Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer
| Autor: | Ann F. Chambers, Nicole Hodgson, David P. Girvan, Carl O. Postenka, Waleed Al-Katib, Leslie Scott, Alison L. Allan, Rosamma George, Toshimitsu Uede, Larry Stitt, Ron L. Holliday, Mark W. Lee, C. Jay Engel, Sharon A. Vantyghem, Alan B. Tuck |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Pathology medicine.medical_specialty Integrins Lymphovascular invasion Sialoglycoproteins Sentinel lymph node Blotting Western Mice Nude Breast Neoplasms Transfection Pathology and Forensic Medicine Mice Breast cancer stomatognathic system Cell Line Tumor Cell Adhesion Medicine Animals Humans Osteopontin Lymph node Aged Cell Proliferation Aged 80 and over biology business.industry Sentinel Lymph Node Biopsy Middle Aged medicine.disease Blotting Northern Flow Cytometry Primary tumor Immunohistochemistry Lymphatic system medicine.anatomical_structure Lymphatic Metastasis Cancer cell biology.protein Mutagenesis Site-Directed Female business Oligopeptides Neoplasm Transplantation Regular Articles |
| Zdroj: | The American journal of pathology. 169(1) |
| ISSN: | 0002-9440 |
| Popis: | Although a primary route of breast cancer metastasis is believed to be via lymphatics, the molecular factors involved are poorly understood. We hypothesized that one such factor may be the integrin-binding protein osteopontin (OPN), and we investigated this clinically and experimentally. In breast cancer patients undergoing sentinel lymph node biopsy, OPN levels were significantly higher in lymph node metastases than in the primary tumor (P < 0.001). To test the functional contribution of OPN to lymphatic metastasis and to determine whether the RGD (Arg-Gly-Asp) integrin-binding sequence of OPN is important for this process, we transfected wild-type OPN or mutant OPN (lacking the RGD sequence) into MDA-MB-468 human breast cancer cells. In vitro, cells overexpressing OPN demonstrated increased anchorage-independent growth in soft agar (P = 0.001) and increased RGD-dependent adhesion (P = 0.045). Following mammary fat pad injection of nude mice, cells overexpressing OPN showed increased lymphovascular invasion, lymph node metastases, and lung micrometastases at earlier time points (P = 0.024). Loss of the RGD region partially abrogated this effect in the lymphatics (P = 0.038). These novel findings indicate that OPN is a key molecular player involved in lymphatic metastasis of breast cancer, potentially by affecting RGD-mediated adhesive interactions and by enhancing the establishment/persistence of tumor cells in the lymphatics. |
| Databáze: | OpenAIRE |
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