Endostatin inhibits murine colon carcinoma sinusoidal-type metastases by preferential targeting of hepatic sinusoidal endothelium

Authors

  • Miren S. Solaun,

    1. Biomedical Research and Technological Development Institute, INBIOMED Foundation, San Sebastian Technological Park, Gipuzkoa, Spain
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    • M.S.S. and L.M. contributed equally to this work.

  • Lorea Mendoza,

    1. Biomedical Research and Technological Development Institute, INBIOMED Foundation, San Sebastian Technological Park, Gipuzkoa, Spain
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    • M.S.S. and L.M. contributed equally to this work.

  • Marco De Luca,

    1. Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
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  • Virginia Gutierrez,

    1. Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
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  • Mari-Paz López,

    1. Biomedical Research and Technological Development Institute, INBIOMED Foundation, San Sebastian Technological Park, Gipuzkoa, Spain
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  • Elvira Olaso,

    1. Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
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  • B. Kim Lee Sim,

    1. EntreMed Inc., Rockville, MD
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  • Fernando Vidal-Vanaclocha

    Corresponding author
    1. Biomedical Research and Technological Development Institute, INBIOMED Foundation, San Sebastian Technological Park, Gipuzkoa, Spain
    2. Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
    • Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Vizcaya, Spain. fax: (34) 94-464-8966.
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Abstract

An angiogenic response originating from peritumoral sinusoids and portal tracts that leads to the formation of metastases with sinusoidal- and portal-type angiogenic patterns, respectively, occurs during the course of liver colonization by murine 51b colon carcinoma (51b-CC) cells. We found a 5-fold increase in endogenous endostatin levels from hepatic blood over baseline (25 ± 6 ng/mL) when micrometastatic foci had a detectable size and a 14-fold increase when macrometastases were developed. Despite this endogenous endostatin production, subcutaneous administration of recombinant human endostatin (rh-E; 50 mg/kg) decreased metastasis number by 60% when dosed from days 1 to 20 after 51b-CC cell injection, by 40% when given from days 10 to 20, and by 30% when administered as a single dose 30 minutes before 51b-CC cell injection compared with controls. In addition, administration of rh-E from days 10 to 20 decreased overall metastasis volume by 90% compared with controls. rh-E increased the number of necrotic sinusoidal-type metastases by 7-fold and decreased their intrametastatic CD31+-microvessel density by 80% without affecting portal-type metastases. Flow cytometry showed rh-E binding to mouse liver sinusoidal cells but not to CD45+ cells (leukocytes and Kupffer cells) or 51b-CC cells. Furthermore, rh-E induced sinusoidal endothelium cell apoptosis. In conclusion, despite the direct correlation between metastasis development and endogenous endostatin generation in the liver, administration of rh-E inhibited micrometastasis generation and macrometastasis growth very efficiently. The antiangiogenic mechanism was selective for sinusoidal-type metastases, in which the neovasculature originating from sinusoidal endothelium cells was targeted by rh-E.

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