Zone‐specific remodeling of tumor blood vessels affects tumor growth

Tilki, Derya; Kilic, Nerbil; Sevinc, S.; Zywietz, F.; Stief, Christian G.; Ergün, Süleyman

doi:10.1002/cncr.23024

Cited by 36 publications

(20 citation statements)

References 31 publications

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“…This is in accordance with the notion that the Ang-1-Tie2 interaction has an inhibitory effect on tumor growth through improved vessel stabilization (42). It has been shown that vascular stabilization per se results in extensive necrosis of tumor tissue (43,44). The decrease of Ang-1 expression in T a compared with normal bladder epithelium as we show here also supports this concept and is probably an important step in bladder carcinogenesis.…”

Section: Discussionsupporting

confidence: 91%

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Szarvas

Jäger

Tötsch³

et al. 2008

Clinical Cancer Research

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Purpose: Vascular endothelial growth factor (VEGF), angiopoietins (Ang-1and Ang-2), and their receptor Tie2 are critically involved in both normal and pathologic angiogenesis. The aim of this study was to explore the role of Ang-1, Ang-2,VEGF, andTie2 in the development and progression of bladder cancer as well as to examine their prognostic value in this tumor type. Experimental Design:Tumor samples of 113 bladder cancer patients, normal bladder epithelium of 5 noncancer patients, and two low-grade (UMUC3 and RT4) and two high-grade (J82 and T24) bladder cancer cell lines were analyzed by quantitative real-time PCR. The expression data were analyzed performing Wilcoxon rank-sum and Kaplan-Meier log-rank tests as well as univariate Cox analyses and Cox proportional hazards regression model. Results: In tissues of noninvasive bladder tumors, Ang-1 expression was significantly lower (P < 0.001), whereasVEGF expression was significantly higher (P = 0.031) than in normal bladder tissue. These findings were also confirmed at the protein level by immunohistochemistry. In contrast, Tie2 and Ang-2 abundance in tumor did not differ significantly from that in normal bladder tissue. Multivariate analysis identified Ang-2 as a strong and independent predictor of tumor recurrence [hazard ratio (HR), 10.18; 95% confidence interval (95% CI), 2.69-38.49; P < 0.001] andTie2 expression as an independent favorable prognostic factor for both metastasis (HR, 0.31; 95% CI, 0.11-0.89; P = 0.029) and disease-specific survival (HR, 0.25; 95% CI, 0.10-0.62; P = 0.003). Conclusions: These data show the strongest change in expression of VEGF and Ang-1 in superficial bladder cancer in comparison with normal bladder epithelium and the invasive tumor stages. The prognostic significance of Ang-2 and Tie2 underlines the essential role of angiopoietins-Tie2 system in progression of bladder cancer.

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Section: Discussionsupporting

confidence: 91%

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Szarvas

Jäger

Tötsch³

et al. 2008

Clinical Cancer Research

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“…While tumor cells organized around the stabilized vessels survive the therapy, tumor tissue areas far from the stabilized vessels become necrotic. Recently, it was demonstrated that blood vessels localized in the central part of tumor become stabilized endogenously by increased integration of SMC or pericytes into the vessel wall and that this process was accompanied by necrosis of tumor tissue (Tilki et al 2007). In line with these Wndings, our current data show for the Wrst time that anti-angiogenic therapy greatly accelerates and extends the process of necrosis.…”

Section: Discussionmentioning

confidence: 98%

“…Especially in the central areas of the tumor blood vessels seem to undergo a partial stabilization, which is associated with a signiWcant reduction in vascular density and an extended necrosis of tumor tissue in these tumor regions (Tilki et al 2007). Recent studies of our group and other groups have shown that a stabilization or a partial "normalization" of the tumor vascular bed to the Wrst is rather harmful than good to the tumor, and secondly, perhaps the eYciency of the previously established therapeutic approaches, such as chemotherapy or radiotherapy could be improved (Ergün et al 2001(Ergün et al , 2006(Ergün et al , 2008Jain 2005;Neskey et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab

Weißhardt

Trarbach

Dürig

et al. 2011

Histochem Cell Biol

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Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.

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“…Consequently, tumor vessels prove to be functionally inferior. The resulting undirected blood flow with areas of oversupply as well as areas of undersupply complicates an efficient administration of intravenous drugs in cancer therapy (2). However, 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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Zone‐specific remodeling of tumor blood vessels affects tumor growth

Cited by 36 publications

References 31 publications

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab

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

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