The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis Journal Article
| Authors: | Khanna, C.; Wan, X.; Bose, S.; Cassaday, R.; Olomu, O.; Mendoza, A.; Yeung, C.; Gorlick, R.; Hewitt, S. M.; Helman, L. J. |
| Article Title: | The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis |
| Abstract: | Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients. |
| Keywords: | immunohistochemistry; osteosarcoma; signal transduction; mitogen activated protein kinase; protein kinase b; child; controlled study; protein expression; survival rate; oncoprotein; proto-oncogene proteins; nonhuman; protein function; cell proliferation; animal cell; mouse; animal; metabolism; animals; mice; cell survival; disease association; metastasis; lung neoplasms; animal experiment; animal model; enzyme activation; pathology; enzyme activity; cell line, tumor; protein serine threonine kinase; physiology; carcinogenesis; animalia; lung tumor; lung metastasis; enzyme phosphorylation; protein-serine-threonine kinases; dog; dogs; tumor cell line; cell membrane; proto-oncogene proteins c-akt; neoplasm metastasis; phosphoproteins; mitogen-activated protein kinases; cytoskeleton; phosphoprotein; cytoskeleton protein; ezrin; cytoskeletal proteins; canis familiaris; akt1 protein, human; humans; human; priority journal; article |
| Journal Title: | Nature Medicine |
| Volume: | 10 |
| Issue: | 2 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-02-01 |
| Start Page: | 182 |
| End Page: | 186 |
| Language: | English |
| DOI: | 10.1038/nm982 |
| PROVIDER: | scopus |
| PUBMED: | 14704791 |
| DOI/URL: | |
| Notes: | Nat. Med. -- Cited By (since 1996):410 -- Export Date: 16 June 2014 -- CODEN: NAMEF -- Source: Scopus |
