Department of Translational Research, Institut Curie, Paris, France.
Department of Molecular Medicine and Biochemistry, The George Washington School of Medicine, Washington, DC, USA.
Angiogenesis. 2020 Feb;23(1):27-41. doi: 10.1007/s10456-019-09695-9. Epub 2019 Nov 12.
Intravascular dissemination of tumor cells is the accepted mechanism of cancer metastasis. However, the phenomenon of angiotropism, pericyte mimicry (PM), and extravascular migratory metastasis (EVMM) has questioned the concept that tumor cells metastasize exclusively via circulation within vascular channels. This new paradigm of cancer spread and metastasis suggests that metastatic cells employ embryonic mechanisms for attachment to the abluminal surfaces of blood vessels (angiotropism) and spread via continuous migration, competing with and replacing pericytes, i.e., pericyte mimicry (PM). This is an entirely extravascular phenomenon (i.e., extravascular migratory metastasis or EVMM) without entry (intravasation) into vascular channels. PM and EVMM have mainly been studied in melanoma but also occur in other cancer types. PM and EVMM appear to be a reversion to an embryogenesis-derived program. There are many analogies between embryogenesis and cancer progression, including the important role of laminins, epithelial-mesenchymal transition, and the re-activation of embryonic signals by cancer cells. Furthermore, there is no circulation of blood during the first trimester of embryogenesis, despite the fact that there is extensive migration of cells to distant sites and formation of organs and tissues during this period. Embryonic migration therefore is a continuous extravascular migration as are PM and EVMM, supporting the concept that these embryonic migratory events appear to recur abnormally during the metastatic process. Finally, the perivascular location of tumor cells intrinsically links PM to vascular co-option. Taken together, these two new paradigms may greatly influence the development of new effective therapeutics for metastasis. In particular, targeting embryonic factors linked to migration that are detected during cancer metastasis may be particularly relevant to PM/EVMM.
肿瘤细胞的血管内播散是癌症转移的公认机制。然而，血管亲和性、周细胞模拟（PM）和血管外迁移转移（EVMM）的现象质疑了肿瘤细胞仅通过血管内循环转移的概念。这种癌症扩散和转移的新范式表明，转移性细胞利用胚胎机制附着在血管的基底外侧表面（血管亲和性），并通过连续迁移扩散，与周细胞竞争并取代周细胞，即周细胞模拟（PM）。这是一种完全血管外的现象（即血管外迁移转移或 EVMM），没有进入（血管内）血管通道。PM 和 EVMM 主要在黑色素瘤中进行了研究，但也发生在其他癌症类型中。PM 和 EVMM 似乎是胚胎发生程序的逆转。胚胎发生和癌症进展之间有许多相似之处，包括层粘连蛋白、上皮-间充质转化和癌细胞重新激活胚胎信号的重要作用。此外，尽管在此期间细胞大量迁移到远处部位并形成器官和组织，但在胚胎发生的头三个月内没有血液循环。因此，胚胎发生迁移是一种连续的血管外迁移，与 PM 和 EVMM 一样，支持这样的概念，即在转移过程中这些胚胎迁移事件似乎异常重现。最后，肿瘤细胞的血管周围位置将 PM 与血管选择内在地联系起来。综上所述，这两个新范式可能会极大地影响转移性疾病新有效治疗方法的发展。特别是，针对在癌症转移过程中检测到的与迁移相关的胚胎因子进行靶向治疗，可能与 PM/EVMM 特别相关。
