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PMID: 9023347 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 3 ·1997-02-04 ·Pages 861-6

Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J

Abstract

The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change likely requires a change in the balance of angiogenic stimulators and angiogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angiogenic switching is accompanied by up-regulation of vascular endothelial growth factor and matrix metalloproteinase (MMP) bioactivity and downregulation of tissue inhibitor of MMP. Furthermore, we show that inhibition of phosphatidylinositol-3-kinase leads to partial inhibition of tumor angiogenesis, thus demonstrating that activated H-ras activates tumor angiogenesis through two distinct pathways. Finally, we show evidence for two forms of tumor dormancy.

MeSH Terms
Androstadienes/pharmacology Animals Antigens, Polyomavirus Transforming/physiology Cell Hypoxia Cell Line, Transformed Endothelial Growth Factors/genetics Endothelium/cytology,metabolism Enzyme Inhibitors Gene Expression Regulation, Neoplastic Glycoproteins/metabolism H-2 Antigens/analysis Lymphokines/genetics Male Metalloendopeptidases/metabolism Mice Mice, Inbred C57BL Mice, Nude Neoplasms, Experimental/blood supply Neovascularization, Pathologic/physiopathology Oncogene Protein p21(ras)/physiology Oncogenes/physiology Phosphatidylinositol 3-Kinases Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors,physiology RNA, Messenger/biosynthesis Simian virus 40/immunology Tissue Inhibitor of Metalloproteinases Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Wortmannin
Chemicals
Androstadienes Antigens, Polyomavirus Transforming Endothelial Growth Factors Enzyme Inhibitors Glycoproteins H-2 Antigens Lymphokines RNA, Messenger Tissue Inhibitor of Metalloproteinases Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Phosphatidylinositol 3-Kinases Phosphotransferases (Alcohol Group Acceptor) Metalloendopeptidases Oncogene Protein p21(ras) Wortmannin
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Arbiser J L
Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
Moses M A
Fernandez C A
Ghiso N
Cao Y
Klauber N
Frank D
Brownlee M
Flynn E
Parangi S
Byers H R
Folkman J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.94.3.861
Published
1997-02-04
Pages
861-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC19604
Subset
IM
Grants
NCI NIH HHS · R01 CA149738 · United States
NIGMS NIH HHS · T32 GM008716 · United States
External Links
PubMed source DOI: 10.1073/pnas.94.3.861 PMC Full Text View journal details
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