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Expression of tyrosine kinase receptors in malignant midgut carcinoid tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2006 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 84, no 1, 42-48 p.Article in journal (Refereed) Published
Abstract [en]

Background: The expression of certain tyrosine kinase receptors (TKR) has been shown to have a prognostic value in many tumor entities. In recent years, inhibitors and monoclonal antibodies directed towards these receptors have been developed. Several have shown antitumoral effects and have been tested in clinical trials. We wanted to investigate whether midgut carcinoid tumors express TKR and therefore would be suitable for clinical trials with TKR inhibitors (TKRI) or monoclonal antibodies. Material and Methods: Tumor tissue from 36 patients (24 women and 12 men) with a malignant midgut carcinoid tumor was obtained. The tissues were examined with immunohistochemistry, using polyclonal antibodies against platelet-derived growth factor receptor-α (PDGFRα), platelet-derived growth factor receptor-β (PDGFRβ), epidermal growth factor receptor (EGFR) and c-kit. Human BON1 cells were cultivated and stimulated with PDGF-BB. We also present a case report of a patient with a malignant midgut carcinoid tumor who had stabilization of tumor growth during treatment with imatinib. Results: Immunohistochemical staining for PDGFRα in tumor cells showed immunoreaction for the receptor in 13/34 (38%) for PDGFRβ in 29/33 (88%), and 24/33 (73%) were immunoreactive for EGFR. No tumor tissue showed immunoreaction for c-kit. In tumor stroma PDGFRα was expressed in 35%, PDGFRβ in 94% and EGFR in 9%. We show that human neuroendocrine tumor cells respond to PDGF, indicating that these tumors express functional PDGF receptors. Conclusion: Malignant midgut carcinoid tumors may express three of the four TKR tested in this investigation. Therefore, these tumors might be susceptible for treatment with TKRI or monoclonal antibodies and this should be further explored in clinical trials.

Place, publisher, year, edition, pages
2006. Vol. 84, no 1, 42-48 p.
Keyword [en]
Carcinoid tumor, Immunohistochemistry, Trastuzumab, treatment, Tyrosine kinase receptors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95344DOI: 10.1159/000096294ISI: 000242846900005PubMedID: 17047316OAI: oai:DiVA.org:uu-95344DiVA: diva2:169519
Available from: 2007-01-19 Created: 2007-01-19 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Midgut Carcinoid Tumours: New Diagnostic Procedures and Treatment
Open this publication in new window or tab >>Midgut Carcinoid Tumours: New Diagnostic Procedures and Treatment
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Midgut carcinoid tumours are rare with an incidence of 0.5-2.1/100 000. The primary tumour is usually small and grows slowly but has almost always set metastases at diagnosis. When radically operated, most patients will eventually recur in their disease.

We evaluated different methods in detecting recurrent disease in 61 malignant midgut carcinoid tumours that had been radically operated. Thirty-eight patients have been diagnosed with a recurrence. In 32/38 of these patients P-Chromogranin A was the first method to indicate a recurrence. We therefore recommend using P-CgA in the work up in these patients.

We investigated characteristics, survival and independent factors that could be of bad prognostic value. We found that in our 284 malignant midgut carcinoid tumours, 208/284 (73%) had distant metastases and 30/284 (11%) had carcinoid heart disease. Median survival was 115.5 months and five-year survival was 77%. In a multivariate analysis liver metastases and carcinoid heart disease were poor prognostic factors.

We performed a phase II study with octreotide pamoate investigating the clinical effect in 12 malignant midgut carcinoid tumours in a progressive phase. We found that 9/12 (75%) were stabilised for a median duration of 12 months. We think that this is a good effect considering the advanced stage.

We investigated the frequency of four different tyrosine kinase receptors, platelet derived growth factor receptor (PDGR) α and β, epidermal growth factor receptor (EGFR) and c-kit, in 36 malignant midgut carcinoid tumours with immunohistochemistry. We found that 13/34 (38%) tumour samples expressed PDGFRα, 29/33 (88%) PDGFRβ, 24/33 (73%) EGFR, whereas none expressed c-kit. This implicates that midgut carcinoid tumours might be susceptible to treatment with tyrosine kinase receptor inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 216
Keyword
Medicine, Midgut carcinoid tumour, Chromogranin A, Carcinoid heart disease, Survival, Octreotide pamoate, Tyrosine kinase receptors, Platelet derived growth factor receptor, Epidermal growth factor receptor, Medicin
Identifiers
urn:nbn:se:uu:diva-7436 (URN)978-91-554-6773-9 (ISBN)
Public defence
2007-02-09, Enghoffsalen, Ing 50 bv, Akademiska sjukhuset, Uppsala, 13:15
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Available from: 2007-01-19 Created: 2007-01-19Bibliographically approved

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