Li Ming, Knight Deborah A, A Snyder Linda, Smyth Mark J, Stewart Trina J
Cancer Immunology Program; Peter MacCallum Cancer Centre; East Melbourne, VIC Australia ; Sir Peter MacCallum Department of Oncology; The University of Melbourne; East Melbourne, VIC Australia.
Oncoimmunology. 2013 Jul 1;2(7):e25474. doi: 10.4161/onci.25474.
The chemokine CCL2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CCL2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CCL2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of or knockout mice or CCL2 neutralization with a monoclonal antibody to further investigate the role of the CCL2/CCR2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CCL2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in or mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic or mice also exhibited a significantly earlier of disease onset. In a chemical carcinogenesis model, anti-CCL2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CCL2 in the establishment of metastases, we have demonstrated that the absence of CCL2/CCR2-signaling results in increased metastatic disease. Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CCL2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CCL2 signaling cascade may also limit immunosurveillance and support metastatic spread.
趋化因子CCL2以其趋化功能最为人所知，它不仅由免疫细胞表达，还由多种恶性细胞和基质细胞表达。CCL2已被证明具有促肿瘤和抗肿瘤作用。然而，最近的研究结果表明CCL2在肿瘤进展和转移中起主要作用，这表明这种趋化因子可能构成抗癌药物的治疗靶点。利用包括可植入肿瘤模型、转基因肿瘤模型和化学诱导肿瘤模型在内的乳腺癌模型，在CCL2基因敲除小鼠或用单克隆抗体中和CCL2的情况下，进一步研究CCL2/CCR2信号轴在肿瘤进展和转移扩散中的作用。在我们的可植入肿瘤模型中，抗CCL2单克隆抗体以双相方式抑制原发性恶性病变的生长并减少转移灶数量。然而，在发生植入性或转基因肿瘤的CCL2基因敲除或CCR2基因敲除小鼠中，尽管原发性肿瘤的生长速度有所降低，但肺转移灶的数量却增加了。转基因CCL2基因敲除或CCR2基因敲除小鼠也表现出疾病发病明显提前。在化学致癌模型中，抗CCL2单克隆抗体抑制已形成病变的生长，但在肿瘤诱导阶段无效。与先前表明CCL2在转移形成中起作用的研究相反，我们已经证明CCL2/CCR2信号缺失会导致转移性疾病增加。因此，CCL2/CCR2信号轴似乎在介导早期肿瘤免疫监视以及维持已形成肿瘤的生长和进展中发挥双重作用。我们的研究结果支持使用抗CCL2疗法治疗已确诊的乳腺癌，尽管完全消除CCL2信号级联反应也可能会限制免疫监视并促进转移扩散。
