Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling.

Diana Klein,Veronika Kleff,Sã¼Leyman Ergã¼N,Holger Jastrow,Verena Jendrossek,Masahiro Yamaguchi,Nicole Meissner

doi:10.3389/fonc.2014.00169

Diana Klein, Veronika Kleff + Show 5 more

Open Access

https://doi.org/10.3389/fonc.2014.00169

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Abstract

Tumor vessels with resistance to anti-angiogenic therapy are characterized by the normalization of the vascular structures through integration of mature pericytes and smooth muscle cells (SMC) into the vessel wall, a process termed vessel stabilization. Unfortunately, stabilization-associated vascular remodeling can result in reduced sensitivity to subsequent anti-angiogenic therapy. We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression. Using xenograft tumors growing on bone-marrow (BM) chimera of C57Bl/6 wildtype and Nestin-GFP transgenic mice, we show for first time that Nestin(+) cells inducing the maturation of tumor vessels do not originate from the BM but presumably reside within the adventitia of adult blood vessels. Complementary ex vivo experiments using explants of murine aortas revealed that Nestin(+) multipotent stem cells (MPSCs) are mobilized from their niche and differentiated into pericytes and SMC through the influence of tumor-cell-secreted factors. We conclude that tissue-resident Nestin(+) cells are more relevant than BM-derived cells for vessel stabilization and therefore have to be considered in future strategies for anti-angiogenic therapy. The identification of proteins mediating recruitment or differentiation of local Nestin(+) cells with potential stem cell character to angiogenic blood vessels may allow the definition of new therapeutic targets to reduce tumor resistance against anti-angiogenic drugs.

Highlights

Abnormal vasculature is a hallmark of solid tumors
Though there is some evidence that pericytes and smooth muscle cells (SMC) might originate from multipotent mesenchymal stem cells the origin of these mural cells and the molecular changes associated with pericyte-mediated vascular remodeling are still poorly understood [5, 6]
In bevacizumab-treated tumor specimen a more intense expression of Nestin in vascular mural cells and a more regular arrangement of Nestin(+) cells around newly formed tumor blood vessels was detected when compared to untreated tumor tissue, indicating vessel stabilization, maturation, and normalization of the vascular bed upon anti-angiogenic treatment (Figure 1B)

Summary

Introduction

Deregulated formation of new blood vessels leads to a pre-dominance of immature blood vessels with patchy endothelial lining. The newly formed vessels cannot actively respond to physiological stimuli because they lack the smooth muscle elements in their walls [1]. Tumor vessels prove to be functionally inferior. The vascular network can mature by recruitment of pericytes and smooth muscle cells (SMC) to stabilize the immature tumor vessels and this process is accelerated when anti-angiogenic agents were used [3, 4]. Though there is some evidence that pericytes and SMC might originate from multipotent mesenchymal stem cells the origin of these mural cells and the molecular changes associated with pericyte-mediated vascular remodeling are still poorly understood [5, 6]

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