Improved survival in tumor-bearing SCID mice treated with interferon-γ-inducible protein 10 (IP-10/CXCL10)
Improved survival in tumor-bearing SCID mice treated with interferon-γ-inducible protein 10 (IP-10/CXCL10)
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DOI：
10.1007/s00262-001-0231-9
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发表时间：
2001-12-01
影响因子：
5.8
通讯作者：
Strieter, RM
中科院分区：
文献类型：
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作者：
Arenberg, DA;White, ES;Strieter, RM
肿瘤生长需要血管生成，而血管生成又需要血管生成因子和血管生成抑制因子的不平衡。我们已经表明，CXC趋化因子家族，由血管生成或血管抑制的成员组成，是非小细胞肺癌（NSCLC）中肿瘤源性血管生成的主要决定因素。肿瘤内注射干扰素诱导蛋白10（IP-10，或CXCL 10），一种血管生成抑制CXC趋化因子，导致SCID小鼠NSCLC模型中肿瘤生长减少。在这项研究中，我们假设用CXCL 10治疗将通过恢复血管抑制平衡来改善携带NSCLC的SCID小鼠的长期存活率。为了检验这一假设，将A549 NSCLC细胞注射到侧腹的皮下组织中，然后瘤内注射CXCL 10连续（组I）或10周（组II），或对照组（人血清白蛋白）。中位生存期分别为169、130和86天（P < 0.0001）。我们扩展了这些研究，以检查CXCL 10治疗小鼠的生存期延长的机制。CXCL 10治疗可抑制肺转移，但依赖于持续治疗，并且与原发性肿瘤细胞凋亡率增加相关，对非小细胞肺癌细胞的增殖没有直接影响。此外，肺转移的抑制是由于CXCL 10对原发性肿瘤的血管生成抑制作用，因为肺转移内的细胞凋亡速率不受影响。这些数据表明，人类肺癌的抗血管生成治疗应无限期持续，以实现持久的利益，并证实了局部血管抑制治疗的抗转移能力。
Tumor growth requires angiogenesis, which in turn requires an imbalance in the presence of angiogenic and angiostatic factors. We have shown that the CXC chemokine family, consisting of members that are either angiogenic or angiostatic, is a major determinant of tumor-derived angiogenesis in non-small-cell lung cancer (NSCLC). Intratumor injection of interferon-inducible protein 10 (IP-10, or CXCL10), an angiostatic CXC chemokine, led to reduced tumor growth in a SCID mouse model of NSCLC. In this study, we hypothesized that treatment with CXCL10 would, by restoring the angiostatic balance, improve long-term survival in NSCLC-bearing SCID mice. To test this hypothesis, A549 NSCLC cells were injected in the subcutis of the flank, followed by intratumor injections with CXCL10 continuously (group I), or for ten weeks (group II), or a control group (human serum albumin). Median survival was 169, 130, and 86 days respectively (P < 0.0001). We extended these studies to examine the mechanism of prolonged survival in CXCL10-treated mice. CXCL10 treatment inhibited lung metastases, but was dependent upon continued treatment, and was associated with an increased rate of apoptosis in the primary tumor, with no direct effect on the proliferation of the NSCLC cells. Furthermore, the inhibition of lung metastases was due to the angiostatic effect of CXCL10 on the primary tumor, since the rate of apoptosis within lung metastases was unaffected. These data suggest that anti-angiogenic therapy of human lung cancer should be continued indefinitely to realize persistent benefit, and confirms the anti-metastatic capacity of localized angiostatic therapy.