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Signaling and Regulation

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

Verto Institute LLC, Neuroendocrine Tumor Research, The Cancer Institute of New Jersey, New Brunswick, New Jersey

Requests for reprints: Frank Leu, Verto Institute LLC, Neuroendocrine Tumor Research, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901. Phone: 732-235-5591; Fax: 732-235-5331. E-mail: fleu{at}verto-institute.org

The dual effect of the ubiquitous inflammatory cytokine transforming growth factor β1 (TGFβ) on cellular proliferation and tumor metastasis is intriguing but complex. In epithelial cell– and neural cell–derived tumors, TGFβ 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 TGFβ 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 TGFβ as a growth inhibitor. We also determined that TGFβ 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, TGFβ 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 TGFβ or SST signaling pathway in BON leads to "reversible" neuroendocrine-mesenchymal transition, which is characterized by the 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, TGFβ-dependent growth inhibition and differentiation is mediated by the SST signaling pathway. Therefore, any disruption of this TGFβ-SST connection allows BON cells to respond to TGFβ 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)