title: Hypoxia stimulates CXCR4 signalling in ileal carcinoids.
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. Vascular endothelial growth factor (VEGF), carbonic anhydrase (CA-IX), hypoxia-inducible factor (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 and development was altered including increased expression of the C-X-C chemokine receptor type 4 (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 (stromal cell-derived factor 1 (SDF-1)), activated the mitogen-activated protein kinase (MAPK) p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, 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 carcinoid tumour disease.
authors.affiliation: Lundberg Laboratory for Cancer Research, Department of Pathology and Cytology, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden. yvonne.arvidsson@gu.se
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Arvidsson
authors.forename: Anders
authors.initials: A
authors.lastname: Bergström
authors.forename: Linda
authors.initials: L
authors.lastname: Arvidsson
authors.forename: Erik
authors.initials: E
authors.lastname: Kristiansson
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlman
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism; D002276:Carcinoid Tumor / Q000378:metabolism*; D015687:Cell Hypoxia; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007078:Ileal Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002256:Carbonic Anhydrases; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020928:Mitogen-Activated Protein Kinases; D019718:Receptors, CXCR4; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C527276:CXCR4 protein, human; C497442:HIF1A protein, human