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Novel Collagen Markers for Early Detection of Bone Metastases in Breast and Prostate Cancer Patients

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Novel Collagen Markers for Early Detection of Bone Metastases in Breast and Prostate Cancer Patients Downloaded from orbit.dtu.dk on: Oct 10, 2021 Novel Collagen Markers for Early Detection of Bone Metastases in Breast and Prostate Cancer Patients Leeming, Diana Julie Publication date: 2010 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Leeming, D. J. (2010). Novel Collagen Markers for Early Detection of Bone Metastases in Breast and Prostate Cancer Patients. Technical University of Denmark. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Novel Collagen Markers for Early Detection of Bone Metastases in Breast and Prostate Cancer Patients Ph.d. Thesis by Diana Julie Leeming, May 2010 Technical University of Denmark, Department of Systems Biology Nordic Bioscience 1 Novel Collagen Markers for Early Detection of Bone Metastases Front page pictures 1. Detection of bone metastases by TC99 scintigraphy from anterior and posterior sides. Bone metastases are visualized as “hot-spots” where local bone turnover is high. Adapted from http://emedicine.medscape.com/article/1255262-overview. 2. Example of a MS/MS spectrum of a peptide from collagen type I cleaved by matrix metalloproteinase 2 (MMP-2). Fragmentation occurs and are denoted y and b ions. The fragmentation pattern reveals the amino acid sequence when analyzing using a MS database such as MASCOT. 3. Example of a competitive enzyme linked immunosorbent assay (ELISA) construction involving a biotinylated peptide (epitope-Bio) for coating of the streptavidin surface; a monoclonal antibody (mAb1); a sample and an anti-mouse labeled with horse radish peroxidase (Anti-mouse-POD). 4. Interactions between tumour cells, osteoblasts, and osteoclasts in the proximity of a bone metastasis. Tumour cells may stimulate bone cells with predominantly osteolytic or osteoblastic mediators. Increased activity of osteoblasts and osteoclasts results in the release of different biomarkers (enzymes, bone matrix components, and degradation peptides from collagen type I), which can be detected in the serum/plasma and/or urine. Adapted from [1]. 2 Novel Collagen Markers for Early Detection of Bone Metastases Supervisors DTU: Vibeke Barkholt, Associate Professor (1st part of the Ph.d) Department of Systems Biology Enzyme and Protein Chemistry Technical University of Denmark Søltofts Plads, Building 224, room 218 2800 Kgs. Lyngby, Denmark [email protected] Per Hägglund, Associate Professor (2nd part of the Ph.d) Department of Systems Biology Enzyme and Protein Chemistry Technical University of Denmark Søltofts Plads, Building 224, room 124 2800 Kgs. Lyngby, Denmark [email protected] Susanne Jacobsen, Associate Professor Department of Systems Biology Enzyme and Protein Chemistry Technical University of Denmark Søltofts Plads, Building 224, room 208 2800 Kgs. Lyngby, Denmark [email protected] Nordic Bioscience: Per Qvist, Ph.d, Vice President Herlev Hovedgade 207 DK-2730 Herlev [email protected] Inger Byrjalsen, DMSc Herlev Hovedgade 207 DK-2730 Herlev [email protected] 3 Novel Collagen Markers for Early Detection of Bone Metastases Acknowledgements This business Ph.d. project was funded by the Ministry of Science, Technology and Innovation (VTU) and Nordic Bioscience A/S, and the Ph.d. was completed in collaboration between the Nordic Bioscience A/S and the Technical University of Denmark. I would like to thank Per Hägglund, Per Qvist, Vibeke Barkholt, Susanne Jacobsen and Inger Byrjalsen who all have provided great support, guidance, and interest for my Ph.d work and for the writing process of papers and this report. I would also like to thank Morten Karsdal for guidance, good discussion and enthusiasm for the work and paper writing. Furthermore, I would like to thank my colleagues at Nordic Bioscience and Nordic Bioscience Beijing for good discussions and for technical help. In particular, I would like to thank Dorthe Vang Larsen, Quoc Hai Treu Nguyen, Yi He, and Chen Zhang for good scientific talks and technical assistance. I would also like to thank my collaborators Mitsuru Koizumi, Japan; Axel Hegele, and Peter Olbert, Germany, for supplying samples from their cancer studies. Finally I would also like to thank Dan Oersnes, my family and friends who all have supported my work. _______________________________ Diana Julie Leeming May 2010 4 Novel Collagen Markers for Early Detection of Bone Metastases Table of Contents Acknowledgement List of abbreviations……..