Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis-and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the B-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear B-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of B-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized B-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against B-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans. (Cancer Res 2005; 65(12): 5263-71)

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Transforming growth factor (TGF)-B is a potent immunosuppressant. Overproduction of TGF-B by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-B1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8 + + T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-B insensitive by infecting with a retrovirus containing dominant-negative TGF-B type II receptor. Results of in vitro cytotoxic assay revealed that these CD8 + T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8 + + T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-B-insensitive CD8 + + T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-B-insensitive CD8 + + T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells may warrant consideration for cancer therapy.

Introduction Erectile dysfunction (ED) caused by pelvic injuries is a common complication of civil and battlefield trauma with multiple neurovascular factors involved, and no effective therapeutic approach is available. Aims To test the effect and mechanisms of low-energy shock wave (LESW) therapy in a rat ED model induced by pelvic neurovascular injuries. Methods Thirty-two male Sprague-Dawley rats injected with 5-ethynyl-2′-deoxyuridine (EdU) at newborn were divided into 4 groups: sham surgery (Sham), pelvic neurovascular injury by bilateral cavernous nerve injury and internal pudendal bundle injury (PVNI), PVNI treated with LESW at low energy (Low), and PVNI treated with LESW at high energy (High). After LESW treatment, rats underwent erectile function measurement and the tissues were harvested for histologic and molecular study. To examine the effect of LESW on Schwann cells, in vitro studies were conducted. Main Outcome Measurements The intracavernous pressure (ICP) measurement, histological examination, and Western blot (WB) were conducted. Cell cycle, Schwann cell activation-related markers were examined in in vitro experiments. Results LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by leading to angiogenesis, tissue restoration, and nerve generation with more endogenous EdU+ progenitor cells recruited to the damaged area and activation of Schwann cells. LESW facilitates more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves from the MPG to the penis. In vitro experiments demonstrated that LESW has a direct effect on Schwann cell proliferation. Schwann cell activation-related markers including p-Erk1/2 and p75 were upregulated after LESW treatment. Conclusion LESW-induced endogenous progenitor cell recruitment and Schwann cell activation coincides with angiogenesis, tissue, and nerve generation in a rat model of pelvic neurovascular injuries.

Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that delivered at a much lower intensity (<3 W/cm2) than traditional ultrasound energy and output in the mode of pulse wave, and it is typically used for therapeutic purpose in rehabilitation medicine. LIPUS has minimal thermal effects due to its low intensity and pulsed output mode, and its non-thermal effects which is normally claimed to induce therapeutic changes in tissues attract most researchers’ attentions. LIPUS have been demonstrated to have a rage of biological effects on tissues, including promoting bone-fracture healing, accelerating soft-tissue regeneration, inhibiting inflammatory responses and so on. Recent studies showed that biological effects of LIPUS in healing morbid body tissues may be mainly associated with the upregulation of cell proliferation through activation of integrin receptors and Rho/ROCK/Src/ERK signaling pathway, and with promoting multilineage differentiation of mesenchyme stem/progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. Hopefully, LIPUS may become an effective clinical procedure for the treatment of urological diseases, such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), erectile dysfunction (ED), and stress urinary incontinence (SUI) in the field of urology. It still needs an intense effort for basic-science and clinical investigators to explore the biomedical applications of ultrasound.