1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.
2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.
Am J Respir Crit Care Med. 2018 May 1;197(9):1164-1176. doi: 10.1164/rccm.201703-0660OC.
C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood.
To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site.
Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed.
High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16.
Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
C5aR1（CD88）是补体过敏毒素 C5a 的受体，是一种有效的免疫介质。其对非小细胞肺癌细胞的恶性生长和扩散的影响尚未可知。
研究 C5a/C5aR1 轴对非小细胞肺癌细胞恶性表型的作用，特别是在骨骼定植方面，骨骼定植是非小细胞肺癌的一个优先肺转移部位。
通过计算机分析评估 C5aR1 表达与临床结局之间的相关性，并通过免疫组织化学进行验证。在肺癌骨转移的体内模型中，通过慢病毒基因沉默和配体 l-适体抑制来评估功能相关性。还进行了信号转导、迁移、侵袭、金属蛋白酶活性和破骨细胞生成的体外功能测定。
人类肺癌肿瘤中高水平的 C5aR1 与无复发生存、总生存和骨转移的时间显著相关。在肺癌细胞中沉默 C5aR1 可显著减少体内骨骼转移负担和骨质溶解。此外，体外刺激或基因沉默 C5aR1 可调节肿瘤细胞的金属蛋白酶、迁移和侵袭活性。l-适体阻断或 C5aR1 沉默可显著降低体内肺癌细胞的骨质转移活性。这种作用与体外破骨细胞生成活性降低有关，并可通过外源性添加趋化因子 CXCL16 得到挽救。
破坏肺癌细胞中的 C5aR1 信号可阻断其肿瘤相关的破骨细胞生成活性，从而破坏骨骼定植。本研究揭示了 C5a/C5aR1 轴在肺癌扩散中的作用，并支持将其作为一种新的治疗靶点的潜力。
