Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634009, Russia.
Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, 634050, Russia.
Biochemistry (Mosc). 2019 Jul;84(7):762-772. doi: 10.1134/S0006297919070071.
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.
浸润是癌症转移的关键步骤，在此过程中，肿瘤细胞穿透血管壁进入循环系统，成为循环肿瘤细胞和潜在的转移性种子。了解浸润的分子机制对于开发预防转移的治疗策略至关重要。本文综述了目前关于癌细胞进入血液和淋巴管的浸润机制的研究数据。成熟的胸腺细胞进入循环系统和树突状细胞进入局部淋巴结的过程被认为是正常生理条件下浸润的范例。病理生理状态下的浸润通过炎症部位的白细胞通过鞘氨醇 1-磷酸与其受体相互作用逆向穿过血管内皮迁移到血液中来说明。浸润涉及依赖侵袭和不依赖侵袭的机制。特别是，间质和阿米巴样细胞侵袭，以及新生血管形成和血管重塑，被认为在肿瘤细胞进入循环系统中起重要作用。特别关注巨噬细胞通过 CSF1/EGF（集落刺激因子 1/表皮生长因子）旁分泌信号通路和 TMEM（转移的肿瘤微环境）介导的机制对浸润的贡献。还讨论了其他机制，包括被血管壁成分包围的肿瘤细胞簇的浸润、协同浸润（侵袭性肿瘤细胞进入循环系统后非侵袭性肿瘤细胞的进入）以及与血管生成拟态（肿瘤细胞形成血管通道）相关的浸润。还提出了尚未在文献中描述的新的浸润特异性机制。强调了针对预防癌症浸润的靶向治疗策略的重要性。
