Role of Cancer Stem Cells in the Development of the Tumor Vasculature

A common strategy to stop tumor growth is to cut the tumor’s blood supply, usually by inhibiting angiogenic factors such as the vascular endothelial growth factor (VEGF). However, recent evidence suggests that anti-angiogenic therapy could also enhance tumor growth and invasiveness in the long-term [1]. Although it is unclear why this occurs, a common hypothesis is that the tumor may develop adaptive strategies to evade anti-angiogenic therapy. Specifically, it is thought that cancer cells may escape anti-angiogenic therapy by migrating towards more oxygenated tissues, possibly by migrating alongside blood vessels [1]. It is also likely that the tumor may have developed intrinsic resistance to anti-angiogenic therapy, although the mechanism of how this might occur is unclear [1].

With the rapid development of stem cell technologies in recent years, researchers recently demonstrated that cancer derived stem cells (CSCs) may also play a role in the tumor’s evasive response to anti-angiogenic therapy [4]. CSCs are a small heterogeneous population of cancer cells in the tumor mass that demonstrate stem cell-like properties such as the capacity for multi-lineage differentiation and self-renewal [2]. Importantly, CSCs are capable of initiating tumors in vivo by producing cancer cells, and by stimulating the formation of new blood vessels necessary to fuel tumor growth [3]. Recent studies by Shen et al (2008) have identified a distinct subpopulation of CSCs in a number of solid tumors that has the capacity to differentiate into endothelial-like cells in vitro, particularly in hypoxic (low oxygen) conditions [4]. They further demonstrated that following implantation of GFP labelled CSCs in SCID mice, the resulting tumor vasculature is constructed in part by GFP labelled cells that express abnormal endothelial markers. This finding suggests for the first time that CSCs may actively contribute to the development of the tumor vasculature by differentiating into abnormal endothelial-like cells. A possible conclusion is that cancer stem cells may be the source of abnormal blood vessels that might not respond well to current anti-angiogenic therapy [4].

Based on this study, it is quite evident that cancer is a complex disease where a cure may not be simply achieved by cutting the tumor’s blood supply. Perhaps further investigation into cancer stem cell biology, and their putative role in the tumor vasculature, may provide clues on how to improve upon existing anti-angiogenic approaches.

1) Loges et al (2009) Cancer Cell, 2009. 15(3): p. 167-70.
2) Wen & Kesari (2008). N Engl J Med, 2008. 359(5): p. 492-507.
3) Bao et al (2006). Nature, 2006. 444(7120): p. 756-60.
4) Shen et al (2008). PLoS ONE 3(2): e1652.

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