Dataset Information

The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts.

ABSTRACT: The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression. Angiogenesis-related factors were characterized in the TIF and plasma, to understand the relationship between the TIF and plasma secretomes. Clear differences were observed between the TIF and plasma angiogenic secretomes in triple negative MDA-MB-231 breast cancer xenografts compared to ER-positive MCF-7 xenografts with or without VEGF overexpression that provide new insights into TIF components and the role of VEGF in modifying the angiogenic secretome.

SUBMITTER: Dore-Savard L

PROVIDER: S-EPMC5171865 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts.

Dore-Savard Louis L Lee Esak E Kakkad Samata S Popel Aleksander S AS Bhujwalla Zaver M ZM

Scientific reports 20161220

The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen ...[more]

PMID: 27995973

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Project description:PURPOSE:To develop a novel fluorine-18 (18F)-labeled arginine-glycine-aspartic acid (RGD)-coupled ultra-small iron oxide nanoparticle (USPIO) (hereafter, referred to as 18F-RGD@USPIO) and conduct an in-depth investigation to monitor the anti-angiogenic therapeutic effects by using a novel dual-modality PET/MRI probe. METHODS:The RGD peptide and 18F were coupled onto USPIO by click chemistry. In vitro experiments including determination of stability, cytotoxicity, cell binding of the obtained 18F-RGD@USPIO were carried out, and the targeting kinetics and bio-distribution were tested on an MDA-MB-231 tumor model. A total of 20 (n?=?10 per group) MDA-MB-231 xenograft-bearing mice were treated with bevacizumab or placebo (intraperitoneal injections of bevacizumab or a volume-equivalent placebo solution at the dose of 5 mg/kg for consecutive 7 days, respectively), and underwent PET/CT and MRI examinations with 18F-RGD@USPIO before and after treatment. Imaging findings were validated by histological analysis with regard to ?3-integrin expression (CD61 expression), microvascular density (CD31 expression), and proliferation (Ki-67 expression). RESULTS:Excellent stability, low toxicity, and good specificity to endothelial of 18F-RGD@USPIO were confirmed. The best time point for MRI scan was 6 h post-injection. No intergroup differences were observed in tumor volume development between baseline and day 7. However, 18F-RGD@USPIO binding was significantly reduced after bevacizumab treatment compared with placebo, both on MRI (P?<?0.001) and PET/CT (P?=?0.002). Significantly lower microvascular density, tumor cell proliferation, and integrin ?3 expression were noted in the bevacizumab therapy group than the placebo group, which were consistent with the imaging results. CONCLUSION:PET/MRI with the dual-modality nanoprobe, 18F-RGD@USPIO, can be implemented as a noninvasive approach to monitor the therapeutic effects of anti-angiogenesis in breast cancer model in vivo.

Project description:BackgroundDifferent isoforms of VEGF-A (mainly VEGF₁₂₁, VEGF₁₆₅ and VEGF189) have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGF(xxx)b, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF₁₂₁/₁₆₅b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential.ResultsRecombinant VEGF₁₂₁/₁₆₅b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF₁₆₅. Furthermore, treatment of endothelial cells with VEGF₁₂₁/₁₆₅b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF₁₆₅. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF₁₂₁/₁₆₅b isoforms. A549 and PC-3 cells overexpressing VEGF₁₂₁b or VEGF₁₆₅b (or carrying the PCDNA3.1 empty vector, as control) and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGF(xxx)b isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p < 0.05) in both VEGF(xxx)b and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033) between VEGF(xxx)b and total VEGF-A was found.ConclusionsOur results demonstrate that VEGF₁₂₁/₁₆₅b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGF(xxx)b isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken into account when considering a possible use of VEGF₁₂₁/₁₆₅b-based therapies in patients.

Dataset Information

The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts.

Publications

The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts.

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