…………………………………………………………………………………………………………………… p.7 Abstract……………………..……………………………………………………………………………………………………………………… p.9 Sammendrag på dansk….…….……………………………………………………………………………………………………………. p.11 Preface………………………………………………………………………………………………………………………………………………..p.13 CHAPTER 1 Objectives of the present study……………………………………………………………………………………p.14 CHAPTER 2 Introduction………………………………………………………………………………………………………………….p.15 State-of-the-art for the detection of bone metastases Biomarkers for the detection of bone metastases I. Bone – Anatomy, Extracellular Matrix, Cells………………………….…………………………..p.18 Bone anatomy Bone structure and extracellular matrix Collagen type I Bone cells Bone remodeling II. Breast- and prostate cancer metastases…….….…………………………………………………p.27 Extracellular matrix remodeling Matrix metalloproteinase’s MMPs - involvement in cancer proliferation The pathogenesis of the vicious cycle III. Biomarkers for the evaluation of bone metastases………………………………………….p.34 Post translational modifications – Neo-epitopes as biomarker targets Identification of biomarkers IV. Assay development –ELISA…………………………………………….……………………………….p.40 Selection of targets Development of monoclonal antibodies ELISA development -Technical optimizations Preclinical and clinical evaluation CHAPTER 3 Original paper 1……..………………………………………………………………………………………………………p.45 “Biochemical Markers for Monitoring Response to Therapy; Evidence for Higher Bone Specificity by a Novel Marker compared to Routine Markers”. Abstract, introduction, Materials & Methods, Results, Discussion, Conclusion. CHAPTER 4 Original paper 2…………………………………………………………………………………………………………….p.58 “Enzyme-linked Immunosorbent Serum Assays (ELISAs) for Rat and Human N- terminal Pro-Peptide of Collagen Type I (PINP) –Assessment of Corresponding Epitopes”. Abstract, introduction, Materials & Methods, Results, Discussion, Conclusion. 5 Novel Collagen Markers for Early Detection of Bone Metastases CHAPTER 5 Original Paper 3…………………………………………………………………………………………………………….p.72 “A Newly Developed Serum N-terminal propeptide of Collagen type I assay was Associated with the number of Bone Metastases in Breast and Prostate cancer”. Abstract, introduction, Materials & Methods, Results, Discussion, Conclusion. CHAPTER 6 Original paper 4…………………………………………………………………………………………………………….p.84 “A novel assay for assessment of extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated neo-epitope of type I collagen destroyed by cathepsin K cleavage” CHAPTER 7 Review paper 5.…………………………………………………………………………………………………………….p.101 “Is Bone Quality Associated to Collagen Age?” Abstract, introduction, Materials & Methods, Results, Discussion, Conclusion. CHAPTER 8 Review paper 6.…………………………………………………………………………………………………………….p.113 “Post-translational modifications of the extracellular matrix are key events in cancer progression - Opportunities for biochemical marker development” CHAPTER 9 Brief overview on additional data..............................................................................p.129 CHAPTER 10 Concluding Remarks………………………….…………………………………………………………………………..p.143 CHAPTER 11 Reference list……………………………………….………………………………………………………………………..p.145 Appendix I: “An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice.” by Leeming DJ, Alexandersen P, Karsdal MA, Qvist P, Schaller S, Tanko LB. Appendix II: “Biochemical approach to the detection and monitoring of metastatic bone disease: What do we know and what questions need answers?” by Tanko LB, Christiansen C, Karsdal MA and Leeming DJ. Appendix III: Fibrosis patent PJS/P16599WO. 6 Novel Collagen Markers for Early Detection of Bone Metastases List of abbreviations 2D Two dimensional ALP Alkaline phosphatase activity BM Basement membrane BMP Bone Morphogenetic Protein BMU Bone multicellular unit BSAP Bone specific alkaline phosphatase CAII Carbonic anhydrase II Cat K Cysteine proteinase cathepsin K CID Collision induced dissociation CSF-1 Colony stimulating factor 1 CTGF Connective tissue growth factor CTR Calcitonin Receptor CTX-I C-telopeptide of collagen type I CXCR4 Chemokine receptor 4 DPD Dexypyridinoline ECM Extracellular matrix ECMR Extracellular matrix remodeling ELISA Enzyme-linked immunosorbent assays ET Endothelin (ET) FGF Fibroblast growth factor HPLC High performance liquid chromatography Hpx Hemopexin HRP Horse radish peroxidase
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