Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling

• Published in: Cell death & disease Vol. 13; no. 1; p. 16
• Main Authors: Zhong, Beiping, Cheng, Bing, Huang, Xiaoming, Xiao, Qian, Niu, Zhitong, Chen, Yu-feng, Yu, Qiang, Wang, Wenyu, Wu, Xiao-Jian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.12.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/91; 42/41; 631/67/327; 692/699/67/1504/1885/1393; 82/51; 82/80; 96/1; 96/44; 96/95; Aged; Animal models; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; Cancer-Associated Fibroblasts - metabolism; Cell Biology; Cell Culture; Cell Movement - genetics; Cell Proliferation - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Models, Animal; Female; Fibroblasts; Follow-Up Studies; Glycoproteins - genetics; Glycoproteins - metabolism; HCT116 Cells; Heterografts; Humans; Immunology; Interleukin 6; Interleukin-6 - metabolism; Janus kinase 2; Life Sciences; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Mesenchyme; Metastases; Metastasis; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Signal Transduction - genetics; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Therapeutic targets; Transfection; Tumors; Up-Regulation - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04461-6

Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.