Extracellular Pressure Stimulates Tumor Cell Adhesion In Vitro by Paxillin Activation

Citation:
J. van der Voort van Zyp, W.C. Conway, D.H. Craig, N. van der Voort van Zyp, V. Thamilselvan and M.D. Basson. Extracellular Pressure Stimulates Tumor Cell Adhesion In Vitro by Paxillin Activation. (2006). Cancer Biology & Therapy, 5 (9), 1169-1178.


Summary:
Tumor metastasis remains the most fatal complication of cancer, yet the mechanisms by which tumor cells are able to extravisate and re-attach to the endothelial lining of remote blood vessels is poorly understood. This paper explores the role that paxillin, which is involved in cytoskeletal regulation and growth, plays in mediating tumor cell adhesion to extracellular matrix. Adhesion of cells had been previously shown to be enhanced by pressure-induced (15 mmHg) phosphorylation of the focal adhesion proteins FAK and Src. In addition, studies have shown that the activity of FAK and Src is linked to the cytoskeleton. However, the mechanism by which these are linked has been poorly characterized. Paxillin is a protein which is known to interact with both cytoskeletal proteins and focal adhesion proteins such as FAK and Src. The authors thus theorized that paxillin might have been the link between these events.

The authors first were able to show that increasing the extracellular pressure increased the phosphorylation of paxillin, and noted an increase in the binding ability of cells versus the control sample. Then, by using small interfering RNA (siRNA) to suppress the expression of paxillin, the authors were able to negate the pressure-induced increase in adhesion observed previously. The authors then investigated the effect of inhibited paxillin expression on the activation of FAK by phosphorylation at the 397 tyrosine residue. Inhibition of paxillin expression was shown to have no effect on FAK 397 phosphorylation under normal conditions, but did inhibit the pressure-induced phosphorylation observed in control samples. Similar results were observed for Src 416 phosphorylation. Blocking of FAK and Src activity by other means was not shown to have any effect on paxillin expression or phosphorylation.

The authors conclude that paxillin is an important intermediary in inside-out adhesion signalling, being somewhere upstream of FAK and Src. Other studies have shown that in addition, paxillin may be phosphorylated by FAK in outside-in adhesion signalling. The authors speculate that this difference in signaling direction may be caused by the actual adherence event; suspended cells exhibit inside-out signaling which mediates adhesion, while adherent cells exhibit outside-in signaling.

Significance:
Most fatal cases of cancer are the result of tumor metastasis. Understanding the mechanisms by which tumor cells are able to enter the bloodstream and adhere to remote locations to establish a secondary tumor can help in the development of effective treatments to prevent the metastasis of tumor cells. Although the mechanism of paxillin inhibition presented in this paper is ineffective in a clinical setting, this paper presents us with another possible route to diagnose and treat uncontrolled tumor cell metastasis.