Étude de la convertase PCSK9 dans les cellules endothéliales sinusoidales du foie au cours des métastases hépatiques du carcinome colorectal

Colorectal cancer (CRC) is a leading cause of cancer-related deaths, mainly due to its high potential for , particularly to the liver. The liver's direct blood supply from the colon makes it a frequent target for CRC , worsening patient outcomes. Understanding the molecular mechanisms of this process is essential for developing new therapies. is a complex process involving local invasion, entry into the bloodstream, survival in circulation, and eventual colonization in distant organs. One key factor in this process is epithelial-mesenchymal transition (EMT), where cancer cells gain the ability to migrate. In the liver, liver sinusoidal endothelial cells (LSECs) interact with CRC cells, promoting tumor survival, immune evasion, and angiogenesis.Recent research highlights the role of PCSK9, a protein primarily involved in cholesterol metabolism, in cancer progression, particularly CRC to the liver. PCSK9 has been found to influence several cancer-related processes such as EMT, cell proliferation, and immune evasion. Elevated levels of PCSK9 in CRC suggest that it contributes to , particularly by influencing LSECs.This study investigates how PCSK9 affects LSECs and facilitates liver . The hypothesis is that PCSK9, upregulated in LSECs in response to tumor signals, promotes tumor cell adhesion, migration, and growth in the liver. Researchers cultured human and murine LSECs and CRC cell lines, inducing a cancer stem cell-like state in CRC cells. Conditioned media from these CRC cells were used to activate LSECs. The effects of PCSK9 on LSECs were studied using inhibitors and siRNA technology.Key findings include the upregulation of PCSK9 in LSECs when exposed to CRC cell signals, increased proliferation and migration of LSECs in response to PCSK9, and a significant reduction in these processes when PCSK9 was inhibited. The study also identified an interaction between PCSK9 and fatty acid-binding protein 5 (FABP5), which regulates the Wnt/β-catenin pathway, a key driver of cell proliferation and angiogenesis. Inhibiting PCSK9 reduced Wnt/β-catenin activity, thereby limiting LSEC activation.In vivo studies using a murine model confirmed that inhibiting PCSK9, especially through siRNA-loaded nanoparticles targeting LSECs, significantly reduced the size of liver metastases. This supports the therapeutic potential of PCSK9 inhibitors in reducing CRC liver .In conclusion, this study demonstrates that PCSK9 plays a crucial role in promoting CRC liver by enhancing LSEC activity. Targeting PCSK9, particularly with nanoparticle-based siRNA delivery, offers a promising therapeutic strategy for CRC patients with liver . Further research is needed to fully understand PCSK9's role in cancer and explore its clinical potential.