Demou Zoe N, Hendrix Mary J C
Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614-4314, USA.
J Cell Biochem. 2008 Oct 1;105(2):562-73. doi: 10.1002/jcb.21855.
Beyond the elemental role of blood vessels in tumor growth, fluid conducting networks lacking endothelium (termed vasculogenic mimicry) were identified previously in metastatic melanoma and other cancer types. The etiology remains unclear, though it appears to involve dysregulation of the tumor-specific phenotype and transdifferentiation. Instigating the molecular deciphering of this phenomenon, we established a novel technique for microdissecting the spontaneously formed vascular-like networks and the randomly arranged cells (nests) from living 3D cultures of melanoma and performed microgenomics analysis. For the first time we show that despite the shared genotype, transcription was differentially regulated among the phenotypically distinct melanoma structures in vasculogenic mimicry. Several angiogenesis-specific genes were differentially expressed in higher levels in network cells of both uveal and cutaneous melanoma with intriguing representation of the ephrin family of angiogenesis factors, which was confirmed with immunocytochemistry. Interestingly, the adjacent nest-cells over-expressed ECM-related genes. Moreover, expression of angiogenesis-specific genes in melanoma resembled that of normal microvascular cells and was enhanced in melanoma disseminating hematogenously. The findings suggest that melanoma plasticity could enable autopoiesis of vascular-mimicking elements within the tumor infrastructure with significant clinical implications, such as response to anti-angiogenic treatments. Identifying factors regulating tumor plasticity and heterogeneity at the molecular level is essential in designing effective anti-cancer therapies.
除了血管在肿瘤生长中的基本作用外，先前在转移性黑色素瘤和其他癌症类型中发现了缺乏内皮的液体传导网络（称为血管生成拟态）。其病因尚不清楚，尽管似乎涉及肿瘤特异性表型的失调和转分化。为了推动对这一现象的分子解读，我们建立了一种新技术，用于从黑色素瘤的活3D培养物中显微切割自发形成的血管样网络和随机排列的细胞（巢），并进行微基因组分析。我们首次表明，尽管具有共同的基因型，但在血管生成拟态中，转录在表型不同的黑色素瘤结构之间受到差异调节。几种血管生成特异性基因在葡萄膜和皮肤黑色素瘤的网络细胞中差异表达水平更高，血管生成因子的ephrin家族有有趣的表现，这通过免疫细胞化学得到了证实。有趣的是，相邻的巢状细胞过度表达与细胞外基质相关的基因。此外，黑色素瘤中血管生成特异性基因的表达类似于正常微血管细胞，并且在经血行播散的黑色素瘤中增强。这些发现表明，黑色素瘤的可塑性能够使肿瘤基质内的血管模拟元件自我生成，具有重大的临床意义，如对抗血管生成治疗的反应。在分子水平上识别调节肿瘤可塑性和异质性的因素对于设计有效的抗癌疗法至关重要。
