Editors' ChoiceCancer

Tumor Endothelial Cells: Mixed Parentage

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Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63ec200
DOI: 10.1126/scitranslmed.3002061

Over three decades ago, Judah Folkman proposed a simple yet radical idea: Blood vessels within the tumor were necessary for tumor growth, and therefore drugs could potentially be developed to target these vessels and starve the tumor. Although tumor cells continuously mutate to evade chemotherapy, blood vessels were thought to be genetically stable and thus more easily targeted. Many drugs failed; others, such as bevacizumab, became some of the most commonly used oncology drugs today. In particular, bevacizumab has activity in one of the deadliest tumors, glioblastoma multiforme (GBM), which is a very vascular tumor and also a tumor type in which the cancer stem cell fraction is thought to drive tumor growth.

Two studies now add a new twist to the angiogenesis field. Groups led by Tabar and De Maria independently observed that a high proportion (up to 90%) of endothelial cells in human GBM tumors carried the same abnormal genomes as the malignant GBM cells, suggesting that endothelial cells are derived from the tumor cells rather than from normal surrounding vessels. In fact, both groups demonstrated this directly by digesting GBM samples into single cells and either growing them in culture or injecting them into mice. In both cases, human endothelial cells were formed. Intriguingly, it was the cancer stem cell fraction—characterized by CD133 expression—that had the ability to form endothelial cells. When these tumor-derived endothelial cells were ablated in the tumors transplanted into mice, the tumors demonstrated profound regression, suggesting that these cells are crucial for tumor growth. Treatment with the vascular endothelial growth factor antibody bevacizumab reduced formation of these new tumor-derived endothelial cells.

These exciting observations raise many questions related to cancer therapeutics. Is this phenomenon unique to GBM, or does it also occur in other tumor types? What are the implications of these data for the cancer stem cell model: Could the unique tumor-forming capacity of these cells be due in part to their ability to generate their own endothelium? And what of the implications for the angiogenesis field: When thinking of tumor blood vessels as a mixture of normal and tumor-derived cells, do we need to design drugs to target both? Answers to these questions could provide a new direction for tumor angiogenesis research and, hopefully, new cancer therapies as well.

L. Ricci-Vitiani et al., Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828 (2010). [Abstract]

R.Wang et al., Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010). [Abstract]

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