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Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids

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Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 929 Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids TAO CUI ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8735-5 UPPSALA urn:nbn:se:uu:diva-205570 2013 Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, Entrance 50, Uppsala Hospital, Uppsala, Friday, October 18, 2013 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Abstract Cui, T. 2013. Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 929. 46 pp. Uppsala. ISBN 978-91-554-8735-5. Small intestine neuroendocrine tumors (SI-NETs) and lung carcinoids (LCs) are relatively indolent tumors, which originate from neuroendocrine (NE) cells of the diffuse NE system. Metastases can spread before diagnosis. Thus, potential cures become unavailable, which entitles new biomarker development. Indeed, we aimed at developing Ma2 autoantibodies and olfactory receptor 51E1 (OR51E1) as potential novel biomarkers and exploring other candidate protein markers in patients’ serum. First, we established a sensitive, specific and reliable anti-Ma2 indirect ELISA to distinguish SI-NET patients from healthy controls. We detected longer progression-free and recurrence- free survivals in patients expressing low anti-Ma2 titers. Moreover, a high anti-Ma2 titer was more sensitive than chromogranin A for the risk of recurrence after radical operation of SI-NET patients. We then investigated OR51E1 expression in SI-NETs and LCs. OR51E1 mRNA expression, analyzed by quantitative real-time PCR, was high in microdissected SI-NET cells, in LC cell lines and in frozen LC specimens. Immunohistochemistry (IHC) showed abundant OR51E1 protein expression in SI-NETs. OR51E1 co-expressed with vesicular-monoamine-transporter-1 in the majority of normal and neoplastic enterochromaffin cells. Furthermore, the study on LCs revealed that OR51E1, somatostatin receptor (SSTR) 2, SSTR3, and SSTR5 are expressed in 85%, 71%, 25% and 39% of typical carcinoids (TCs), whereas in 86%, 79%, 43% and 36% of atypical carcinoids (ACs). Based on the proposed IHC scoring system, in the LC cases, where all SSTR subtypes were absent, membrane OR51E1 expression was detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 scores were detected in 5 out of 6 OctreoScan-negative LC lesions. In addition, the last presented study used a novel suspension bead array, which targeted 124 unique proteins, by using Human Protein Atlas antibodies, to profile biotinylated serum samples from SI-NET patients and healthy controls. We showed 9 proteins, IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP as significant contributors to tumor classification. In conclusion, we proposed Ma2 autoantibodies as a sensitive circulating marker for SI-NET recurrence; OR51E1 as a candidate therapeutic target for SI-NETs; whereas as a novel diagnostic marker for LCs and 9 serum proteins as novel potential SI-NET markers. Keywords: small intestine neuroendocrine tumors, lung carcinoids, Ma2 autoantibodies, immunohistochemistry, olfactory receptor 51E1, blood samples, antibody suspension bead array Tao Cui, Uppsala University, Department of Medical Sciences, Endocrine Oncology, Akademiska sjukhuset, SE-751 85 Uppsala, Sweden. © Tao Cui 2013 ISSN 1651-6206 ISBN 978-91-554-8735-5 urn:nbn:se:uu:diva-205570 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205570) To my parents, Fang, baby and friends 致爸妈，昉，宝宝及朋友们 List of Papers This thesis is based on the following papers, which are listed by their Roman numerals. I Cui T, Hurtig M, Elgue G, Li SC, Veronesi G, Essaghir A, Demoulin JB, Pelosi G, Alimohammadi M, Öberg K, Giandomenico V. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS One. 2010 Dec 30;5(12):e16010. II Cui T*, Tsolakis AV*, Li SC, Cunningham JL, Lind T, Öberg K, Giandomenico V. Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas. Eur J Endocrinol. 2013 Jan 17;168(2):253-61. III Giandomenico V*, Cui T*, Grimelius L, Öberg K, Pelosi G, Tsolakis AV. Olfactory receptor 51E1 as a novel target for diagnosis in somatostatin receptor negative lung carcinoids. J Mol Endocrinol, Advanced online publication 2013 Aug 22. IV Darmanis S, Cui T, Drobin K, Li SC, Öberg K, Nilsson P, Schwenk JM, Giandomenico V. Identification of candidate serum proteins for classifying well-differentiated small intestinal neuroendocrine tumors. Submitted Manuscript. *The authors contributed equally. Reprints were made with permission from the respective publishers. Other related works I Li SC, Martijn C, Cui T, Essaghir A, Luque RM, Demoulin JB, Castaño JP, Öberg K, Giandomenico V. The somatostatin analogue octreotide inhibits growth of small intestine neuroendocrine tumour cells. PLoS One. 2012. 