Accelerated Perinecrotic Outgrowth of Colorectal Liver Metastases Following Radiofrequency Ablation is a Hypoxia-Driven Phenomenon
Accelerated Perinecrotic Outgrowth of Colorectal Liver Metastases Following Radiofrequency Ablation is a Hypoxia-Driven Phenomenon
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DOI：
10.1097/sla.0b013e3181a38ef5
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发表时间：
2009-05-01
影响因子：
9
通讯作者：
Rinkes, Inne H. M. Borel
中科院分区：
文献类型：
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作者：
Nijkamp, Maarten W.;van der Bilt, Jarmila D. W.;Rinkes, Inne H. M. Borel
目的：本研究的目的是评估结直肠肝转移瘤的热消融如何影响两种不同小鼠模型中消融组织和未受影响的参考区 (RZ) 之间的过渡区 (TZ) 中微转移瘤的生长。背景：不可切除的结直肠肝转移瘤的热破坏疗法，包括射频消融 (RFA)，可以清除肿瘤，但局部复发很常见。方法：术后三天脾内注射C26结肠癌细胞，RFA应用于左肝叶。随着时间的推移，对坏死周围微循环、组织缺氧、缺氧诱导因子 (HIF)-1 α 和 HIF-2 α 以及 TZ 和 RZ 中微转移瘤的生长进行评估。 结果：在 2 种不同的动物模型中，RFA 后 TZ 中微转移瘤的生长受到刺激，与 RZ 中的肿瘤生长相比大约是 4 倍。 TZ 中肿瘤生长的加速与肿瘤细胞中的微循环紊乱、长期缺氧以及 HIF-1 α 和 HIF-2 α 的稳定有关。此外，RFA 诱导新肝血管的形成，这些新肝血管从现有的肝窦中萌发并生长成产生的坏死病灶。令人惊讶的是，肿瘤生长的加速与这些血管无关。 17DMAG 治疗可防止 HIF-1 α 和 HIF-2 α 稳定，并选择性地将 TZ 中的肿瘤生长减少 -40%，而不影响假手术小鼠或 RFA 治疗小鼠 RZ 中的肿瘤生长。 PTK787/ZK-222584 是一种非选择性血管内皮生长因子 (VEGF) 受体抑制剂，可在类似程度上减少 RFA 刺激的肿瘤生长和 RZ 中的肿瘤生长。结论：我们得出结论，RFA 刺激病灶周围肿瘤细胞的生长。血管生成并不是 RFA 刺激肿瘤生长的驱动力，但其他缺氧/HIF 激活途径可能很重要。
Objective: The aim of this study was to assess how thermal ablation of colorectal liver metastases affects the outgrowth of micrometastases in the transition zone (TZ) between ablated tissue and the unaffected reference zone (RZ) in 2 different murine models.Background: Thermal destruction therapies of nonresectable colorectal liver metastases, including radiofrequency ablation (RFA), can provide tumor clearance, but local recurrences are common.Methods: Three days after intrasplenic injection of C26 colon carcinoma cells, RFA was applied to the left liver lobe. Perinecrotic microcirculation, tissue hypoxia, hypoxia inducible factor (HIF)-1 alpha and HIF-2 alpha, and the outgrowth of micrometastases both in the TZ and in the RZ were evaluated over time.Results: In 2 different animal models, the outgrowth of micrometastases in the TZ following RFA was stimulated approximately 4-fold compared to tumor growth in the RZ. Accelerated tumor growth in the TZ was associated with microcirculatory disturbances, prolonged hypoxia, and stabilization of HIF-1 alpha and HIF-2 alpha in the tumor cells. In addition, RFA induced the formation of new hepatic vessels that sprouted from existing sinusoids and grew into the generated necrotic lesion. Surprisingly, the accelerated tumor growth was not associated with these vessels. Treatment with 17DMAG prevented HIF-1 alpha and HIF-2 alpha stabilization and selectively reduced tumor growth in the TZ by -40% without affecting tumor growth in sham-operated mice or in the RZ of RFA-treated mice. PTK787/ZK-222584, a nonselective Vascular Endothelial Growth Factor (VEGF)-receptor inhibitor, reduced RFA-stimulated tumor growth and tumor growth in the RZ to a similar extent.Conclusions: We conclude that RFA stimulates the outgrowth of tumor cells at the lesion periphery. Angiogenesis is not the driving force behind RFA-stimulated tumor growth, but other hypoxia/HIF-activated pathways are likely to be important.