Molecular biology of breast metastasis: 'Has it spread?' Disarming one of the most terrifying questions

The number of clinicians whose eyes glaze over as metastasis researchers dutifully recite the many steps of the metastatic process, and go on to examine tumor cell invasion in minute detail, signals either that we give boring lectures or that we have evoked the 'so what?' response. Those who would favor the latter response might state that, even for the greater than 90% of patients without detectable distant metastases at surgery, it remains possible that tumor cells have already invaded out of the primary tumor and are sitting contentedly in distant sites undetected. Only 'growth' and angiogenesis remain. Why study metastasis when it may be virtually complete by the time the patient walks into the clinic? Has the barn door been left open? Should we all drop our experiments and switch to antiangiogenesis projects?Two reviews in this series have addressed this critical question, and arrived at similar answers. Investigators from Dr Ann Chambers' laboratory have watched it all happen. She and others have tagged tumor cells and watched them metastasize to the livers and lungs of experimental animals using in vivo videomicroscopy [1]. She reports that the clinicians are partially correct; both metastatically competent and poorly metastatic cell lines arrive at the metastatic site and extravasate at high frequencies. What separates the cells with high from those with low metastatic potential is their ability to colonize in that distant site. Differences in metastatic colonization potential are observable at the micrometastatic stages, before angiogenesis is a rate-limiting step. In addition to Dr Chambers' in vivo work, other researchers using nonbreast cancer cell lines have recently identified different points of metastatic blockade in distant organs, such as metastatic colonization attached to lung endothelium [2]. Both findings, however, point to colonization at the secondary site as the metastasis-limiting point. Thus, intravital videomicroscopy efforts have confirm