Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis.

Abstract

The "a disintegrin and metalloprotease" (ADAM) family contributes to regulation of the cell-cell and cell-matrix interactions that are critical determinants of malignancy. To determine the relationship between metastasis and ADAM proteins, we compared the mRNA levels of ADAM9, -10, -12, -15, and -17 in sublines of an EBC-1 lung cancer cell line that were highly metastatic to either brain or bone. ADAM9 mRNA levels were significantly higher in highly brain-metastatic sublines than in the parent or highly bone-metastatic sublines. To elucidate the role of ADAM9 in brain metastasis, we stably transfected A549 and EBC-1 cells with a full-length ADAM9 expression vector. Compared with mock-transfectants, ADAM9 overexpression resulted in increased invasive capacity in response to nerve growth factor, increased adhesion to brain tissue, and increased expression of integrin alpha 3 and beta 1 subunits. Administration of the anti-beta 1 monoclonal antibody attenuated this increase in invasive and adhesive activity. Intravenous administration of ADAM9-overexpressing A549 cells to mice resulted in micrometastatic foci in the brain and multiple metastatic colonies in the lungs. In contrast, administration of parent and mock-transfected A549 cells to mice resulted in lung tumors without brain metastasis. These results suggest that ADAM9 overexpression enhances cell adhesion and invasion of non-small cell lung cancer cells via modulation of other adhesion molecules and changes in sensitivity to growth factors, thereby promoting metastatic capacity to the brain.

• Authors: Yasushi Shintani, Shigeki Higashiyama, Mitsunori Ohta, Hirohisa Hirabayashi, Sakae Yamamoto, Tatsuya Yoshimasu, Hikaru Matsuda, Nariaki Matsuura
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 12 Pg. 4190-6 (Jun 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15205330 (Publication Type: Journal Article)

Chemical References

• Chemotactic Factors
• Disintegrins
• Membrane Proteins
• RNA, Messenger
• Nerve Growth Factor
• ADAM Proteins
• ADAM9 protein, human
• Adam9 protein, mouse
• Metalloendopeptidases

Topics

• ADAM Proteins
• Animals
• Brain Neoplasms (genetics, metabolism, secondary)
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, secondary)
• Cell Adhesion (physiology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Chemotactic Factors (pharmacology)
• Disintegrins (biosynthesis, genetics)
• Female
• Gene Expression
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Membrane Proteins (biosynthesis, genetics)
• Metalloendopeptidases (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Nerve Growth Factor (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Transfection