Through activation of ERK1/2 to induce EMT during renal fibrogenesis, and

Through activation of ERK1/2 to induce EMT during renal fibrogenesis, and that Snail is an immediate early target of PTHrP in murine parietal endoderm formation. One or a combination of these pathways is likely to explain the induction of EMT and invasion that were observed in our experiments, in which we confirmed the induction of Snail by PTHrP. Though it has been shown previously that PTHrP is able to upregulate Snail transcription in the absence of de novo protein synthesis, it remains unclear whether this effect is through direct binding to the Snail promoter or through activation of signaling pathways such as Akt that are known to regulate Snail. Either way, further studies would be needed to confirm the mechanism of PTHrP-induced EMT in prostate cancer. It is possible that various other pathways rely on PTHrP to promote EMT, invasion and metastasis. TGF-b, a potent inducer of EMT, has been shown in breast cancer to promote PTHrP expression resulting in bone destruction. Various oncoproteins including Ras, Tpr-Met, Src have all been shown to target PTHrP and also have proven roles in EMT, invasion and metastasis. Of particular interest would be Indian hedgehog, which is known to regulate PTHrP during early bone and cartilage growth. Members of the hedgehog family are MedChemExpress MNS aberrantly activated in a variety of cancers including prostate cancer, have been shown to indirectly promote EMT, and are theorized to have a role in the transformation of adult stem cells into cancer stem cells. It would be Microcystin-LR interesting to determine whether Ihh relies on PTHrP for induction of EMT and other malignant properties in cancer. Ongoing research continues to reinforce the theory that cancer stem cells are the main drivers of cancer progression and key determinants of therapeutic response. Thus, an important question to consider is whether PTHrP may regulate prostate cancer stem cells through an EMT-mediated pathway. As EMT has been shown previously to induce cancer stem cell properties, it follows that PTHrP should potentially be able to regulate stem cell properties in prostate cancer and thus may be a valuable therapeutic target for preventing recurrence and metastasis. Prostate cancer stem cells have previously been isolated and characterized by a CD44+/CD133+/a2b1hi phenotype. Future work must focus on the ability of PTHrP to regulate this compartment in prostate cancer. The finding that PTHrP induces EMT while promoting invasion and tumor growth suggests that treatments that target PTHrP may be used in conjunction with conventional treatments for inhibiting invasion and metastasis in prostate cancer, especially for recurrent tumors. We have previously screened a library of compounds and identified several that are capable of inhibiting PTHrP expression and cell growth in lung cancer. It would be of great clinical interest to extend these results to prostate cancer and to determine whether such drugs are also capable of blocking PTHrP-induced EMT and invasion. Meanwhile, further efforts to characterize the pathways involved in PTHrP-induced EMT may lead to the elucidation of a role for PTHrP in cancer stem cell development and to novel therapies that could significantly improve the prognosis of metastatic prostate cancer. Author Contributions Conceived and designed the experiments: WMO DB JWR LJD. Performed the experiments: AK EA SZK ER DB MY. Analyzed the data: WMO AK DB AK SZK ER. Contributed reagents/materials/ analysis tools: RMH MY LJD WMO. Wrote t.Through activation of ERK1/2 to induce EMT during renal fibrogenesis, and that Snail is an immediate early target of PTHrP in murine parietal endoderm formation. One or a combination of these pathways is likely to explain the induction of EMT and invasion that were observed in our experiments, in which we confirmed the induction of Snail by PTHrP. Though it has been shown previously that PTHrP is able to upregulate Snail transcription in the absence of de novo protein synthesis, it remains unclear whether this effect is through direct binding to the Snail promoter or through activation of signaling pathways such as Akt that are known to regulate Snail. Either way, further studies would be needed to confirm the mechanism of PTHrP-induced EMT in prostate cancer. It is possible that various other pathways rely on PTHrP to promote EMT, invasion and metastasis. TGF-b, a potent inducer of EMT, has been shown in breast cancer to promote PTHrP expression resulting in bone destruction. Various oncoproteins including Ras, Tpr-Met, Src have all been shown to target PTHrP and also have proven roles in EMT, invasion and metastasis. Of particular interest would be Indian hedgehog, which is known to regulate PTHrP during early bone and cartilage growth. Members of the hedgehog family are aberrantly activated in a variety of cancers including prostate cancer, have been shown to indirectly promote EMT, and are theorized to have a role in the transformation of adult stem cells into cancer stem cells. It would be interesting to determine whether Ihh relies on PTHrP for induction of EMT and other malignant properties in cancer. Ongoing research continues to reinforce the theory that cancer stem cells are the main drivers of cancer progression and key determinants of therapeutic response. Thus, an important question to consider is whether PTHrP may regulate prostate cancer stem cells through an EMT-mediated pathway. As EMT has been shown previously to induce cancer stem cell properties, it follows that PTHrP should potentially be able to regulate stem cell properties in prostate cancer and thus may be a valuable therapeutic target for preventing recurrence and metastasis. Prostate cancer stem cells have previously been isolated and characterized by a CD44+/CD133+/a2b1hi phenotype. Future work must focus on the ability of PTHrP to regulate this compartment in prostate cancer. The finding that PTHrP induces EMT while promoting invasion and tumor growth suggests that treatments that target PTHrP may be used in conjunction with conventional treatments for inhibiting invasion and metastasis in prostate cancer, especially for recurrent tumors. We have previously screened a library of compounds and identified several that are capable of inhibiting PTHrP expression and cell growth in lung cancer. It would be of great clinical interest to extend these results to prostate cancer and to determine whether such drugs are also capable of blocking PTHrP-induced EMT and invasion. Meanwhile, further efforts to characterize the pathways involved in PTHrP-induced EMT may lead to the elucidation of a role for PTHrP in cancer stem cell development and to novel therapies that could significantly improve the prognosis of metastatic prostate cancer. Author Contributions Conceived and designed the experiments: WMO DB JWR LJD. Performed the experiments: AK EA SZK ER DB MY. Analyzed the data: WMO AK DB AK SZK ER. Contributed reagents/materials/ analysis tools: RMH MY LJD WMO. Wrote t.

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