Plasticity of CD44s expression during progression and metastasis of fibrosarcoma in an animal model system

CD44s (standard isoform), which binds hyaluronan (HA), has been analyzed for its significance during fibrosarcoma progression and metastasis in an athymic nude mouse model using Balb/c 3T3 cells transformed with ras or sis oncogenes. While ras (but not sis) transformation leads to upregulated expression of mouse CD44s and HA binding, transfection/overexpression of human CD44s gene (hCD44s) elicited remarkable plasticity of expression during progression and metastasis. In 3T3, hCD44s induced tumorigenesis, HA binding, and micrometastatic competence to lungs and other organs. In tumorigenic (but nonmetastatic) sis transformants or ras-deleted revertants, it also induced micrometastatic competence. Conversely, large primary tumors and overt metastases lost hCD44s expression and HA binding via hypermethylation of hCD44s gene. Tail vein injections revealed that hCD44s greatly increased the efficiency of colonization of the lung microvasculature at the earliest stages. These studies indicate that hCD44s overexpression and possibly its HA binding are critical for conveying metastatic competence but are antagonistic or selected against during aggressive primary tumor or overt metastasis outgrowth. This remarkable plasticity of expression and its consequences offer an ideal system for dissecting the molecular mechanisms operating during fibrosarcoma progression and metastasis.