多功能的腫瘤幹細胞能生成腫瘤血管內皮細胞

一直對腫瘤血管的產生比較感興趣。絕大多數腫瘤都有很高密度的腫瘤血管，這些血管是腫瘤細胞能獲取營養和快速生長的關鍵。最近一期的《自然》有數篇論文闡述了這方麵研究的新發現。

多形性膠質母細胞瘤[Glioblastoma multiforme (GBM)]是一種高度惡性的大腦腫瘤，其特點是腫瘤血管密度極高。


GBM

過去一直認為GBM的腫瘤血管是從大腦原有的毛細血管分化而來。

但最新的研究顯示，GBM中有膠質母細胞瘤幹細胞樣細胞[glioblastoma stem-like cells (GSCs)]的存在，而且這些細胞的前身可能不僅僅是神經細胞。

正常的神經幹細胞可以分化成血管內皮細胞。

在膠質母細胞瘤中，神經幹細胞和血管內皮細胞的關係很密切也至關重要，腫瘤幹細胞和血管床密切接觸，產生血管內皮細胞生長素[vascular endothelial growth factor (VEGF)]和間質生成素（stromal-derived factor 1），促進血管生成。

膠質母細胞瘤中的約60%的血管內皮細胞有腫瘤細胞一樣的基因改變，證明很大一部分的血管內皮細胞是從腫瘤細胞分化而來的。

Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1. Here we show that a variable number (range 20–90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.

Nature (volume:468, pages:824–828，date published: 09 December 2010)



Glioblastomas are aggressive brain cancers that are nourished by an extensive network of blood vessels. Two groups now show that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells and seem to be derived from glioblastoma stem-like cells. This work suggests that some putative cancer stem cells promote cancer growth both directly and indirectly, and may explain the failure of certain anti-angiogenic cancer drugs and aid the design of new therapies.