Anti-CD151 treatment immobilizes GFP-expressing tumour cells proliferating within the stroma of the chick embryo's Chorioallantoic Membrane. Tumour cells: green; Vasculature: red.

Image courtesy of Dr Andries Zijlstra, Vanderbilt University, TN, USA.

The key steps leading to metastasis are tumour cell mobilization, followed by intravasation of the tumor vasculature and extravasation at secondary sites. The extent of the requirement for functional migration machinery in tumour dissemination remains unclear. In Cancer Cell, James Quigley and colleagues now report that blocking the function of the integrin-associated tetraspanin CD151 in vivo prevents tumour dissemination by inhibiting migration and subsequent intravasation at primary tumour sites.

Tetraspanins are transmembrane proteins that interact with -integrin subunits and mediate integrin function by regulating cytoplasmic signalling. In this study, injecting anti-CD151 monoclonal antibody (mAb 1A5) into chick embryos or mice bearing human tumours led to a reduction of more than 80% in spontaneous metastasis without having any affect on primary tumour growth.

But how does blocking tetraspanin CD151 interfere with metastasis? The authors first showed that mAb 1A5 treatment both reduced cell migration on different matrices and enhanced focal adhesion formation, suggesting that blocking CD151 inhibits migration by promoting cell-matrix interactions. They then analysed tumour cell behaviour in vivo using real-time intravital imaging of individual cells. The authors initially intravenously injected GFP-expressing tumour cells with mAb 1A5 to assess whether the anti-CD151 antibody interferes with vascular extravasation. Tumour cells underwent arrest in the vasculature, extravasation and proliferation, but failed to disseminate throughout the stroma. Thus, blocking CD151 does not affect cell extravasation but does prevent migration within the stroma after departing from the vasculature.

As migration inhibition does not limit the metastatic colonization of injected intravenously tumour cells, the authors reasoned that CD151 must be important for cell departure from the primary tumour site. Normally, aggressive metastatic tumours show irregular invasive fronts due to cell migration into the surrounding stroma and along the vasculature. In contrast, antibody-treated tumours had a clearly defined border at the tumour-stromal interface and showed little or no invasion of the surrounding tissue and vasculature. The authors observed that although some residual movement was present, both migration velocity and persistence were reduced within primary tumours, resulting in an inefficiency of cells moving away from their start position. Furthermore, enhanced single-cell images revealed that although cells moved forward, the rear remained attached to the original location. Interestingly, the loss of CD151 has little impact on in vivo cell migration suggesting that antibody binding promotes tumour cell immobility. Finally, James Quigley and colleagues observed that treating animals with mAb 1A5 prevented tumour cells from entering the vasculature.

This work shows that cell migration is an active contributor to tumour dissemination. Blocking the tetraspanin CD151 prevents de-adhesion at the cells' rear and prevents motility. It does not affect tumour growth or extravasation, but interferes with two critical steps in the metastatic cascade: detachment from primary tumour and intravasation. Inhibition of de-adhesion could thus be a powerful approach to prevent metastasis.

Author: Kim Baumann