Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

Area of Science:

• Oncology
• Biophysics
• Cell Biology

Background:

• Hepatocellular carcinoma (HCC) is the most prevalent liver cancer, characterized by rising incidence and poor prognosis.
• Limited understanding exists regarding the role of biomechanical forces, like interstitial fluid flow (IFF), in HCC invasion.
• Early detection of HCC is challenging, leading to limited treatment options and low survival rates.

Purpose of the Study:

• To investigate the mechanisms by which interstitial fluid flow (IFF) influences hepatocellular carcinoma (HCC) cell invasion.
• To determine the role of chemokine-mediated autologous chemotaxis in IFF-induced HCC invasion.
• To explore the involvement of specific signaling pathways, including CXCR4/CXCL12 and MEK/ERK, in this process.

Main Methods:

• Utilized a 3D in vitro invasion assay to model HCC invasion.
• Quantified the effect of interstitial fluid flow on HCC cell lines.
• Investigated the involvement of the CXCR4/CXCL12 and MEK/ERK signaling pathways.

Main Results:

• Interstitial fluid flow (IFF) significantly promoted the invasion of hepatocellular carcinoma (HCC) cell lines in a 3D in vitro model.
• Autologous chemotaxis, specifically via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis, was identified as a key mediator of IFF-induced HCC invasion.
• Mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling was also found to affect IFF-induced invasion, operating independently of the CXCR4/CXCL12 pathway.

Conclusions:

• This study provides the first evidence for the role of interstitial fluid flow (IFF) in promoting hepatocellular carcinoma (HCC) invasion.
• The findings highlight the importance of biomechanical forces and specific signaling pathways (CXCR4/CXCL12, MEK/ERK) in HCC progression.
• Understanding these mechanisms offers potential for developing novel therapeutic strategies to improve HCC treatment outcomes.