Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling.
Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling.
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纤维化微环境通过激活纤连蛋白 1/分泌磷蛋白 1-整合素信号传导促进肿瘤细胞的转移播种。
DOI：
10.18632/oncotarget.10157
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Zhang C;Wu M;Zhang L;Shang LR;Fang JH;Zhuang SM
肿瘤细胞的种植是转移过程中的关键步骤，但靶器官的微环境是否以及如何影响转移性种植仍然是未知的。基于细胞和小鼠模型，我们发现在纤维化肺中肿瘤细胞的转移性种植和生长显著增强。纤维化肺和纤维化肺源性成纤维细胞（CM-FLF）的条件培养液具有较强的趋化肿瘤细胞和抑制肿瘤细胞凋亡的活性。随后的研究表明，纤维连接蛋白1（FN 1）和分泌型磷蛋白1（SPP 1）的水平显着增加，在纤维化的肺。在纤维化肺来源的成纤维细胞中，FN 1的沉默显著降低了CM-FLF的趋化活性，而成纤维细胞中FN 1或SPP 1的沉默减弱了CM-FLF的抗凋亡活性。此外，当肿瘤细胞中FN 1和SPP 1的共同受体ITGAV被RNA干扰沉默或被GRGDS处理阻断时，CM-FLF诱导的肿瘤细胞的凋亡抗性或趋化性被减弱。一致地，ITGAV沉默或GRGDS处理显著抑制体内纤维化肺中肿瘤细胞的接种和生长。总的来说，我们认为纤维化微环境可能通过化学吸引肿瘤细胞并通过激活FN 1/SPP 1-ITGAV信号转导抑制其凋亡来增强肿瘤细胞在肺中的转移性种植。这些发现为肿瘤转移的调控机制提供了新的见解，并为抗转移治疗提供了潜在的靶点。
The seeding of tumor cells is a critical step in the process of metastasis, but whether and how the microenvironment of target organs affects metastatic seeding remain largely unknown. Based on cell and mouse models, we found that the metastatic seeding and outgrowth of tumor cells were significantly enhanced in fibrotic lungs. The conditioned medium from both fibrotic lungs and the fibrotic lung-derived fibroblasts (CM-FLF) had a strong activity to chemoattract tumor cells and to inhibit the apoptosis of tumor cells. Subsequent investigations revealed that the levels of fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1) were significantly increased in fibrotic lungs. Silencing of FN1 in the fibrotic lung-derived fibroblasts dramatically decreased the chemoattracting activity of CM-FLF, while silencing of FN1 or SPP1 in fibroblasts attenuated the anti-apoptosis activity of CM-FLF. Moreover, the CM-FLF-induced apoptosis resistance or chemotaxis of tumor cells was attenuated when ITGAV, the common receptor of FN1 and SPP1, was silenced by RNA interference or blocked by GRGDS treatment in tumor cells. Consistently, ITGAV silencing or GRGDS treatment significantly inhibited the seeding and outgrowth of tumor cells in fibrotic lungs in vivo. Collectively, we suggest that fibrotic microenvironment may enhance the metastatic seeding of tumor cells in the lung by chemoattracting tumor cells and inhibiting their apoptosis via activating the FN1/SPP1-ITGAV signaling. These findings give a novel insight into the regulatory mechanisms of cancer metastasis and provide a potential target for anti-metastasis therapy.