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Hypoxia stimulates CXCR4 signalling in ileal carcinoids.

Journal article
Authors Yvonne Arvidsson
Anders Bergström
Linda Arvidsson
Erik Kristiansson
Håkan Ahlman
Ola Nilsson
Published in Endocrine-related cancer
Volume 17
Issue 2
Pages 303-316
ISSN 1479-6821
Publication year 2010
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Neuroscience and Physiology
Institute of Biomedicine, Department of Pathology
Department of Zoology
Pages 303-316
Language en
Links dx.doi.org/10.1677/ERC-09-0085
Subject categories Medical and Health Sciences

Abstract

Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. VEGF, CA-IX, HIF-1alpha and HIF-2alpha were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2alpha expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition (EMT) and development was altered including increased expression of the chemokine receptor CXCR4, an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand CXCL12 (SDF-1) activated the MAPK p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, and HIF-2alpha and CXCR4. Signalling through the CXCL12-CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for this carcinoid tumour disease.

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