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Tumor-specific Regulation of Angiogenic Growth Factors and Their Receptors during Recovery from Cytotoxic Therapy^{1 ,,2}

Tumor Biology, Garden State Cancer Center, Belleville, New Jersey 07109 [A. P. T., L. O., R. C., D. M. G., R. D. B.]; Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27514 [J. A. R.]; and Department of Biostatistics, Rutgers University, Piscataway, New Jersey 08854 [Z. Y.]

After cytotoxic treatment, up-regulation of vascular growth factors and theirreceptors may be crucial for tumor relapse or progression. Todetermine how cytotoxic therapy (radioimmunotherapy) alters expression of angiogenic growth factors and receptors, athymic mice bearing LoVo, GW-39, HT-29, or Calu3 human tumor xenografts were treated with one dose (240 µCi) of ¹³¹I-MN-14 anti-CEA IgG or (295 µCi) ¹³¹I-RS-7–3G11 anti-EGP-1 IgG. Tumors removed at 1-week intervals up to week 6 were probed by immunohistochemistry (n = 3–11 samples) for vascular endothelial growth factor (VEGF), placental growth factor (PlGF), flk-1 and flt-1, angiopoietin-1 and -2, and Tie-1 and -2. Tumor extracts were also assayed for VEGF by immunoblot and for PlGF by comparative reverse transcription-PCR. During weeks 2–5 after radioimmunotherapy, significantly up-regulated tumor cell VEGF was only detected in HT-29 (immunohistochemistry; 2-fold; week 4; P < 0.05). The increased VEGF of HT-29 was paralleled by a 2-fold (week 4) rise in VEGF receptor flk-1 on vessels as well as increased ang-2/Tie-2. HT-29, GW-39, and Calu-3 increased tumor cell expression of PlGF by week 2 (HT-29 and Calu-3, P < 0.05). In Calu-3, PlGF mRNA increased 8-fold at week 5. PlGF was detected in hypoxic areas at week 2. Vascular expression of orphan receptor Tie-1 increased in all four of the tumors by week 2 (LoVo, GW-39, and Calu-3, P < 0.05). Regulation of angiogenic factors and angiogenesis after tumoricidal therapy may be tumor-specific. Antiangiogenic therapy may require a tumor-specific combination of inhibitors for PlGF, the angiopoietins, or their receptors, in addition to VEGF/flk-1.

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