Consistent Loss of Functional Transforming Growth Factor β Receptor Expression in Murine Plasmacytomas

Murine plasmacytomas are tumors of Ig-secreting plasma cells that can be induced in genetically susceptible BALB/c mice. The deregulation of the c-myc protooncogene is a critical oncogenic event in the development of plasmacytomas (PCTs) although it is not sufficient for their malignant transformation. We have demonstrated that PCTs produce active transforming growth factor β (TGF-β) in vitro. Because TGF-β is a potent negative regulator of the proliferation and differentiation of B lymphocytes, we examined its role in plasmacytomagenesis by comparing responsiveness to TGF-β of nonneoplastic plasma cells and PCTs. The nontransformed plasma cells that accumulate in interleukin 6 transgenic mice undergo accelerated apoptosis upon treatment with TGF-β, but the 15 PCTs studied, including primary and transplanted tumors as well as established cell lines, were refractory to TGF-β-mediated growth inhibition and apoptosis. Although PCTs lack functional TGF-β receptors as demonstrated by chemical crosslinking to radiolabeled TGF-β1, they nonetheless contain mRNA and protein for both type I and II TGF-β receptors, suggesting a potential defect in receptor trafficking or processing. The results clearly show the consistent inactivation of TGF-β receptors in plasmacytoma cells, demonstrating for the first time that interruption of a tumor suppressor pathway contributes to plasmacytomagenesis.