Tumor-specific regulation of angiogenic growth factors and their receptors during recovery from cytotoxic therapy.
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.
Taylor
Alice P
AP
Tumor Biology, Garden State Cancer Center, Belleville, New Jersey 07109, USA. amptaylor@aol.com
Osorio
Louis
L
Craig
Russell
R
Raleigh
James A
JA
Ying
Zhiliang
Z
Goldenberg
David M
DM
Blumenthal
Rosalyn D
RD
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008222:Lymphokines / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000532:radiotherapy; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016499:Radioimmunotherapy; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D002272:Carcinoembryonic Antigen; D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; D008562:Membrane Glycoproteins; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1