Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome

Xue, Yuan; Religa, Piotr; Cao, Renhai; Hansen, Anker Jón; Lucchini, Franco; Jones, Bernt; Wu, Yan; Zhu, Zhenping; Pytowski, Bronislaw; Liang, Yu‐Xiang; Zhong, Weide; Vezzoni, Paolo; Rozell, Björn; Cao, Yihai

doi:10.1073/pnas.0807967105

Cited by 73 publications

(112 citation statements)

References 16 publications

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“…To study the impact of VEGF-specific blockades on vasculatures in various healthy tissues, we used three specific anti-VEGF agents known to block VEGF-induced biological activities: a rabbit anti-mouse neutralizing monoclonal antibody (BD0801) (22); a rat anti-mouse VEGFR-1 neutralizing monoclonal antibody (MF-1) (23)(24)(25); and a rat anti-mouse VEGFR-2 neutralizing monoclonal antibody (DC101) (23)(24)(25). These antibodies were systemically delivered for 2 wk to healthy mice using doses known to block tumor angiogenesis (22)(23)(24)(25).…”

Section: Resultsmentioning

confidence: 99%

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Yang

Zhang

Cao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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122

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Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti–VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1–specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF–specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF–specific drugs.

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Section: Resultsmentioning

confidence: 99%

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Yang

Zhang

Cao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

122

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“…In subsets of experiments, tumor-bearing mice were randomly divided into different groups (n ϭ 6 -8 per group) and received treatment with VEGFR1, VEGFR2 or VEGFR1/VEGFR2 blockades as previous described (49,51). The treatment started at day 0 after tumor implantation and administration of anti-VEGFR1 (MF1, Imclone Inc., 600 g/mouse) or anti-VEGFR2 (DC101, Imclone Inc., 600 g/mouse) twice a week for a total of 2-week therapy.…”

Section: Methodsmentioning

confidence: 99%

“…To study vascular remodeling effects of various members in the VEGF family in tumors, we generated murine T241 fibrosarcoma and Lewis lung carcinoma (LLC) cell lines that stably expressed human PlGF-1, PlGF-2, and VEGF 165 and expression levels of these cytokines were equivalent (35,36,48,49). Additionally, the mature form of VEGF-C was also overexpressed in T241 fibrosarcoma.…”

Section: Plgf-1 and Plgf-2 Promotes Vascular Normalization And Remodementioning

confidence: 99%

“…Consistent with our previous reports, s.c. implantation of PlGF-1-and PlGF-2-expressing tumor cells resulted in delayed tumor growth rates (35,36,49). In contrast to PlGF tumors, implantation of both VEGF-A-and VEGF-Cexpressing tumor resulted in significantly accelerated tumor growth rates (36,48,49). To study vascular remodeling effects, tumors from different groups were grown to a similar size and tumor vasculatures were detected using a whole-mount technique with anti-CD31 immunostaining.…”

Section: Plgf-1 and Plgf-2 Promotes Vascular Normalization And Remodementioning

confidence: 99%

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Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

Hedlund

Hosaka

Zhong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy. vascular permeability ͉ vascular remodeling

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“…Xenograft tumour experiments were performed as previously described 22,[29][30][31][32] . When tumour sizes in experimental (4-6 mice per group, 2-4 experiments) groups became equal, that is, 1.5 cm 3 , tumourbearing mice were killed by a lethal dose of CO 2 .…”

Section: Measurement Of Ctcs Using Facsmentioning

confidence: 99%

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

et al. 2013

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Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dosedependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-b signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-b and inactivation of the PDGF-b signalling decreases integrin a1b1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.

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Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome

Cited by 73 publications

References 16 publications

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

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