Effect of tumour cell-conditioned medium on endothelial macromolecular permeability and its correlation with collagen

Utoguchi, Naoki; Mizuguchi, Hiroyuki; Dantakean, A; Makimoto, Hiroo; Wakai, Yukiko; Tsutsumi, Ysauo; Nakagawa, Shinsaku; Mayumi, Tadanori

doi:10.1038/bjc.1996.5

Cited by 30 publications

(16 citation statements)

References 33 publications

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“…14) Conversely, the phenotype of normal tissue-derived endothelial cells can be changed to a tumor-derived endothelial cell phenotype by culturing the endothelial cells in tumor cell-conditioned medium. 19,20) In this paper, we report that human umbilical vein endothelial cells (HUVEC) cultured in the presence of human tumor cell (HT1080)-conditioned medium (tEC; tumor-derived endothelial-like cells) acquired preferential TNF-sensitivity compared with HUVEC cultured in a normal medium (nEC) as well as two characteristic properties of tumor-derived endothelial cells: hyperpermeability, and deficient cell-adhesive function. Using this human model cell system, we investigated whether RGD-V29 acted more selectively on tumorderived endothelial cells compared to rhTNF.…”

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confidence: 99%

Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells

Kuroda

Miyata

Tsutsumi

et al. 2000

Japanese Journal of Cancer Research

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Tumor-derived endothelial-like cells (tEC) were prepared by culturing human umbilical vein endothelial cells (HUVEC) in the presence of HT1080 human fibrosarcoma-conditioned medium. tEC showed higher permeability and less cell-adhesion activity than normal HUVEC (nEC). Tumor necrosis factor-α α α α (TNF) is known to have tumor-vasculature disrupting activity. tEC showed higher cytotoxicity to recombinant human TNF (rhTNF) than nEC, and was not observed using HUVEC cultured with WI38 human diploid cell-conditioned medium as a medium-control. These results demonstrate that tEC acquire physiological properties of tumor-associated vasculature, and may be a useful model system for the study of the mechanisms of TNF antitumor action. The TNF-mutant RGD-V29 (code No. F4614), which has an inserted 4 Arg-Gly-Asp sequence and an 29 Arg→ → → →Val replacement, was found to induce greater preferential destruction of tEC compared to rhTNF. When the preferential activities were evaluated in terms of 30% cytotoxicity (IC 30 ) ratio (nEC/tEC), the ratio was 460 for RGD-V29 compared to 4.2 for rhTNF. RGD-V29 also exhibited cell-adhesive function and bound preferentially to the p55 TNF-receptor. Both these properties of RGD-V29 contributed to the tEC selective cytotoxicity, indicating that the RGD ligands and selective p55 receptor binding on the cells, although uncharacterized, are involved in tEC targeting. Therefore, the TNF mutant RGD-V29 may show greater selectivity toward tumor vasculature than wild-type TNF.

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confidence: 99%

Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells

Kuroda

Miyata

Tsutsumi

et al. 2000

Japanese Journal of Cancer Research

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“…However, it is impossible to explain the entire process of implantation only by the function of adhesion molecules, such as integrin. In this process, the involvement of certain soluble factors, which are produced by cancer cells and which induce the retraction of endothelial cells, enhancing permeability, may be a possibility [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Involvement of adhesion molecules in metastasis of SW1990, human pancreatic cancer cells

et al. 1998

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“…13,14) In addition, we previously reported that endothelial cells cultured in conditioned medium prepared from tumor cells, converted normal endothelial cells to have various character similar to tumor endothelial cells, and these cells had highly sensitivity to TNF-a. 15,16) Therefore, the increased permeability of the newly formed vessels in the system at 1-2 h after the administration of PEG-TNF-a would result from the increasing of the permeability of tumor endothelial cells and the cytotoxicity of PEG-TNF-a on tumor vascular endothelial cells. On the other hand, TNF-a is known to have procoagulant effects on tumor neovasculature, by causing fibrin deposition and localized thrombosis, which, in turn, leads to ischaemic necrosis of tumors.…”

Section: Resultsmentioning

confidence: 99%

Selective Enhancer of Tumor Vascular Permeability for Optimization of Cancer Chemotherapy

Yoshioka

Tsutsumi

Kamada

et al. 2004

Biological & Pharmaceutical Bulletin

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With the development of tumor biology, molecular biology, and combinatorial chemistry, many therapeutic agents have been developed for tumors. However, the clinical application of antitumor agents such as cytokines, antibodies and chemotherapeutic drugs has failed because of poor accumulation in the tumor tissue.1,2) Heterogeneous tumor perfusion, vascular permeability, and increased interstitial pressure restricted the penetration of therapeutic agents into tumor tissue from circulation. 1,2)It has been suggested that tumor necrosis factor-alpha (TNF-a) can overcome these problems. TNF-a was identified as a cytokine that specifically injures tumors and has been highlighted as a potent anti-tumor agent.3) Furthermore, TNF-a destroyed the tumor vasculature selectively and enhanced the tumor vascular permeability. 4) Regional isolated limb perfusion using TNF-a in combination with melphalan or doxorubicin showed greater therapeutic effects on softtissue sarcoma or melanoma than chemotherapeutic drugs alone.5) It is believed that the synergistic effect between TNF-a and chemotherapeutic drugs results from TNF-a-induced destruction of tumor vasculature and enhancement of tumor vasculature permeability. However, because of its high instability and pleiotropic action in vivo, attempts to use TNF-a as a systemic anticancer agent and an enhancer of tumor vascular permeability in humans, failed due to severe systemic side effects such as fever and decreased blood pressure as seen in case of an endotoxin-like shock, before therapeutic doses could be administered. 6)To overcome these drawbacks and apply TNF-a as a systemic administrator, we have attempted to conjugate TNF-a with polyethylene glycol (PEG) and other water-soluble polymeric modifiers. [7][8][9][10] We showed that the antitumor effects of PEG-TNF-a, obtained by PEGylation with a molecular weight of 5000, was enhanced to 100 times that of unmodified TNF-a, without increasing their toxic side effects. 7,8) In this study, we examined the usefulness of PEG-TNF-a as a selective enhancer of tumor vascular permeability. We showed that PEG-TNF-a enhanced the permeability of tumor vasculature without having any effect on the permeability of normal tissue. We considered that PEG-TNF-a would be used with chemotherapeutic drugs for tumor therapy. MATERIALS AND METHODS Preparation of125 I-Labeled Polymers Radiolabeled polymeric modifiers were prepared by the chloramine-T method. PEGs (average molecular weight: 12000, 50000, 70000, 500000) (purchased from Wako Pure Chemical Industries, Ltd., Osaka, Japan) dissolved in 1,4-dioxan were reacted with N,NЈ-carbonyldiimidazole for 6 h at room temperature. After dialysis in water, the activated polymers were reacted with a 2-fold molar excess of thyramine hydrochloride for 48 h at 4°C. These reaction mixtures were also dialyzed in water and lyophilized. The polymer-thyramine conjugates, dissolved in a 0.4 M sodium phosphate buffer (2.5 mg/ml) and Na 125 I (100 mCi/ml), were mixed in a microcentrifuge tube on ice. The labeling reac...

show abstract

Effect of tumour cell-conditioned medium on endothelial macromolecular permeability and its correlation with collagen

Cited by 30 publications

References 33 publications

Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells

Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells

Involvement of adhesion molecules in metastasis of SW1990, human pancreatic cancer cells

Selective Enhancer of Tumor Vascular Permeability for Optimization of Cancer Chemotherapy

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