Of note, our data showed that both CAFs and overexpression of LRG1 were capable of promoting phosphorylation of Smad1/5, and blockade of Smad1/5 signaling by inhibitor can effectively inhibit LRG1-induced EMT and invasion of cancer cells, indicating that activation of Smad pathway may be essential for metastasis induced by CAFs-LRG1 axis and further studies are warranted to address this question in depth. This evidence concerns the gene SMAD1 and cancer.