血管生成拟态——肿瘤治疗的新靶点

Vasculogenic Mimicry-Potential Target for Tumor Therapy

在研究黑色素瘤过程中,Maniotis报道了一种独立于肿瘤血管生成的新的肿瘤微循环模式——血管生成拟态:强调它是无内皮细胞参与、细胞外基质界限的管道,肿瘤细胞沿管道外壁排列。Folberg等在脉络膜黑色素瘤中确认了血管生成拟态的7种PAS染色阳性管道模式,并归纳为二类,即中空的和实芯的PAS阳性网络结构。研究认为PAS染色阳性的血管生成拟态网状管道结构可能是肿瘤微循环的一种模式,不同于血管生成,也不同于肿瘤间充质反应。血管生成拟态现象的报道还见于乳腺癌、前列腺癌、卵巢癌、肺癌、胶质母细胞瘤、滑膜肉瘤、横纹肌肉瘤、嗜铬细胞瘤和细胞滋养层形成胎盘的过程。黑色素瘤细胞基因表达谱分析发现瘤细胞呈现遗传学失调和可塑性,其血管生成拟态调解过程中起重要作用的分子包括VE-cadherin、EphA2、laminin5γ2、MMPs、VEGF-C、LYVE1、TF、和NOTCH蛋白等。血管生成拟态概念的提出及其分子生物学调控机制的探讨为抗肿瘤治疗提供了新思路和可能的新靶点。

In 1999, Maniotis described a novel process by which tumors develop a highly patterned microcirculation that was independent of angiogenesis, in aggressive primary and metastatic melanomas, tumor cells generate non-endothelial cell-lined microcirculatory channels composed of extracellular matrix and lined externally by tumor cells. They named the process “vasculogenic mimicry” （VM）. Folberg used PAS staining to show VM network, and identified 7 morphologic patterns of PAS-positive channels uveal melanomas which were confirmed as tubular type and patterned matrix type. Maniotis suggested PAS-positive patterns of VM in uveal melanoma are indeed a form of tumor microcirculation which is different from angiogenesis, and it is not a stromal host response at the interface between the tumor and the surrounding host stroma. VM has also been observed in carcinomas of the breast, prostate, ovary and lung, glioblastoma, synoviosarcoma, rhabdomyosarcoma, and phaeochromocytoma, and in the process of placenta formation from cytotrophoblasts. The molecular “signature” of aggressive melanoma cells is illustrative of an undifferentiated cell with a gene expression profile that is similar to that of embryonic-like cells. VE-cadherin, EphA2, laminin5 γ2, matrix metalloproteinases （MMPs）, vascular endothelial growth factor-C （VEGF-C）, LYVE1, TF and NOTCH are important components of molecular switch of vasculogenic mimicry. The heterogeneity of tumor vasculature and the molecular regulation mechanisms present an opportunity for tumor therapy.