Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice.
BACKGROUND
By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice.


METHODS
Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies.


RESULTS
Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/ VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery.


CONCLUSIONS
The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.
Yoneda
J
J
Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Kuniyasu
H
H
Crispens
M A
MA
Price
J E
JE
Bucana
C D
CD
Fidler
I J
IJ
D000818:Animals; D015152:Blotting, Northern; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D018093:Gelatinases / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics*; D015345:Oligonucleotide Probes; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2