignancy in the 65 colorectal adenoma-carcinoma sequence

Submitted

Chapter 5

Interaction between colon cancer cells and fibroblasts generates 83 myofibroblasts via activation of Transforming Growth Factor-1

Submitted

Chapter 6

VEGF release by MMP-9 mediated heparan sulphate cleavage induces 107 colorectal cancer angiogenesis

European Journal of Cancer 2008; 44, 1904-1913

Chapter 7

Endothelium specific matrilysin (MMP-7) expression in human cancers 127 Matrix Biology 2008; 27, 267-271

Chapter 8

Determination of matrilysin activity in gastrointestinal neoplasia 137 European Journal of Clinical Investigation 2007; 37, 598-599

Chapter 9

Efficient degradation-aided selection of protease inhibitors by phage display 145 Biochemical and Biophysical Research Communications 2007; 364, 549-555

Chapter 10

Endoglin shedding in colorectal cancer 159 Manuscript in preparation

Chapter 11

Summarizing discussion 175

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Chapter 12

Nederlandse samenvatting voor niet-ingewijden 189

List of publications 195

Curriculum vitae 197

Nawoord 199

Full-colour illustrations 201

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Abbreviations:

ADAM(T) A disintegrin and metalloproteinase (with thrombospondin motive) APC Adenomatous polyposis coli

ALK Activin receptor-like kinase BIA Bioactivity assay

bFGF basic Fibroblast growth factor BMP Bone morphogenic protein BSA Bovine serum albumin CAF Cancer-associated fibroblast CM Conditioned medium CRC Colorectal cancer

CTGF Connective tissue growth factor DMEM Dulbecco’s modified eagle medium ECM Extracellular matrix

EMMPRIN Extracellular matrix metalloproteinase inducer EMT Epithelial to mesenchymal transition

FAP Familiar adenomatous polyposis

HNPCC Heriditary non-polyposis colorectal cancer HB-EGF Heparin binding epidermal growth factor HIF Hypoxia inducible factor

HRP Horse radish peroxidase HSPG Heparan sulphate proteoglycan

HUVEC Human umbilical vein endothelial cells IGF Insulin like growth factor

IL Interleukin kDa kilo Dalton

LAP Latency associated protein LLC Large latent TGF- complex LTBP Latent TGF- binding protein MAPK Mitogen activated protein kinases MCP-1 Monocyte chemoattractant protein-1 MHC Major histocompatibility complex MMP Matrix metalloproteinases

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Abbreviations

- 10 - MT-MMP Membrane type matrix metalloproteinases PAI-1 Plasminogen activator inhibitor-1

RT Room temperature SDS Sodium dodecyl sulphate SLC Small latent TGF- complex SMA Smooth muscle actin

TGF- Transforming growth factor-

TGF- RII Transforming growth factor- receptor II TIMP Tissue inhibitor of metalloproteinase TNF- Tumour necrosis factor-

TNM Tumour node metastasis

tPA tissue-type Plasminogen activator TSP Thrombospondin

uPA urokinase type Plasminogen activator uPAR uPA receptor

VEGF Vascular endothelial growth factor

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