Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin α5 Signaling
Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin α5 Signaling
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DOI：
10.1016/j.juro.2015.01.079
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发表时间：
2015-08-01
影响因子：
6.6
通讯作者：
Brenner, Walburgis
中科院分区：
文献类型：
--
作者：
Haber, Tobias;Joeckel, Elke;Brenner, Walburgis
目的：30% 的肾细胞癌患者发生骨转移。我们阐明了导致和预测肾细胞癌骨转移的机制。材料和方法：收集肾切除术后5年内3例无转移的患者和10例肺或骨转移的患者，收集9个肾细胞癌原代细胞系和30个肾细胞癌组织标本（正常组织和肿瘤组织）。在博伊登室中分析细胞迁移，并通过溴脱氧尿苷掺入评估增殖。细胞染色后测定对纤连蛋白、I 型和 IV 型胶原蛋白的粘附。通过Western blot定量细胞信号分子的表达和/或活性。 结果：与未转移患者的肾细胞癌细胞相比，骨转移患者的细胞迁移能力增强13.5倍（p = 0.034），对纤连蛋白和I型胶原的粘附增强5.8倍和6.1倍（分别为p = 0.002和0.014）。一般来说，转移细胞的增殖减少。根据这些结果，我们检测到骨转移患者的原代细胞与非转移细胞相比，AKT (p = 0.011) 和 FAK (p = 0.054) 活性较高，整合素 α 5 表达较高 (p = 0.052)，PTEN 表达较低。在肾细胞癌组织标本和骨转移患者的正常肾组织中也观察到几乎类似的表达模式改变。结论：我们描述了分子倾向决定肾细胞癌发生骨转移的可能性的证据，这可以作为初始肿瘤检测后的预后标志物。
Purpose: Bone metastasis develops in 30% of all patients with renal cell carcinoma. We elucidated the mechanisms that lead to and predict bone metastasis of renal cell carcinoma.Materials and Methods: Nine renal cell carcinoma primary cell lines and 30 renal cell carcinoma tissue specimens (normal and tumor tissue) were collected from 3 patients with no metastasis and 10 with lung or bone metastasis within 5 years after nephrectomy. Cell migration was analyzed in a Boyden chamber and proliferation was assessed by bromodeoxyuridine incorporation. Adhesion to fibronectin, and collagen I and IV was determined after cell staining. The expression and/or activity of cellular signaling molecules was quantified by Western blot.Results: Compared to renal cell carcinoma cells from patients without metastasis, the migration of cells from patients with bone metastasis was enhanced 13.5-fold (p = 0.034), and adhesion to fibronectin and collagen I was enhanced 5.8-fold and 6.1-fold (p = 0.002 and 0.014, respectively). In general proliferation was decreased in metastasizing cells. In accordance with these results we detected higher activity of AKT (p = 0.011) and FAK (p = 0.054), higher integrin alpha 5 expression (p = 0.052) and lower PTEN expression in primary cells from patients with bone metastasis compared to nonmetastasizing cells. An almost similarly altered expression pattern was also observed in the renal cell carcinoma tissue specimens and the normal renal tissue of patients with bone metastasis.Conclusions: We describe evidence that molecular predispositions determine the potential for bone metastasis to develop in renal cell carcinoma, which may serve as prognostic markers after initial tumor detection.