The Effect of Transforming Growth Factor {beta} on Human Neuroendocrine Tumor BON Cell Proliferation and Differentiation Is Mediated through Somatostatin Signaling.

摘要

The dual effect of the ubiquitous inflammatory cytokine transforming growth factor beta1 (TGFbeta) on cellular proliferation and tumor metastasis is intriguing but complex. In epithelial cell- and neural cell-derived tumors, TGFbeta serves as a growth inhibitor at the beginning of tumor development but later becomes a growth accelerator for transformed tumors. The somatostatin (SST) signaling pathway is a well-established antiproliferation signal, and in this report, we explore the interplay between the SST and TGFbeta signaling pathways in the human neuroendocrine tumor cell line BON. We defined the SST signaling pathway as a determinant for neuroendocrine tumor BON cells in responding to TGFbeta as a growth inhibitor. We also determined that TGFbeta induces the production of SST and potentially activates the negative growth autocrine loop of SST, which leads to the downstream induction of multiple growth inhibitory effectors: protein tyrosine phosphatases (i.e., SHPTP1 and SHPTP2), p21(Waf1/Cip1), and p27(Kip1). Concurrently, TGFbeta down-regulates the growth accelerator c-Myc protein and, collectively, they establish a firm antiproliferation effect on BON cells. Additionally, any disruption in the activation of either the TGFbeta or SST signaling pathway in BON leads to reversible loss of neuroendocrine markers (i.e., chromogranin A and PGP 9.5), as well as the altered expression of mesenchymal proteins (i.e., elevated vimentin and Twist and decreased E-cadherin), which has previously been associated with elevated metastatic potential. In summary, TGFbeta-dependent growth inhibition and differentiation is mediated by the SST signaling pathway. Therefore, any disruption of this TGFbeta-SST connection allows BON cells to respond to TGFbeta as a growth accelerator instead of a growth suppressor. This model can potentially apply to other cell types that exhibit a similar interaction of these pathways. (Mol Cancer Res 2008;6(6):1029-42).