After cytotoxic treatment, up-regulation of vascular
growth factors and their receptors may be crucial for
tumor relapse or progression. To determine 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 microCi) of (131)I-MN-14 anti-CEA
IgG or (295 microCi) (131)I-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.