Exosomes from the tumor microenvironment as reciprocal regulators that enhance prostate cancer progression.

Distant organ metastasis of prostate cancer is a puzzle, and various theories have successively arisen to explain the mechanism of lethal cancer progression. While perhaps agreeable to many cancer biologists, the very statement of "seed and soil" proposed by Stephan Paget in 1881 is arguably still the major statement for organ-specific cancer metastasis. Since recent studies showed important correlations of regulation of cancer cells and the microenvironment, exosomes from cancer and stromal cells seem to create another important niche for metastasis. Stromal cells pretreated with exosomes from metastatic cancer cells increase the potential of change stromal cells. The poorly metastatic cancer cells could also enhance malignancy through transfer of proteins, microribonucleic acid and messenger ribonucleic acid to recipient cancer cells. Herein, we reviewed extracellular exosomes as a factor involved in cross-talk between stromal and prostate cancer epithelial cells.

Evaluation of the efficiency, trueness, and clinical application of novel artificial intelligence design for dental crown prostheses.

OBJECTIVE: The unique structure of human teeth limits dental repair to custom-made solutions. The production process requires a lot of time and manpower. At present, artificial intelligence (AI) has begun to be used in the medical field and improve efficiency. This study attempted to design a variety of dental restorations using AI and evaluate their clinical applicability. METHODS: Using inlay and crown restoration types commonly used in dental standard models, we compared differences in artificial wax-up carving (wax-up), artificial digital designs (digital) and AI designs (AI). The AI system was designed using computer calculations, and the other two methods were designed by humans. Restorations were made by 3D printing resin material. Image evaluations were compared with cone beam computed tomography (CBCT) by calculating the root mean squared error. RESULTS: Surface truth results showed that AI (68.4 µm) and digital-designed crowns (51.0 µm) had better reproducibility. Using AI for the crown reduced the time spent by 400% (compared to digital) and 900% (compared to wax-up). Optical microscopic and CBCT images showed that AI and digital designs had close margin gaps (p < 0.05). The margin gap of the crown showed that the wax-up group was 4.1 and 4.3 times greater than those of the AI and digital crowns, respectively. Therefore, the utilization of artificial intelligence can assist in the production of dental restorations, thereby enhancing both production efficiency and accuracy. SIGNIFICANCE: It is expected that the development of AI can contribute to the reproducibility, efficiency, and goodness of fit of dental restorations.

Combined Dynamic Alterations in Urinary VEGF Levels and Tissue ADAM9 Expression as Markers for Lethal Phenotypic Progression of Prostate Cancer.

Recent evidence has demonstrated that detection of changes in the levels of urinary vascular endothelial growth factor (VEGF) and tissue a disintegrin and metalloproteinase 9 (ADAM9) is effective in determining prostate cancer progression. To evaluate the combined application of VEGF and ADAM9 as early progression markers of lethal phenotypic cancer, quantification of urinary VEGF and tissue ADAM9 expression was studied in patients with late stage prostate cancer. Tissue biopsies were collected during palliative transurethral resection of prostate (TURP) surgery, and urine samples were collected before hormone therapy and 3, 6 and 12 months post-TURP. We observed a nearly 100% correlation between increasing urinary VEGF levels over time and prostate cancer progression, but no correlation was observed when comparing urinary VEGF concentrations at a single time point and cancer progression. In addition, we also observed correlation of increasing ADAM9 nuclear positive staining and lethal phenotypic transition. Statistical analysis revealed that both the increase in urinary VEGF level and the presence of the tissue ADAM9 nuclear staining were significantly correlated with the risk of patients with relapse prostate cancer (P < 0.05). Thus, we suggest that combination of detection of changes in urinary VEGF and tissue staining of ADAM9 may be accurate for predicting the mortality of patients with prostate cancer during hormone therapy.

2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside-stimulated dental pulp stem cells-derived conditioned medium enhances cell activity and anti-inflammation.

BACKGROUND/PURPOSE: Dental pulp stem cells (DPSCs) contribute to the regeneration of various tissues and have superior proliferation, immune privilege, and anti-inflammation properties to other mesenchymal stem cells. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) not only enhances the aforementioned properties of DPSCs but also promotes self-renewal and reprogramming-like ability. However, whether THSG enhances the aforementioned properties and abilities through direct or indirect interaction mechanisms remains unclear. To address this knowledge gap, we examined the effects of THSG-stimulated DPSC-derived conditioned medium (THSG-CM) on the activity and anti-inflammation properties of cells. MATERIALS AND METHODS: DPSCs were treated with various concentrations of THSG to produce THSG-CM, which was then collected, analyzed, and lyophilized. A cytokine profiling antibody assay was used to compare protein components between THSG-treated and nontreated CM. Human skin fibroblasts (HSFs) and human gingival fibroblasts (HGFs) were used to investigate the effect of THSG-CM on cell proliferation, anti-inflammation, and wound healing abilities; for this investigation, MTS assay, quantitative real-time PCR analysis, and 2-well silicone inserts wound model were conducted. RESULTS: We observed that THSG enhanced the secretion of growth- and immune-associated proteins in THSG-CM and increased the proliferation of HSFs and HGFs. Furthermore, THSG-CM significantly attenuated lipopolysaccharide-stimulated mRNA levels of cytokines in both cells and improved wound healing abilities. CONCLUSION: We conclude that THSG-CM had more beneficial effects on cell activity and anti-inflammation in the HSFs and HGFs than DPSC-derived CM. DPSC-derived CM can be developed into a cell-free regenerative strategy in the future, and its therapeutic efficacy may be improved by THSG-CM.

Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression.

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.