NATURE:CCL2抑制剂的中断会造成乳腺癌的转移
导读 | 近日,瑞士巴塞尔弗里德里希Miescher生物医学研究所(FMI)的 Mohamed Bentires-Alj等人在NATURE上发表文章,对CCL2抑制剂用于防止乳腺癌转移的治疗进行研究,得出了不同于前人的结果。
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而近日的研究,为阻止乳腺癌的转移,有提供了新的理论。
通过乳腺肿瘤分泌的C-C趋化因子配体2(CCL2)会招募表达CCR2的炎性单核细胞到肿瘤原发处和肿瘤的转移位置处,并且在小鼠中CCL2的中立状态抑制了肿瘤在骨髓中的转移,这是通过保留单核细胞实现的。在这里,我们报告了CCL2在四种同系小鼠模型中,在乳腺癌转移的过程中矛盾的影响作用。出人意料的是,CCL2抑制剂的中断会导致转移的偏离,并且加速死亡。从骨髓释放出来的单核细胞的结果是增强了肿瘤从原发位置的转移性,以及增强了血管的形成,并且在白细胞介素-6和血管内皮生长因子(VEGF)-A依赖的方式中,造成了肺中转移性细胞的增殖的增加。值得注意的是,CCL2和IL-6的抑制显著的减少了转移,并且增加了动物的存活率。CCL2与各种肿瘤都有联系,可以作为靶向治疗的目标位置。然而,我们的研究结果表明,我们需要谨慎考虑将CCL2抑制剂作为治疗转移性疾病的单药,并且我们强调,肿瘤的微环境是抗肿瘤转移治疗的一个起决定性的关键因素。(转化医学网360zhyx.com)
原文:
Secretion of C–C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.
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