Liver metastases remain a major cause of death from gastrointestinal tract cancers and other malignancies, such as breast and lung carcinomas. Understanding the underlying biology is essential for the design of effective therapies. We previously identified the chemokine CCL7 and its receptor CCR3 as critical mediators of invasion and metastasis in lung and colon carcinoma cells. Here we show that the CCL7/CCR3 axis regulates a late stage in invadopodia genesis namely, the targeting of MMP-9 to the invadopodia complex, thereby promoting invadopodia maturation and collagen degradation. We show that this process could be blocked by overexpression of a dominant negative RhoA in highly invasive cells, while a constitutively active RhoA upregulated invadopodia maturation in CCL7-silenced and poorly invasive and metastatic cells and also enhanced their metastatic potential in vivo, collectively, implicating RhoA activation in signaling downstream of CCL7. Blockade of the ERK or PI3K pathways by chemical inhibitors also inhibited invadopodia formation, but affected the initiation stage of invadopodia genesis. Our data implicate CCL7/CCR3 signaling in invadopodia maturation and suggest that chemokine signaling acts in concert with extracellular matrix-initiated signals to promote invasion and liver metastasis.

中文翻译：

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趋化因子CCL7调节肝转移癌细胞中侵袭足的成熟和MMP-9介导的胶原蛋白降解。

肝转移仍然是胃肠道癌和其他恶性肿瘤（如乳腺癌和肺癌）死亡的主要原因。了解基础生物学对于设计有效的疗法至关重要。我们先前确定趋化因子CCL7及其受体CCR3是肺癌和结肠癌细胞侵袭和转移的关键介质。在这里，我们显示CCL7 / CCR3轴可调节invadopodia发生的后期，即将MMP-9靶向invadopodia复合物，从而促进invadopodia的成熟和胶原蛋白的降解。我们表明，在高侵袭性细胞中，显性负性RhoA的过表达可能会阻止此过程，同时，具有活性的RhoA上调了CCL7沉默和侵袭性差的转移性细胞中的伪足成熟，并且还增强了它们在体内的转移潜能，共同暗示RhoA激活会影响CCL7下游的信号传导。化学抑制剂对ERK或PI3K途径的阻断也抑制了小脚印的形成，但影响了小脚印的起始阶段。我们的数据暗示了侵袭性足足成熟中的CCL7 / CCR3信号传导，并提示趋化因子信号传导与细胞外基质引发的信号协同作用，以促进侵袭和肝转移。但影响了小脚印发生的起始阶段。我们的数据暗示了侵袭性足足成熟中的CCL7 / CCR3信号传导，并提示趋化因子信号传导与细胞外基质引发的信号协同作用，以促进侵袭和肝转移。但影响了小脚印发生的起始阶段。我们的数据暗示了侵袭性足足成熟中的CCL7 / CCR3信号传导，并提示趋化因子信号传导与细胞外基质引发的信号协同作用，以促进侵袭和肝转移。