Highly‐metastatic colorectal cancer cell released miR‐181a‐5p‐rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment

Abstract

Liver metastasis of colorectal cancer (CRLM) is the most common cause of CRC‐related mortality, and is typically caused by interactions between CRC cells and the tumour microenvironment (TME) in the liver. However, the molecular mechanisms underlying the crosstalk between tumour‐derived extracellular vesicle (EV) miRNAs and the TME in CRLM have yet to be fully elucidated. The present study demonstrated that highly metastatic CRC cells released more miR‐181a‐5p‐rich EVs than cells which exhibit a low metastatic potential, in‐turn promoting CRLM. Additionally, we verified that FUS mediated packaging of miR‐181a‐5p into CRC EVs, which in‐turn persistently activated hepatic stellate cells (HSCs) by targeting SOCS3 and activating the IL6/STAT3 signalling pathway. Activated HSCs could secrete the chemokine CCL20 and further activate a CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p positive feedback loop, resulting in reprogramming of the TME and the formation of pre‐metastatic niches in CRLM. Clinically, high levels of serum EV containing miR‐181a‐5p was positively correlated with liver metastasis in CRC patients. Taken together, highly metastatic CRC cells‐derived EVs rich in miR‐181a‐5p could activate HSCs and remodel the TME, thereby facilitating liver metastasis in CRC patients. These results provide novel insight into the mechanism underlying liver metastasis in CRC.

A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer

“…According to the diverse components, TME is widely accepted to be classified into three subtypes: immune-desert, immune-inflamed, and immuneexcluded (39). With more and more focus on TME, researchers have found that TME is closely associated with the p r o g n o s i s o f m u l t i p l e t u m o r s a n d r e s p o n s e t o chemoradiotherapy and immunotherapy, such as colorectal cancer, melanoma, gastric cancer, and intrahepatic cholangiocarcinoma (40)(41)(42)(43)(44). In colorectal cancer, the high level of infiltrated cytotoxic CD8 + T cells at the center or margin of the tumor predicts a low risk of recurrence at 5 years (45).…”

Collagen-binding fibroblast growth factor ameliorates liver fibrosis in murine bile duct ligation injury

“…Therefore, substantial efforts that target HSCs have been made for the treatment of liver fibrosis that show promising results. 41,42 bFGF exerts antifibrotic effect in chronic liver injury. While the underlying mechanism of bFGF-mediated regulation of liver fibrosis is not completely clear, different bFGF-related signaling pathways have been discovered, including the c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and Janus kinase (JAK) pathways.…”

The Hepatic Pre-Metastatic Niche

“…Recently, Zhao et al demonstrated that HSCs could communicate back with the primary tumor following activation by miR-181a-5p released from CRC cells. Following EV uptake, HSCs facilitated CRC cell migration, invasion, and metastasis formation by increasing expression of α-SMA and fibronectin in the liver ECM while reducing vitronectin and tenascin C. Moreover, they also secreted CCL20 into circulation, which upregulated further miR-181a-5p production by primary tumor cells in a positive feedback loop [ 25 ]. This cross-communication between the PMN and the primary tumor expands past the notion of unidirectional signaling and offers additional targets for therapeutic blockade.…”