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DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.ORCID iD: 0000-0002-9615-5079
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 2, 170-181 p.Article in journal (Refereed) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

Place, publisher, year, edition, pages
2017. Vol. 105, no 2, 170-181 p.
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-307769DOI: 10.1159/000452891ISI: 000407672700008PubMedID: 27829249OAI: oai:DiVA.org:uu-307769DiVA: diva2:1048332
Funder
Swedish Cancer Society
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2017-11-17Bibliographically approved
In thesis
1. Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
Open this publication in new window or tab >>Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small Intestinal Neuroendocrine Tumors (SI-NETs) are indolent neoplasms with an increasing annual incidence of approximately 1/100 000 people. They are often diagnosed at a late stage, restricting treatment efficacy. The aim of this thesis was to investigate clinical aspects of patients with advanced and/or disseminated disease with regard to clinical signs and management of abdominal fibrosis, the role of locoregional surgery and liver transplantation, as well as the ex vivo sensitivity of tumor samples to cytotoxic and targeted agents. Additionally, novel serum biomarkers for the diagnosis and prognosis of SI-NETs were investigated. In Paper I, abdominal fibrosis induced by serotonin and other cytokines from tumor cells, was associated with clinically significant symptoms of intestinal ischemia and/or obstructive uropathy, and was linked to advanced disease. Prompt recognition and minimally invasive intervention with superior mesenteric vein stenting and/or percutaneous nephrostomy and J stent treatment were effective in disease palliation. Paper II challenged the role of prophylactic, upfront locoregional surgery in Stage IV, which conferred no survival advantage in asymptomatic SI-NET patients. The option of delayed surgery as needed seemed to be comparable in all the outcomes examined, whilst also offering the advantage of fewer re-operations for intestinal obstruction in patients with already disseminated disease. Paper III confirmed that most young patients (<65 years) with SI-NET and liver metastases had a favorable survival with standardized multimodality treatment and that survival figures reported after liver transplantation for NETs do not surpass these figures. In Paper IV, 145 biomarkers were analyzed in blood serum using two different multiplex proximity assays. Subsequent ELISA and immunohistochemical analyses identified DcR3, TFF3 and midkine as novel serum biomarkers for SI-NETs. In Paper V, SI-NET samples were profiled with respect to sensitivity ex vivo to a panel of standard chemotherapeutics and targeted agents using a short-term total cell kill assay. SI-NETs exhibited variable but generally intermediate sensitivity ex vivo compared with other cancer diagnoses, calling for individualized selection of therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 84 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1386
Keyword
SI-NET, fibrosis, locoregional surgery, liver transplantation, biomarkers, ex vivo sensitivity.
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-330554 (URN)978-91-513-0113-6 (ISBN)
Public defence
2017-12-08, Rosénsalen, Akademiska sjukhuset, ing 95-96, Uppsala, 09:00 (Swedish)
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Supervisors
Available from: 2017-11-16 Created: 2017-10-02 Last updated: 2017-11-16
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Edfeldt, KatarinaDaskalakis, KosmasBäcklin, ChristoferNorlén, OlovTiensuu Janson, EvaWestin, GunnarHellman, PerStålberg, Peter

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