There are also contradictory findings showing that LRG1 suppresses migration and invasion of esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC). In accordance, serum LRG1 was significantly increased in PDAC and correlated with progressive clinical stage. Overexpression of LRG1 has been found in multiple cancers such as pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer, where it promotes cell proliferation, migration and invasion. Since then, accumulating studies have focused on unveiling the potential roles of LRG1 in regulating tumor progression. Leucine Rich Alpha-2-Glycoprotein 1(LRG1) was firstly identified as an inflammatory protein in human serum by Haupt and Baudner in 1977, but with little attention paid until 2013, when Wang et al reported that LRG1 could promote angiogenesis by modulating endothelial transforming growth factor β (TGFβ) signaling. With the unraveling relationship between cancer cells and CAFs, CAFs and/or its secretome are now being considered as potential targets for anti-tumor therapy. Consistently, many studies have elucidated that secreted factors derived from CAFs such as exosomes, non-coding RNA and cytokines act as the “intermediates” for CAFs to crosstalk with cancer cells and exert their functions. A recent delicate study using single-cell technology combined with high-content digital imaging has demonstrated that the abundance of CAFs was linked with cancer heterogeneity and invasive potential in pancreatic cancer. Ĭancer-associated fibroblasts (CAFs), the most abundant component in the stroma, have been implicated in modulating tumor progression and therapeutic response. Moreover, CMS4 is more aggressive and metastatic than other CMSs, indicating an important role of stromal cells in mediating metastasis in CRC. Hence, a better understanding of molecular mechanism leading to metastasis is of urgent need and critical to improve metastatic patients’ survival.Īccording to a recently available classification system, CRC can be divided into four consensus molecular subtypes (CMSs), by which CMS4 is characterized by prominent transforming growth factor β activation and stromal invasion. However, the underlying mechanisms of CRC metastasis have not been fully understood yet. Liver metastasis has been the most frequent and predominant reason accounting for patient mortality, with an overall 5-year survival rate less than 20%.
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.Ĭolorectal cancer (CRC) is the third most common malignancy and also the third leading cause of cancer-related death.
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. 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 addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. 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. 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.