Liver Extracellular Matrix in Colorectal Liver Metastasis

Abstract

The liver is the most common site of metastasis of colorectal cancer (CRC), and colorectal liver metastasis is one of the major causes of CRC-related deaths worldwide. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a critical role in CRC metastasis and chemoresistance. Based on findings from clinical and basic research, this review attempts to offer a complete understanding of the role of the ECM in colorectal liver metastasis and to suggest potential ways for therapeutic intervention. First, the ECMs' role in regulating cancer cell fate is explored. We then discuss the hepatic ECM fingerprint and its influence on the metastatic behavior of CRC cells, highlighting key molecular interactions that promote metastasis. In addition, we examine how changes in the ECM within the metastatic niche contribute to chemoresistance, focusing on ECM remodeling by ECM stiffening and the activation of specific signaling pathways. Understanding these mechanisms is crucial for the development of novel strategies to overcome metastasis and improve outcomes for CRC patients.

Keywords: CRLM; ECM; chemoresistance; metastatic niche.

Figure 1

Colorectal liver metastatic cascade.

Figure 2

Pre-metastatic Liver Niche Formation. (1) Angiogenesis and intravasation: High angiogenic and matrix metalloproteinase (MMP) activity at the primary tumor site leads to vascular disruption, facilitating tumor cell intravasation and entry into circulation. Circulating tumor cells (CTCs) may secrete extracellular matrix (ECM) components to evade immune surveillance. (2) Interaction with neutrophils and NETs: CTCs interact with neutrophil extracellular traps (NETs) and NETotic neutrophils via integrin-mediated matrix-like connections, enhancing their survival in circulation. (3) Endothelial cell remodeling and CTC attachment: Endothelial cells (ECs) assemble fibrillar fibronectin, promoting CTC adhesion to the endothelial wall at distant sites via CAF action. Elevated MMP activity disrupts vascular integrity, facilitating CTC extravasation. Tumor-derived factors, including growth factors, MMPs, lysyloxidase (LOX), and ECM proteins (e.g., fibronectin), create a liver pre-metastatic niche. (4) Dormancy and metastasis initiation: CTCs that extravasate into the liver may enter dormancy. Proteases within NETs, such as neutrophil elastase and MMP-9, cleave laminin to generate specific matrikines that can awaken dormant tumor cells. These ECM remodeling processes collectively support the establishment and progression of metastasis.