7(10):e48411. II Naboulsi R, Bergström J, Li SC, Cui T, Öberg K, Nystrand M, Giandomenico V. The immunoCAP ISAC technology to develop a novel diagnostic tumor immunoassay for rare small intestinal neuroendocrine tumor patients. Submitted manuscript. Supervisors Assoc. Prof. Valeria Giandomenico, PhD, Dept of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden Prof. Kjell Öberg, MD, PhD, Dept of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden Dr. Apostolos V Tsolakis, MD, PhD, Dept of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden Chair Prof. Magnus Essand, PhD, Dept of Immunology, Genetics and Pathology, Clinical Immunology, Research Group Essand, Rudbeck laboratory, Uppsala University, Uppsala, Sweden Faculty Opponent Assoc. Prof. Marco Volante, MD, PhD , Dept of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Turin, Italy Review Board Prof. Gunnar Westin, PhD, Dept of Surgical Sciences, Endocrine Surgery, Uppsala University Assoc. Prof. Ali Ata Moazzami, PhD, Dept of Chemistry, Organic Chemistry, Swedish Univeristy of Agricultural Sciences Dr. Anders Sundqvist, PhD, Ludwig Institute for Cancer Research, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden Program Controller Prof. Eva Tiensuu Janson, MD, PhD, head of Dept of Medical Sciences Contents Introduction ................................................................................................... 11 Neuroendocrine cells ................................................................................ 11 General NE markers ................................................................................. 11 Specific markers of NE cells in the GI-tract ............................................ 12 Small intestine neuroendocrine tumors .................................................... 13 Lung carcinoids ........................................................................................ 15 Novel biomarkers in SI-NETs and LCs ................................................... 17 Paraneoplastic antigen Ma2 autoantibodies ............................................. 18 Olfactory receptor 51E1 ........................................................................... 19 Aims of the study .......................................................................................... 22 Materials and Methods .................................................................................. 23 Laser capture microdissection (Paper II) .................................................. 23 Indirect enzyme-linked immunosorbent assay (Paper I) .......................... 23 In vitro transcription-translation (ITT) and sequential immunoprecipitation (IP) (Paper I) .......................................................... 24 Immunohistochemistry (Paper I, II, III) ................................................... 24 Antibody suspension bead array (Paper IV) ............................................. 25 Statistical Analysis (Paper I, II, III, IV) ................................................... 27 Results and Discussion ................................................................................. 28 Paper I. .................................................................................................... 28 Paper II. .................................................................................................... 30 Paper III. ................................................................................................... 31 Paper IV. .................................................................................................. 33 Concluding Remarks and Perspectives ......................................................... 35 Abstract in Chinese (中文摘要) ................................................................... 37 Acknowledgements ....................................................................................... 38 References ..................................................................................................... 41 Abbreviations 5-HIAA 5-hydroxyindoleacetic acid 5-HT 5-hydroxytryptamine, serotonin 5-HTP 5-hydroxytryptophan AC atypical (lung) carcinoid Akt protein kinase B AUC area under (ROC) curve Bax B-cell lymphoma 2-associated X protein BGA between group analysis cAMP cyclic
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