Rofstad Einar K, Mathiesen Berit, Galappathi Kanthi
Group of Radiation Biology and Tumor Physiology, Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
Cancer Res. 2004 Jan 1;64(1):13-8. doi: 10.1158/0008-5472.can-03-2658.
Cancer patients showing local failure after radiation treatment have increased probability for developing metastatic disease. The mechanisms behind this observation have not been identified. In the present work, metastatic spread after inadequate radiation therapy was studied by using R-18 human melanoma xenografts as models of cancer in humans. Pimonidazole was used as a hypoxia marker, and hypoxia and urokinase-type plasminogen activator receptor (uPAR) expression were detected by immunohistochemistry. R-18 tumors regrowing after subcurative irradiation showed a higher frequency of lymph node metastasis than unirradiated tumors. The expression of uPAR was up-regulated in hypoxic tumor regions, and the fractions of hypoxic and uPAR-positive cells were approximately 2-fold higher in regrowing irradiated tumors than in untreated tumors. Treatment with anti-uPAR antibody blocked metastasis almost completely in irradiated as well as unirradiated tumors. The metastatic frequency was higher in tumors regrowing after irradiation than in unirradiated tumors because the irradiation induced tumor hypoxia, and tumor hypoxia induced up-regulation of uPAR.
放射治疗后出现局部失败的癌症患者发生转移性疾病的概率增加。这一观察结果背后的机制尚未明确。在本研究中，以R-18人黑色素瘤异种移植瘤作为人类癌症模型，研究了放疗不足后的转移扩散情况。匹莫硝唑用作缺氧标志物，通过免疫组织化学检测缺氧和尿激酶型纤溶酶原激活物受体（uPAR）的表达。亚根治性照射后复发的R-18肿瘤发生淋巴结转移的频率高于未照射的肿瘤。uPAR的表达在缺氧肿瘤区域上调，复发的照射后肿瘤中缺氧和uPAR阳性细胞的比例比未治疗的肿瘤高约2倍。用抗uPAR抗体治疗几乎完全阻断了照射和未照射肿瘤的转移。照射后复发的肿瘤转移频率高于未照射的肿瘤，因为照射诱导肿瘤缺氧，而肿瘤缺氧诱导uPAR上调。
