Autocrine TransformingGrowth Factor-β Growth Pathway in MurineOsteosarcoma Cell Lines Associated with Inability to AffectPhosphorylation of Retinoblastoma Protein

[摘要] Purpose.Production of active transforming growth factor-β (TGF-β )by human osteosarcoma may contribute to malignant progression through mechanismsthat include induction of angiogenesis, immune suppression and autocrine growthstimulation of tumor cell growth.To study events associated with induction of cell proliferationby TGF-β , we have evaluated the TGF-β pathway in two murine osteosarcoma cell lines, K7and K12.Results.Northern and immunohistochemical analyses show that each cellline expressesTGF-β1 and TGF-β3 mRNA and protein. Both cell lines secrete activeTGF-β 1and display a 30–50% reduction in growth when cultured in the presence of a TGF-β blockingantibody. Expression of TGF-β receptors TβRI, TβRII and TβRIII is demonstrated by affinitylabeling withI125-TGF-β 1, and the intermediates, Smads 2, 3 and 4, are uniformly expressed.Smads 2 and 3 are phosphorylated in response toTGF-β , while pRb phosphorylation in eachosteosarcoma cell line is not affected by either exogenousTGF-β or TGF-β antibody.Conclusions.The data implicate events downstream of Smad activation,including impaired regulation of pRb, in the lack of a growth inhibitory response toTGF-β ,and indicate that this murine model of osteosarcoma is valid for investigating the roles ofautocrineTGF-βin vivo.

[学科分类] 肿瘤学