A "class action" against the microenvironment: do cancer cells cooperate in metastasis?

The authors review how cancer cells may cooperate in metastasis by means of microenvironmental changes. The main mechanisms underlying this cooperation are clustered migration of cancer cells, extracellular matrix degradation, paracrine loops of released signaling factors and/or induction of adhesion molecules on stromal cells. Another critical factor could be temporal cooperation: successive waves of cancer cells may induce progressive conditioning of the microenvironment. The "class action" of cancer cells against the microenvironment involves successive steps of the metastatic process: invasion of the primary tumor microenvironment, collective migration through the extracellular matrix, blood vessel disruption, vascular or lymphatic tumor emboli, establishment of a premetastatic niche by secreted factors and endothelial precursor recruitment, induction of cell adhesion molecule expression in endothelial cells, extravasation, micrometastasis dormancy and establishment of a new growth in distant sites. As a result, after completion of the metastatic process, the series of microenvironmental changes from the primary tumor to the metastatic site may promote colonization of metastases by nonmetastatic cancer cells of the primary tumor.