Article

Human blood late outgrowth endothelial cells for gene therapy of cancer: Determinants of efficacy

University Children's Hospital, Ulm, Germany.
Gene Therapy (Impact Factor: 4.2). 03/2007; 14(4):344-56. DOI: 10.1038/sj.gt.3302860
Source: PubMed

ABSTRACT Human adult blood late outgrowth endothelial cells (BOECs) are potential yet untested cellular vehicles to target tumor-cytotoxic effectors to tumors. We show that, following intravenous injection into irradiated mice, BOECs home to Lewis lung carcinoma (LLC) lung metastases, but less so to liver or kidney metastases. BOECs targeted most but not all of the lung metastases, to a different degree. While most of the homed BOECs took up an extravascular position, some integrated into tumor vessels. Sequestration into normal tissue was low. Placental growth factor mediated both migration and invasion of BOECs into LLC spheroid masses in vitro, as did VEGF. When armed with a suicide gene, BOECs exerted a bystander effect on LLC cells in vitro and in vivo. Surprisingly, i.v. administration of armed BOECs into mice bearing multi-organ LLC metastases did not prolong survival. In addition to homing efficacy other parameters impacted upon the efficacy of BOECs. These include the ultimate susceptibility of BOECs to suicide gene-induced cell death, their paracrine proliferative effect on LLC cells and their low proliferation rate compared to LLC cells. Addressing these determinants may make BOECs a useful addition to the arsenal of tumor-targeting moieties.

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    • "However, recent studies have confirmed that human ECFCs, which truly belong to the endothelial lineage , may be recruited to sites of tumor angiogenesis upon their direct injection into the bloodstream of several murine models of human malignancies . More specifically, DiI-labeled ECFCs actively home to subcutaneously implanted glioma [40] and breast cancer [41] xenografts as well as to LLC metastases [42]. It turns out that ECFC represents the most suitable subset to investigate the molecular mechanisms driving EPC incorporation into tumor vasculature and, consequently, to identify the most effective target(s) to adverse metastatic progression. "
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    ABSTRACT: Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca(2+) entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca(2+)-sensor, Stim1, and the plasmalemmal Ca(2+) channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca(2+) toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naïve RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca(2+) toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca(2+) content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca(2+) signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti-angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 10/2014; DOI:10.1016/j.bbamcr.2014.10.024
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    • "However, when high levels of the transgene are needed, like in the treatment of the bleeding disorder von Willebrand disease [29], the engraftment capacity of BOECs might form a limitation in developing an efficient gene therapy strategy. Hence, studying the homing of BOECs to different tissues after intravenous administration is of utmost importance to understand this process and to develop strategies which will allow improved engraftment of these cells [26]. To date, the localization of the cells and their migration capacity within the body is still an issue of debate and ongoing research [26,30e32]. "
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    ABSTRACT: The use of contrast material to stimulate magnetic resonance imaging (MRI) of migrating cells has become an important area of research. In the present study, cationic magnetoliposomes (MLs) were used to magnetically label human blood outgrowth endothelial cells (BOECs) and follow their homing by magnetic resonance imaging (MRI). The biodistribution and functional integration capacity of BOECs, which have shown extensive promise as gene delivery vehicles, have thus far only rarely been investigated. MLs were avidly internalized by BOECs giving clear MRI contrast in phantom studies and the magnetic labeling did not affect cell proliferation, viability, morphology or homeostasis and elicited only minor reactive oxygen species levels. Intravenous injection of labeled BOECs was compared with injection of free MLs and unlabeled BOECs, resulting in homing of BOECs toward the liver and spleen, which was confirmed by histology. The MLs used offer great potential for cellular tracking studies by MRI when low levels of widely distributed cells are present. In particular, the use of these MLs will allow to evaluate the efficacy of new methods to enhance BOEC homing and integration to optimize their use as efficient vehicles for gene therapy.
    Biomaterials 03/2011; 32(17):4140-50. DOI:10.1016/j.biomaterials.2011.02.037
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    ABSTRACT: Human blood outgrowth endothelial cells (BOECs), used as cellular vehicles for experimental cancer therapy, infiltrate tumors. Infiltration may determine their therapeutic efficacy. The role of matrix metalloproteinases (MMPs) in BOEC infiltration and its potential enhancement by irradiation were investigated. Infiltration of BOECs into spheroids made of tumor cells and fibroblasts was determined in the presence of low-dose EDTA, a potent inhibitor of MMPs. Expression and secretion of MMP-2 and -9 by these tumor cells and tumor-stromal cells were investigated with zymography and immunohistochemistry. Infiltration of BOECs into spheroids was blocked by low-dose EDTA. Irradiation enhanced secretion of MMP-2 and, less so, of MMP-9 by tumor-stromal cells and tumor cells, and increased the amount of MMP-2 and -9 in subcutaneous LLC tumors. However, irradiation did not increase infiltration by BOECs. MMPs are involved in the infiltration of BOECs into spheroids. Infiltration of BOECs is not increased by irradiation at the doses employed.
    Anticancer research 01/2007; 27(3B):1415-21.
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