The effect of low-intensity ultrasound and met signaling on cellular motility and morphology

During the past decade, the potential of low-intensity ultrasound (LIUS) was demonstrated in medical research including microvascular remodeling, wound repair, blood flow restoration, angiogenesis and activation of mechanosensitive signaling pathways. However, the current clinical application of LIUS hasn't been extended beyond physiotherapy. In cancer therapy, LIUS related research is focused on ultrasound-mediated techniques for chemotherapeutic drug activation, drug delivery enhancement and gene transfection improvement. While clinical trials show highly promising results, the ambiguity regarding the mechanism of ultrasound-cell interaction is a major limitation in the road to clinical applications. In 2011, the bilayer sonophore (BLS) model suggested that cell intramembrane cavitation is the underlying mechanism for ultrasound-induced bio-effects. According to the BLS model, ultrasound affects cell shape and functionality by inducing intramembrane gas bubbles that deform the cell membrane. This mechanical effect might involve alterations in the bio-chemical signaling pathways. Many biological processes such as cell motility, proliferation and angiogenesis are triggered by MET tyrosine kinase growth factor receptor and its ligand HGF/SF (Hepatocyte growth factor/Scatter Factor). The activation of MET receptor increases cancer cell motility via membrane alterations, leading to epithelial to mesenchymal transformation (EMT), invasion and metastasis. The aim of this work is to examine the crosstalk between MET-activation and LIUS under the assumption that both induce cell membrane alterations whereby affecting cell morphology and motility. In this paper, we present preliminary observations regarding the effect of MET-activation, LIUS exposure and their combined effect on living cells. Measurements of morphokinetic parameters using single cell time-lapse analysis are presented as well. The analysis demonstrates that LIUS inhibits the motility and modulates the morphology of MET-activated cells. These findings demonstrate the balance between the inner cellular processes (MET signaling pathways) and the external forces (LIUS exposure). Understanding the mechanism of LIUS on motile cells might improve the performance of existing LIUS-based cancer treatment modalities and help develop new ones.