Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells.

Abstract

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin alpha v beta 3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin alpha v beta 3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either alpha v beta 3, alpha IIb beta 3 or no beta 3 integrin, we found that only alpha v beta 3 strongly supported metastasis. Inhibition of tumor cell alpha v beta 3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow alpha v beta 3, but not alpha IIb beta 3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing alpha v beta 3, but not those expressing alpha IIb beta 3 or no beta 3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between alpha v beta 3 expression and protease processing. Furthermore, alpha v beta 3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin alpha v beta 3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin alpha IIb beta 3 cannot substitute for alpha v beta 3 in this respect.

• Authors: Brunhilde Felding-Habermann, Emilia Fransvea, Timothy E O'Toole, Lisa Manzuk, Barbara Faha, Mary Hensler
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 19 Issue 5 Pg. 427-36 ( 2002) ISSN: 0262-0898 [Print] Netherlands
• PMID: 12198771 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Fibronectins
• Mmp14 protein, mouse
• Neoplasm Proteins
• Platelet Glycoprotein GPIIb-IIIa Complex
• RNA, Messenger
• RNA, Neoplasm
• Receptors, Vitronectin
• Vitronectin
• Tissue Inhibitor of Metalloproteinase-2
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 14

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Extracellular Matrix (metabolism)
• Female
• Fibronectins (metabolism)
• Humans
• Injections, Intravenous
• Lung Neoplasms (secondary)
• Matrix Metalloproteinase 14
• Matrix Metalloproteinase 2 (biosynthesis, genetics)
• Matrix Metalloproteinases, Membrane-Associated
• Melanoma (metabolism, pathology)
• Melanoma, Experimental (secondary, therapy)
• Metalloendopeptidases (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Neoplasm Transplantation
• Neoplastic Cells, Circulating
• Platelet Glycoprotein GPIIb-IIIa Complex (physiology)
• RNA, Messenger (analysis)
• RNA, Neoplasm (analysis)
• Receptors, Vitronectin (immunology, physiology)
• Tissue Inhibitor of Metalloproteinase-2 (genetics)
• Tumor Cells, Cultured (transplantation)
• Vitronectin (metabolism)