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Science 22 September 2006:
Vol. 313. no. 5794, pp. 1785 - 1787
DOI: 10.1126/science.1127592
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Reports
Therapy-Induced Acute Recruitment of Circulating Endothelial Progenitor Cells to Tumors
Yuval Shaked1*,
Alessia Ciarrocchi2*,
Marcela Franco1,
Christina R. Lee1,
Shan Man1,
Alison M. Cheung3,
Daniel J. Hicklin4,
David Chaplin5,
F. Stuart Foster3,
Robert Benezra2 and
Robert S. Kerbel1
1 Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
2 Program of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
3 Department of Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
4 ImClone Systems, 180 Varick Street, 7th Floor, New York, NY 10014, USA.
5 OXiGENE Inc., 230 Third Avenue, Waltham, MA 02451, USA.
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Fig. 1. Elimination of the VDA-induced spike in CEPs, reduction in viable tumor rim blood vessel perfusion as well as blood flow, and increased hypoxia induced by prior treatment with VEGFR-2 monoclonal antibody DC101. (A) Eight-week-old non–tumor-bearing BALB/cJ mice (n = 5 mice per group) were bled from the retro-orbital sinus 4 and 24 hours after they were treated with OXi-4503 (100 mg/kg), DC101 (800 µg per mouse), or a combination of the two drugs, as indicated. CEP levels were determined using four-color flow cytometry as in (17) for each treatment group. Error bars ± SD; **0.05 > P > 0.01, ***P < 0.01. (B to D) The same drug schedule was used on orthotopically implanted MeWo human melanoma tumor cells. Six- to eight-week-old nude mice were subdermally transplanted with MeWo cells (2 x 106) that were allowed to reach  500 mm3, at which point they were treated with DC101 (800 µg), OXi-4503 (100 mg/kg), or DC101 24 hours before 100 mg/kg (at the same dosages). Three days after OXi-4503 treatment, tumors were harvested and evaluated for (B) necrosis (scale bar, 100 µm) and (C) hypoxia (green) and perfusion (blue) (scale bar, 50 µm). In a parallel experiment, mice were evaluated for functional blood flow (D) using high-frequency microultrasound (scale bar, 1 mm). See fig. S4 for summary of quantitative data.
[View Larger Version of this Image (90K GIF file)]
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Fig. 2. Homing and incorporation of GFP+ bone marrow–derived cells in mouse tumors after treatment of the tumor-bearing mice with DC101, OXi-4503, or the combination of the two drugs, and effect of OXi-4503 on CEPs and tumors in Idmut mice. (A) GFP+ bone marrow–transplanted C57Bl/6J mice (n = 5 mice per group) were used as recipients of LLC cells (0.5 x 106) injected subcutaneously and treated with DC101, OXi-4503, and the combination of the two drugs at the same doses and schedule described for Fig. 1, B and C; treatment was initiated when tumor volumes reached 500 mm3. Three days later, tumors were removed and stained for CD31 (red) to mark endothelial cells. GFP+ bone marrow–derived cells are green; scale bars, 50 µm for left images, 20 µm for right images. (B) Eight- to 10-week-old non–tumor-bearing Idmut mice and their age-matched wild-type (wt) controls (n = 4 or 5 mice per group) were treated with OXi-4503 (100 mg/kg). Blood drawn from the retro-orbital sinus at baseline, 4 and 24 hours, was processed for viable CEPs as in (17). Error bars ± SD; **0.05 > P > 0.01. (C) Eight- to 10-week-old Idmut mice, their age-matched wild-type controls, lethally irradiated Idmut mice transplanted with 106 bone marrow cells obtained from wild-type control mice, and lethally irradiated wild-type mice transplanted with 106 bone marrow cells derived from Idmut mice were implanted with LLC cells (0.5 x 107). When tumors reached 500 mm3, treatment with a single dose of OXi-4503 (100 mg/kg) was initiated. Three days later, mice were killed and tumors were harvested and evaluated for necrosis. Scale bar, 100 µm; BM, bone marrow. See fig. S9 for summary of quantitative data.
[View Larger Version of this Image (87K GIF file)]
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