Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels.
Angiogenesis is a crucial process for tumor growth and metastasis regulated by the balance of positive and negative factors. Vascular endothelial growth factor (VEGF/VPF) is a specific mitogen for endothelial cells that has been shown to be overexpressed in a variety of tumors and other inflammatory diseases. To analyze the implication of VEGF/VPF during tumorigenesis, we have studied its expression at different stages of tumor development using the mouse skin carcinogenesis model. VEGF/VPF mRNA was induced in skin in vivo after 12-O-tetradecanoylphorbol-13-acetate treatment. Constitutive up-regulation of VEGF/VPF at the mRNA and protein levels was also observed in premalignant papillomas and, at a higher level, in squamous carcinomas, suggesting a correlation between VEGF/VPF expression and tumor progression. A direct positive correlation between VEGF/VPF mRNA expression and the level of activated H-ras gene was found in a series of cell lines representing different stages of epidermal tumor development. Consequently, a clone of one of these cell lines, HaCa4, which has lost most of its v-ras expression, down-regulated VEGF mRNA expression concomitantly with its metastatic potential. Direct evidence of H-ras involvement in VEGF induction was obtained when an immortalized mouse keratinocyte cell line transduced with a retrovirus carrying v-H-ras showed highly increased VEGF/VPF mRNA levels. These data show that in mouse skin carcinogenesis, the VEGF/VPF angiogenic stimulus occurs early during premalignant papilloma development and further increases at later stages. Moreover, we demonstrate that increasing the activated H-ras dose, a phenomenon that takes place sequentially throughout mouse skin tumor development, may play an additional role by facilitating malignant in vivo progression through the modulation of VEGF/VPF-mediated angiogenesis.
Larcher
F
F
Department of Cell and Molecular Biology, CIEMAT, Madrid, Spain.
Robles
A I
AI
Duran
H
H
Murillas
R
R
Quintanilla
M
M
Cano
A
A
Conti
C J
CJ
Jorcano
J L
JL
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D053590:Interleukin 1 Receptor Antagonist Protein; D015603:Keratinocytes / Q000187:drug effects; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018632:Mice, Inbred SENCAR; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000503:physiopathology; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D013045:Species Specificity; D013755:Tetradecanoylphorbol Acetate; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D008222:Lymphokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012795:Sialoglycoproteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate