E-liquid exposure induces bladder cancer cells to release extracellular vesicles that promote non-malignant urothelial cell transformation.

The vaping of electronic cigarettes (E-cigarettes) has recently emerged as a popular alternative to traditional cigarette smoking, but its association with bladder cancer (BC) risk remains to be established. BC patients exhibit high rates of recurrent disease, possibly as a consequence of the field cancerization effect. We have shown that BC-derived extracellular vesicles (BCEVs) can permanently alter recipient urothelial cells in predisposed fields such that they become fully transformed malignant cells.

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril.

Purpose: Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury.

Bladder Cancer Extracellular Vesicles Elicit a CD8 T Cell-Mediated Antitumor Immunity.

Tumor-derived extracellular vesicles (TEVs) play crucial roles in mediating immune responses, as they carry and present functional MHC-peptide complexes that enable them to modulate antigen-specific CD8 T-cell responses. However, the therapeutic potential and immunogenicity of TEV-based therapies against bladder cancer (BC) have not yet been tested. Here, we demonstrated that priming with immunogenic Extracellular Vesicles (EVs) derived from murine MB49 BC cells was sufficient to prevent MB49 tumor growth in mice.

Non-stem bladder cancer cell-derived extracellular vesicles promote cancer stem cell survival in response to chemotherapy.

Background: Chemosenstive non-stem cancer cells (NSCCs) constitute the bulk of tumors and are considered as part of the cancer stem cell (CSC) niche in the tumor microenvironment (TME). Tumor-derived extracellular vesicles (EVs) mediate the communication between tumors and the TME. In this study, we sought to investigate the impacts of EVs released by NSCCs on the maintenance of CSC properties and chemoresistance.

Active vitamin D induces gene-specific hypomethylation in prostate cancer cells developing vitamin D resistance.

Prostate cancer (PCa) is a leading cause of cancer death in men. Despite the antiproliferative effects of 1α,25-dihydroxyvitamin D [1,25(OH)D] on PCa, accumulating evidence indicates that 1,25(OH)D promotes cancer progression by increasing genome plasticity. Our investigation of epigenetic changes associated with vitamin D insensitivity found that 1,25(OH)D treatment reduced the expression levels and activities of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively).

Enhanced metastatic potential in the MB49 urothelial carcinoma model.

Recent data suggest that patients with a basal/stem-like bladder cancer (BC) subtype tend to have metastatic disease, but this is unconfirmed. Here we report the identification of murine MB49 cell line sub-clones with stem-like characteristics in culture. Subcutaneous implantation of S2 and S4 MB49 sub-clones into immunocompetent mice resulted in lung metastases in 50% and 80% of mice respectively, whereas none of the mice implanted with the parental cells developed metastasis.

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells.

The field cancerization effect has been proposed to explain bladder cancer's multifocal and recurrent nature, yet the mechanisms of this effect remain unknown. In this work, using cell biology, flow cytometry, and qPCR analyses, along with a xenograft mouse tumor model, we show that chronic exposure to tumor-derived extracellular vesicles (TEVs) results in the neoplastic transformation of nonmalignant human SV-HUC urothelial cells. Inhibition of EV uptake prevented this transformation.

Extracellular Vesicles in Bladder Cancer: Biomarkers and Beyond.

Tumor-derived extracellular vesicles (TEVs) are membrane-bound, nanosized vesicles released by cancer cells and taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. In this report, we summarize the pivotal roles of TEVs involved in bladder cancer (BC) development, progression and treatment resistance through transferring their bioactive cargos, including proteins and nucleic acids. We also report on the molecular profiling of TEV cargos derived from urine and blood of BC patients as non-invasive disease biomarkers.

Identification of extracellular vesicle-borne periostin as a feature of muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high mortality, and heterogeneity in MIBC results in variable clinical outcomes, posing challenges for clinical management. Extracellular vesicles (EVs) derived from MIBC have been shown to promote cancer progression. EVs derived from bladder cell lines were subjected to proteomic analysis, and periostin was chosen for further characterization due to its stage-specific gene expression profile.

Cell-to-cell communication in cancer: workshop report.

Recent advances in cancer biology and the development of new research tools have enabled interrogations of single cells and cell-cell interactions. Emerging technologies are capable of revealing data on the physical characteristics of cells, differences in the genome and proteome between cancerous and healthy cells, and variations in distinct cell subpopulations. Dynamic measurements enable studies that can reveal the evolution of cell characteristics.

E-selectin ligand-1 controls circulating prostate cancer cell rolling/adhesion and metastasis.

Circulating prostate cancer (PCa) cells preferentially roll and adhere on bone marrow vascular endothelial cells, where abundant E-selectin and stromal cell-derived factor 1 (SDF-1) are expressed, subsequently initiating a cascade of activation events that eventually lead to the development of metastases. To elucidate the roles of circulating PCa cells' rolling and adhesion behaviors in cancer metastases, we applied a dynamic cylindrical flow-based microchannel device that is coated with E-selectin and SDF-1, mimicking capillary endothelium. Using this device we captured a small fraction of rolling PCa cells.

TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system.

Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia development.

Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression.

Purpose: High grade bladder cancer is an extremely aggressive malignancy associated with high rates of morbidity and mortality. Understanding how exosomes may affect bladder cancer progression could reveal novel therapeutic targets.

Materials And Methods: Exosomes derived from human bladder cancer cell lines and the urine of patients with high grade bladder cancer were assessed for the ability to promote cancer progression in standard assays.

1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer.

Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells.

Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D.

The anti-tumor effect of vitamin D has been well recognized but its translational application is hindered by side effects induced by supra-physiological concentration of vitamin D required for cancer treatment. Thus, exploring the vitamin D tumor suppressive functional mechanism can facilitate improvement of its clinical application. We screened miRNA profiles in response to vitamin D and found that a tumor suppressive miRNA, miR-98, is transcriptionally induced by 1α,25-dihydroxyvitamin D(3) (1,25-VD) in LNCaP.

Reduced osteoblast activity in the mice lacking TR4 nuclear receptor leads to osteoporosis.

Background: Early studies suggested that TR4 nuclear receptor might play important roles in the skeletal development, yet its detailed mechanism remains unclear.

Methods: We generated TR4 knockout mice and compared skeletal development with their wild type littermates. Primary bone marrow cells were cultured and we assayed bone differentiation by alkaline phosphatase and alizarin red staining.

Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis.

It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells; however, definitive proof of androgen hormone action in prostate cancer (PRCA) progression is lacking. Here we demonstrate through genetic loss of function experiments that PRCA progression is androgen dependent and that androgen dependency occurs via prostatic stromal androgen receptors (AR) but not epithelial AR. Utilizing tissue recombination models of prostatic carcinogenesis, loss of AR function was evaluated by surgical castration or genetic deletion.

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation.

The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death.

A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D.

Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation.

The roles of testicular nuclear receptor 4 (TR4) in male fertility-priapism and sexual behavior defects in TR4 knockout mice.

Background: Successful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events. TR4 nuclear receptor is known to be involved in male fertility via controlling spermatogenesis, yet its roles in regulating other biological events related to reproduction have not been completely revealed.

Methods: Male TR4 knockout (TR4 -/-) and wild type mice were used for the sexual behavior and penile dysfunction studies.

Testicular nuclear receptor 4 (TR4) regulates UV light-induced responses via Cockayne syndrome B protein-mediated transcription-coupled DNA repair.

UV irradiation is one of the major external insults to cells and can cause skin aging and cancer. In response to UV light-induced DNA damage, the nucleotide excision repair (NER) pathways are activated to remove DNA lesions. We report here that testicular nuclear receptor 4 (TR4), a member of the nuclear receptor family, modulates DNA repair specifically through the transcription-coupled (TC) NER pathway but not the global genomic NER pathway.

Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I.

The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4(-/-) mice.