Lundberg Laboratory for Cancer Research, Department of Pathology and Cytology, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
Endocr Relat Cancer. 2010 Jun 1;17(2):303-16. doi: 10.1677/ERC-09-0085. Print 2010 Jun.
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.
肿瘤缺氧与转移潜能增加以及对放疗和化疗的抵抗有关。回肠类癌通常在诊断时就已经转移，并且对化疗反应不佳。本研究旨在探讨回肠类癌中的缺氧程度以及肿瘤细胞对诱导性缺氧的反应。通过免疫组织化学方法研究了 24 例回肠类癌患者活检组织中的血管内皮生长因子 (VEGF)、碳酸酐酶 (CA-IX)、缺氧诱导因子 (HIF)-1alpha 和 HIF-2alpha。所有缺氧标志物在肿瘤的局部区域均高度表达，无论肿瘤位置或分期如何。然而，与同一患者的原发性肿瘤相比，HIF-2alpha 在远处转移中的表达明显更高。GOT1 类癌细胞的全基因组表达谱分析显示对缺氧有明显反应。与上皮间质转化和发育相关的基因表达发生改变，包括 CXCR4（C-X-C 趋化因子受体 4）的表达增加，这是一种重要的侵袭性生长和转移形成调节剂。肿瘤活检组织的免疫组织化学证实了 CXCR4 的高表达。CXCR4 配体 CXCL12（基质细胞衍生因子 1 (SDF-1)）刺激 GOT1 细胞，激活丝裂原活化蛋白激酶 (MAPK) p42/44 信号通路并增加肿瘤细胞迁移。我们得出结论，回肠类癌含有表达 HIF-1alpha、HIF-2alpha 和 CXCR4 的缺氧区域。通过 CXCL12-CXCR4 轴的信号传递可能有助于回肠类癌的转移潜能。针对 HIFs 和/或 CXCR4 信号通路可能为类癌肿瘤疾病提供新的治疗策略。
