Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases
Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases
复制标题
DOI：
10.1093/jnci/djv155
复制
发表时间：
2015-09-01
影响因子：
10.3
通讯作者：
Padera, Timothy P.
中科院分区：
文献类型：
--
作者：
Jeong, Han-Sin;Jones, Dennis;Padera, Timothy P.
背景：迄今为止，抗血管生成治疗在辅助治疗（局部区域疾病，无可检测的全身转移）时未能提高癌症患者的总生存率。淋巴结转移的存在使预后恶化，但其依赖血管生成生长尚未见报道。方法：在此，我们引入一种新的慢性淋巴结窗口（CLNW）模型，以促进对淋巴结转移瘤生长和扩散的新发现。我们在多个小鼠自发性淋巴转移模型中使用CLNW来研究转移淋巴结的血管系统（n = 9-12）。我们在患者样本中进一步检验我们的结果（n = 20名结肠癌患者；n = 20名头颈癌患者）。最后，我们测试了抗血管生成治疗抑制CLNW转移性生长的能力。所有统计检验均为双侧检验。结果：使用CLNW，我们揭示了在转移生长过程中令人惊讶的缺乏发芽血管生成，尽管在一些病变中存在缺氧。两种不同的抗血管生成疗法治疗对淋巴结转移瘤的生长或血管密度没有影响（第10天：未治疗平均= 1.2%，95%可信区间[CI] = 0.7%至1.7%；对照平均= 0.7%,95% CI = 0.1%至1.3%；DC101平均= 0.4%,95% CI = 0.0%至3.3%；舒尼替尼平均= 0.5%,95% CI = 0.0%至1.0%，方差分析P = 0.34）。我们在临床标本中证实了这些发现，包括在接受贝伐单抗治疗的患者中，淋巴结转移的血管密度没有减少(无贝伐单抗组平均= 257血管/mm(2), 95% CI = 149至365血管/mm(2)；贝伐单抗组平均= 327个血管/mm（2), 95% CI = 140 ~ 514个血管/mm(2), P = 0.78）。结论：我们提供的临床前和临床证据表明，在淋巴结转移的生长过程中不会发生新生血管生成，从而揭示了辅助环境下抗血管生成治疗抵抗的新机制。临床批准的血管生成抑制剂的靶点在淋巴结的早期癌症进展中不活跃，这表明作为一类新生血管生成抑制剂在治疗淋巴结转移中不会有效。
Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported.Methods: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided.Results: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78).Conclusion: We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.