Endothelial activation during the diapedesis of cancer cells: between the kiss of death and therapeutic breakthrough.

Cancer development is a complex process, initiated by the combination of epigenetic and genetic changes in normal cells. Selective microenvironmental pressure within the primary tumors prompts the microevolution of invasive cell lineages that efficiently penetrate circulation and lymphatic systems and extravasate in distant organs, initiating the formation of metastases. Extravasation (diapedesis), i.e., the multistep penetration of the endothelial layer by circulating cancer cells, is regarded as the decisive step and one of the bottlenecks of the metastatic cascade. It limits malignant cancer dissemination, while initiating the formation of metastases. The efficiency of extravasation depends equally on the properties of circulating cancer cells and the local functional status of the endothelium, which remains sensitive to paracrine, adhesive, and juxtacrine stimuli generated by cancer and immune cells. Here, we review the current state of knowledge on the significance of endothelial activation for the diapedesis of circulating cancer cells, with the emphasis on the intercellular communication pathways that mediate this process. We also address the potential and limitations of endothelial activation as the target for novel strategies of cancer treatment.