Nestin(+) Tissue-Resident Multipotent Stem Cells Contribute to Tumor Progression by Differentiating into Pericytes and Smooth Muscle Cells Resulting in Blood Vessel Remodeling

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.

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…Wild-type C57BL/6 and NestGFP transgenic donor mice (mixed gender) received 15 Gy of WTI in a single dose of a Cobalt 60 source ( 60 Co c-rays at 0.5 Gy/min) as previously described (43,44,81). Single cell suspensions of cultured MSCs (0.5 · 10 6 cells) were intravenously transplanted into the tail vein of WTI mice 24 h or 14 days after irradiation or in sham-irradiated (0 Gy) control animals as previously described (44).…”

“…A mouse TBI model was used as described before (43,44). In brief, BM cells were harvested aseptically by flushing the tibias and femurs of adult animals and subjected to erythrocyte lysis.…”

“…Vascular wall-resident MSCs were isolated from aortas of C57BL/6-Tg(CAG-EGFP)1Osb/J mice ( Jackson Laboratory, Bar Harbor, ME) as previously described (43,44). In brief, tissue pieces were mechanically minced and dissociated for 15 min at 37°C in OptiMEM I medium containing 0.2% type 2-collagenase (CLS2, 43J14367B; Worthington, Lakewood, WA).…”

Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B

“…Although nestin is expressed during early stages of normal cells development, under pathological conditions this protein could be also found in cancer stem cells, as well as in perivascular and endothelial cells suggesting its role in various malignant tumors neoangiogenesis [11,12]. In recent years, an increased nestin expression has been reported in multiple malignant masses including CNS tumors, gastrointestinal stromal tumors, pancreatic cancer, prostate cancer, breast cancer, malignant melanomas, and thyroid tumors [13][14][15]. High expression of nestin correlated with aggressive growth, metastasis, and poor prognosis in these cancers.…”

“…Remodeling of blood vessels network requires tissue-resident nestin-positive progenitor cells that represent the basic source for pericytes and smooth muscle cells. The assessment of nestin expression as a potential marker for mural pericytes was suggested to determine the mechanisms of pericytes recruitment and differentiation [13]. Pericytes are not only found close to endothelial cells, but can be searched by their localiztion to the abluminal side of the blood vessel wall in combination with the expression of various cell surface markers such as α-smooth muscle actin (α-SMA), CD146, neural glial 2 (NG2 and/or leptin receptor (LepR).…”