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Interaction between CD44 and osteopontin as a potential basis for metastasis formation
G F Weber1, S Ashkar, H Cantor
1Dana-Farber Cancer Institute, Division of Immunopathology, Boston, MA 02115, USA.
Abstract:
Malignant growth has been associated with oncogene activation, telomerase activity, and expression of CD44 splice variants on the cell surface. Though dysregulation of growth control due to expression of oncogene products is fairly well understood, the mechanism of CD44-mediated homing and colony formation in specific tissues has remained cryptic. We have identified the cytokine osteopontin as a ligand for CD44. Osteopontin binds to naturally expressed and stably transfected CD44 in a manner that is specific, dose-dependent, inhibitable by anti-CD44 antibodies, insensitive to competition by Gly-Arg-Gly-Asp-Ser, and sensitive to competition by hyaluronate. The receptor-ligand interaction mediates chemotaxis or attachment, depending on presentation of osteopontin in soluble or immobilized form. In contrast, binding of CD44 to hyaluronate mediates aggregation or attachment but not chemotaxis. We found that two events occurring in malignancy-secretion of osteopontin and expression of CD44v-are linked in such a way that they may cause migration of tumor cells to specific sites of metastasis formation.
Insights
The cytokine osteopontin binds to CD44, a cell surface molecule. This interaction may drive tumor cell migration and metastasis formation in cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Malignant growth involves oncogene activation, telomerase activity, and CD44 splice variant expression.
- The role of CD44 in tumor cell homing and tissue colonization is not fully understood.
Purpose of the Study:
- To identify ligands for CD44 and elucidate their role in cancer progression.
- To investigate the interaction between osteopontin and CD44 and its functional consequences.
Main Methods:
- Investigated the binding of osteopontin to CD44 using various assays, including antibody inhibition and competition studies.
- Assessed the functional effects of osteopontin-CD44 interaction on cell migration (chemotaxis) and attachment.
- Examined the role of osteopontin presentation (soluble vs. immobilized) on cellular responses.
Main Results:
- Identified osteopontin as a specific, dose-dependent ligand for CD44.
- Osteopontin binding to CD44 mediated cell chemotaxis or attachment, depending on osteopontin's form.
- CD44 binding to hyaluronate mediated aggregation or attachment but not chemotaxis.
- The co-occurrence of osteopontin secretion and CD44v expression in malignancy links these events to tumor cell migration.
Conclusions:
- Osteopontin is a functional ligand for CD44, mediating cell migration and attachment.
- The interaction between osteopontin and CD44 provides a mechanism for tumor cell homing to specific metastatic sites.
- Targeting the osteopontin-CD44 pathway may offer therapeutic strategies for inhibiting cancer metastasis.