Colorectal cancer (CRC) ranks second in the world in cancer-related mortality, with 50% of CRC deaths caused by liver metastases. The interaction of tumor cells with the tumor microenvironment (TME) plays an important role in colorectal cancer liver metastasis (CRLM). Therefore, elucidating the mechanism by which tumor cells interact with TME is critical to improving our understanding of CRLM.
Extracellular vesicles (Evs), characterized by their lipid bilayer membranes and carrying many biomolecules, are often thought to be messengers involved in TME cell-to-cell communication and have been shown to play an important role in the progression of several types of cancer. However, whether colorectal cancer-derived EVs induce liver metastasis by secreting MIRNA-rich EVs to regulate HSCs, and miRNAs involved in this process remains to be determined.
Image source: https://doi.org/10.1002/jev2.12186
Recently, researchers at the Shanghai Cancer Center of Fudan University published a paper in the journal J Extracell Vesicles titled "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" article, the study found that highly metastasized colorectal cancer cells release MIR-181a-5p-rich EVs, which promote liver metastasis by regulating the interaction between CRC cells and HSCs, as well as the remodeling of TME. The findings identify a new specific biomarker for CRLM, as well as a new strategy for predicting the risk of secondary liver cancer caused by colorectal cancer.
The authors first examined whether CRC cells can activate HSCs by EVS. The authors selected two colorectal cancer cell lines with weak metastasis potential (HT29 and SW480) and two high-metastatic cell lines (RKO and SW620) and isolated and purified EVs from conditioned medium (CM). Notably, the authors found that highly metastatic CRC cells can deliver more EVS to HSCs, suggesting that highly transferred CRC-derived EVS may play a key role in the interaction between HSCs and CRC cells.
In addition, the authors validated that miR-181a-5p was packaged into CRC EVS, which in turn continued to activate hepatic astellate cells (HSCs) by targeting SOCS3 and activating the IL6/STAT3 signaling pathway. Activated HSCs secrete the chemokine CCL20, which activates the CCL20/CCR6/ERK1/2/Elk-1/miR-181a-5p positive feedback loop, resulting in TME reprogramming and the formation of a pre-transfer niche at CRLM.
In addition, the authors further verified that activated HSCs can secrete the chemokine CCL20, which activates the CCL20/CCR6/ERK1/2/Elk-1/miR-181a-5p positive feedback loop, resulting in TME reprogramming and the formation of a pre-transfer niche in CRLM. Clinically, high levels of EV containing miR-181a-5p in the serum of colorectal cancer patients are positively correlated with liver metastasis.
Schematic model of a positive feedback loop between highly metastatic colorectal cancer cells and hematopoietic stem cells in CRLM
In summary, the authors demonstrate that EV miR-181a-5p of a highly metastatic CRC source activates HSCs by modulating the IL6/STAT3 signal. This promotes the secretion of CCL20 by α-HSCs and further activates the ERK1/2/ELK-1 pathway through CCR6, upregulating the expression of colorectal cancer cells miR-181a-5p, leading ultimately to reprogramming of TME and the formation of pre-metastatic niches in hepatic CRLM.
The authors' research uncovers a new molecular mechanism of crosstalk between colorectal cancer cells and hepatic stellate cells during the CRLM process and may highlight new targets for predicting CRLM risk. In addition, inhibitory feedback loops may prove to be a promising strategy for improving outcomes in PATIENTS with CRLM.
bibliography:
Senlin Zhao et al. 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. J Extracell Vesicles. 2022 Jan;11(1):e12186. doi: 10.1002/jev2.12186.