Neuroendocrine differentiation in prostate cancer0_2.doc
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Neuroendocrine differentiation in prostate cancer
Jiaoti Huang, MD, Ph.D.
Department of Pathology, Urology and the James P. Wilmot Cancer Center, University of Rochester Medical Center, Box 626, 601 Elmwood Avenue, Rochester, NY 14642 (Email: Jiaoti_Huang@urmc.rochester.edu)
The treatment of choice for advanced/metastatic prostate cancer (PC) is hormonal therapy, consisting of androgen deprivation and/or inhibition of androgen action. Although most patients respond initially to this therapy, the tumor will eventually recur and enter the androgen-independent (or hormone-refractory) state, which is the major obstacle in therapy. The mechanism by which PC cells proliferate in the androgen-deprived environment is unclear and many hypotheses have been proposed, mostly focusing on altered signaling by the androgen receptor (AR).
There are two types of epithelial cells in PC, the secretory-type tumor cells and a minor component of neuroendocrine (NE) cells. The number of NE cells is increased in high grade and high stage tumors, particularly in hormonally-treated and androgen-independent tumors. Through in-vitro and in-vivo studies, we and others have shown that NE cells may secret neuropeptides and cytokines to act on the adjacent non-NE tumor cells to promote their androgen-independent proliferation, and this paracrine action may contribute to tumor recurrence.
The origin of NE cells in PC is unclear and there is evidence that they may be derived from the non-NE tumor cells. LNCaP cells, a PC cell line, can be induced to show NE differentiation when cultured in androgen-deprived media, which supports the transdifferentiation model. With this in-vitro model, we have demonstrated that protein tyrosine phosphatase PTP1B is required for NE differentiation of PC cells. The PI3 kinase-AKT-mTOR pathway also plays an essential role in NE differentiation of PC. We have also shown that a major effector secreted by the NE cells is IL-8, a mitogenic and angiogenic factor for many tumors including PC. The non-NE secretory type tumor cells overexpress IL-8 receptor CXCR1, suggesting a paracrine mechanism by which IL-8 secreted by NE cells may promote androgen-independent proliferation of PC in a paracrine mechanism, through activation of G-protein-coupled receptor CXCR1.
Neuroendocrine differentiation in prostate cancer
Jiaoti Huang, MD, Ph.D.
Department of Pathology, Urology and the James P. Wilmot Cancer Center, University of Rochester Medical Center, Box 626, 601 Elmwood Avenue, Rochester, NY 14642 (Email: Jiaoti_Huang@urmc.rochester.edu)
The treatment of choice for advanced/metastatic prostate cancer (PC) is hormonal therapy, consisting of androgen deprivation and/or inhibition of androgen action. Although most patients respond initially to this therapy, the tumor will eventually recur and enter the androgen-independent (or hormone-refractory) state, which is the major obstacle in therapy. The mechanism by which PC cells proliferate in the androgen-deprived environment is unclear and many hypotheses have been proposed, mostly focusing on altered signaling by the androgen receptor (AR).
There are two types of epithelial cells in PC, the secretory-type tumor cells and a minor component of neuroendocrine (NE) cells. The number of NE cells is increased in high grade and high stage tumors, particularly in hormonally-treated and androgen-independent tumors. Through in-vitro and in-vivo studies, we and others have shown that NE cells may secret neuropeptides and cytokines to act on the adjacent non-NE tumor cells to promote their androgen-independent proliferation, and this paracrine action may contribute to tumor recurrence.
The origin of NE cells in PC is unclear and there is evidence that they may be derived from the non-NE tumor cells. LNCaP cells, a PC cell line, can be induced to show NE differentiation when cultured in androgen-deprived media, which supports the transdifferentiation model. With this in-vitro model, we have demonstrated that protein tyrosine phosphatase PTP1B is required for NE differentiation of PC cells. The PI3 kinase-AKT-mTOR pathway also plays an essential role in NE differentiation of PC. We have also shown that a major effector secreted by the NE cells is IL-8, a mitogenic and angiogenic factor for many tumors including PC. The non-NE secretory type tumor cells overexpress IL-8 receptor CXCR1, suggesting a paracrine mechanism by which IL-8 secreted by NE cells may promote androgen-independent proliferation of PC in a paracrine mechanism, through activation of G-protein-coupled receptor CXCR1.