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DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.ORCID-id: 0000-0002-9615-5079
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
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2017 (Engelska)Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, nr 2, s. 170-181Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2017. Vol. 105, nr 2, s. 170-181
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
URN: urn:nbn:se:uu:diva-307769DOI: 10.1159/000452891ISI: 000407672700008PubMedID: 27829249OAI: oai:DiVA.org:uu-307769DiVA, id: diva2:1048332
Forskningsfinansiär
CancerfondenTillgänglig från: 2016-11-21 Skapad: 2016-11-21 Senast uppdaterad: 2018-02-20Bibliografiskt granskad
Ingår i avhandling
1. Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
Öppna denna publikation i ny flik eller fönster >>Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 84
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1386
Nyckelord
SI-NET, fibrosis, locoregional surgery, liver transplantation, biomarkers, ex vivo sensitivity.
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:uu:diva-330554 (URN)978-91-513-0113-6 (ISBN)
Disputation
2017-12-08, Rosénsalen, Akademiska sjukhuset, ing 95-96, Uppsala, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2017-11-16 Skapad: 2017-10-02 Senast uppdaterad: 2018-03-07

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Edfeldt, KatarinaDaskalakis, KosmasBäcklin, ChristoferNorlén, OlovTiensuu Janson, EvaWestin, GunnarHellman, PerStålberg, Peter

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Edfeldt, KatarinaDaskalakis, KosmasBäcklin, ChristoferNorlén, OlovTiensuu Janson, EvaWestin, GunnarHellman, PerStålberg, Peter
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EndokrinkirurgiCancerfarmakologi och beräkningsmedicinOnkologisk endokrinologi
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