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

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

  • Cell Death Dis. 2021 Dec 20;13(1):16. doi: 10.1038/s41419-021-04461-6.
Beiping Zhong  # 1 2,  Bing Cheng  # 1 2,  Xiaoming Huang 1 2 3,  Qian Xiao 1 2,  Zhitong Niu 1 2,  Yu-Feng Chen 1 2,  Qiang Yu 4 5 6 7 8,  Wenyu Wang 9 10,  Xiao-Jian Wu 11 12
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
  • 2 Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
  • 3 Department of Hepatobiliary Surgery, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
  • 4 Department of Colorectal Surgery, Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • 5 Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • 6 Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672, Singapore. [email protected].
  • 7 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. [email protected].
  • 8 Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore, 169857, Singapore. [email protected].
  • 9 Department of Colorectal Surgery, Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • 10 Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • 11 Department of Colorectal Surgery, Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • 12 Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. [email protected].
  • # Contributed equally.
PMID: 34930899 DOI: 10.1038/s41419-021-04461-6
Abstract

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.

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