Abstract |
The switch to the angiogenic phenotype represents a critical checkpoint during tumor progression. The acquisition of new capillary vessels provides newly vascularized tumor nodules with a distinct biological advantage over their avascular counterparts by conferring upon them the ability to expand and develop both locally and metastatically. To identify the molecules and mechanisms underlying this rate-limiting step in successful tumorigenesis, we have developed an in vivo tumor model that reproducibly recapitulates the angiogenic switch. Using this model, we have analyzed vascular endothelial growth factor ( VEGF), basic fibroblast growth factor (bFGF), and hypoxia-inducible factor-1alpha (HIF-1alpha) expression and activity in both avascular and vascular growth phases of the tumor. A significantly higher level of VEGF protein was detected in avascular tumor nodules compared with vascular nodules. As avascular tumors became vascularized, VEGF levels decreased approximately 10-fold. In contrast, bFGF levels were not elevated in avascular nodules but rather were detected at levels approximately 2 times higher in vascular nodules compared with the avascular tumor nodules. Given that VEGF is transcriptionally regulated by HIF-1alpha, immunohistochemical studies of chondrosarcoma nodules were conducted and revealed that the nuclear translocation of HIF-1alpha was detected exclusively in avascular tumor nodules. This study implicates HIF-1alpha-mediated up-regulation of VEGF but not bFGF in the switch to the angiogenic phenotype during tumorigenesis.
|
Authors | J Fang, L Yan, Y Shing, M A Moses |
Journal | Cancer research
(Cancer Res)
Vol. 61
Issue 15
Pg. 5731-5
(Aug 01 2001)
ISSN: 0008-5472 [Print] United States |
PMID | 11479208
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- DNA-Binding Proteins
- Endothelial Growth Factors
- Hif1a protein, rat
- Hypoxia-Inducible Factor 1
- Hypoxia-Inducible Factor 1, alpha Subunit
- Lymphokines
- Nuclear Proteins
- Transcription Factors
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
- Fibroblast Growth Factor 2
|
Topics |
- Animals
- Cattle
- Cell Nucleus
(metabolism)
- Chondrosarcoma
(blood supply, metabolism)
- DNA-Binding Proteins
(biosynthesis, genetics, physiology)
- Endothelial Growth Factors
(biosynthesis, genetics)
- Fibroblast Growth Factor 2
(biosynthesis, physiology)
- Gene Expression Regulation, Neoplastic
(physiology)
- Hypoxia-Inducible Factor 1
- Hypoxia-Inducible Factor 1, alpha Subunit
- Lymphokines
(biosynthesis, genetics)
- Male
- Neoplasm Transplantation
- Neovascularization, Pathologic
(metabolism)
- Nuclear Proteins
(biosynthesis, genetics, physiology)
- Rats
- Rats, Sprague-Dawley
- Transcription Factors
- Up-Regulation
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
|