Intravasation as a Key Step in Cancer Metastasis

Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as example of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized.