Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer.
Inflammatory breast cancer (IBC) is a specific type of breast tumor that generally has a poor prognosis, in spite of recent advances in treatment. In the present study, semiquantitative reverse transcriptase polymerase chain reaction examination of resected specimens showed that angiogenic factors, not lymphangiogenic factors, are overexpressed in IBC tumors, compared with non-IBC tumors. Immunohistochemical analysis of the specimens revealed a significantly higher population of tumor-infiltrating (TI) endothelial cells (ECs) or endothelial precursor cells (EPCs) in tumor-associated stroma of IBC specimens than in non-IBC specimens. In a previous study, we examined the phenotype of host cells in response to transplanted IBC cells, using an established human IBC xenograft model (WIBC-9) (Shirakawa et al., Cancer Res 2001;61:445-51). The data obtained in that study are consistent with the findings of the present study. To explore the therapeutic potential of blocking vascular endothelial growth factor (VEGF) and angiopoietin (Ang) pathways in IBC, established vectors encoding soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) were injected directly into WIBC-9. Both vectors produced growth inhibition ratios of WIBC-9 that were significantly higher than those of a non-IBC xenograft (MC-5). Also, both vectors suppressed WIBC-9 lung metastases. The efficacy correlated with the number of TI ECs/EPCs, which was determined by fluorescence-activated cell sorting. These ECs/EPCs incorporated acetylated lipoprotein and were integrated within a HUVEC monolayer in vitro culture on day 5.
Shirakawa
Kazuo
K
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Shibuya
Masabumi
M
Heike
Yuji
Y
Takashima
Shigemitsu
S
Watanabe
Ichiro
I
Konishi
Fumio
F
Kasumi
Fujio
F
Goldman
Corey K
CK
Thomas
Kenneth A
KA
Bett
Andrew
A
Terada
Masaaki
M
Wakasugi
Hiro
H
D042683:Angiopoietin-1; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D017931:DNA Primers / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; 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; C467628:Angpt1 protein, mouse; D018952:Antigens, CD34; D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1