aphidicolin and Urinary-Bladder-Neoplasms

Continued reports of associations between environmentally induced chromosomal fragile sites and cancer prompted us to undertake a review of current literature to examine whether there might be a relationship between fragile sites and chromosomal alterations reported for bladder cancer. It was found that more than half (56%; odds ratio [OR] = 4.70) of chromosomal rearrangements reported for bladder cancer were located at 77 (65%) of the 118 recognized fragile sites (OR = 6.88). Furthermore, 55% of the fragile sites implicated coincided with one or more genes that have been associated with human cancer (such as oncogenes, tumor suppressor, relonc, transloc, disorder, apoptotic, and angiogenic genes). The most common fragile sites involved were FRA1D, FRA1F, FRA8C, FRA9D, FRA9E, and FRA11C. This correlation suggests that there may be profiles of genetic damage via fragile site expression that lead to the development of at least a proportion of bladder cancers.

Topics: Aphidicolin; Carcinoma, Transitional Cell; Cell Transformation, Neoplastic; Chromosome Breakage; Chromosome Fragile Sites; Chromosome Fragility; Chromosomes, Human; Distamycins; Folic Acid; Humans; Urinary Bladder Neoplasms

Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. beta-catenin plays a dual role in this process: as a member of adherens junctions it is essential to link cadherins to the cytoskeleton thereby allowing tight intercellular adhesion, and as a member of the Wnt-signaling pathway, beta-catenin is translocated into the nucleus and serves together with the LEF1/TCF-transcription factors to drive gene expression necessary for the epithelial-to-mesenchymal transition (EMT). Activated beta-catenin signaling has been implicated in the genesis of a variety of tumors. Here we demonstrate a pivotal function for beta-catenin signaling in epithelial cell migration and tumorigenesis. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) induce beta-catenin signaling under conditions where they stimulate cell motility. Ectopic expression of either stabilized beta-catenin or a regulatable form of activated beta-catenin induces cell migration in different cell types and cooperates with EGF and HGF in this process. Activation of beta-catenin signaling induces expression of the new target gene osteopontin during migration. Cells expressing stabilized beta-catenin also exhibit significantly increased capability to form tumors in a nude mouse xenograft model. The data suggest that a critical threshold of beta-catenin signaling, activated by cooperative mechanisms, may be important during the EMT and tumorigenesis.

Topics: Animals; Aphidicolin; beta Catenin; Carcinoma; Cell Line; Cell Movement; Cycloheximide; Cytoskeletal Proteins; Enzyme Inhibitors; Epidermal Growth Factor; Epithelial Cells; Gene Targeting; Mice; Mice, Nude; Neoplasms; Osteopontin; Protein Synthesis Inhibitors; Rats; Sialoglycoproteins; Signal Transduction; Trans-Activators; Transcriptional Activation; Tumor Cells, Cultured; Urinary Bladder Neoplasms

Organophosphate-based pesticides have been associated with pathology and chromosomal damage in humans. There are also epidemiologic links with cancer. The few screening tests for low-level occupational exposure are of doubtful sensitivity; this investigation evaluated four methods. Blood samples were studied from 10 farmers before and after occupational exposure to organophosphate-based pesticides and five unexposed controls. The standard cholinesterase test was insensitive to the exposure (P=0.815). However, a significant increase in Howell-Jolly bodies within erythrocytes was observed (P=0.001). Cytogenetic studies on routine and aphidicolin-induced blood cultures revealed that following organophosphate exposure the total number of gaps and breaks on human chromosomes was significantly increased (P=0.004 and P=0.0006, respectively). We concluded that Howell-Jolly body and fragile site analysis were sensitive indicators of nuclear damage resulting from low-level occupational exposure to organophosphate. Such nuclear damage could be implicated in carcinogenesis. The development of bladder cancer is one such example.

Topics: Aphidicolin; Cholinesterases; Chromosome Fragile Sites; Chromosome Fragility; Chromosomes, Human; DNA Damage; DNA, Neoplasm; Enzyme Inhibitors; Erythrocyte Inclusions; Erythrocytes; Humans; Insecticides; Male; Middle Aged; Occupational Diseases; Occupational Exposure; Organophosphorus Compounds; Urinary Bladder Neoplasms

We have previously reported that human gastric (TMK1) and urinary bladder (UMUC2) cancer cell lines show markedly reduced expression of an actin-regulatory protein, gelsolin [S. Moriya et al., (1994), Int. J. Oncol. 5, 1347-1351, M. Tanaka et al. (1995), Cancer Res. 55, 3228-3232]. When gelsolin expression is restored by transfection, cancer cells lost tumorigenicity in vivo [M. Tanaka et al. (1995), Cancer Res. 55, 3228-3232]. Here, we show that gelsolin-overexpressing TMK1 and UMUC2 cells are more resistant to UVC irradiation. Increased resistance is associated with increases in the proportion of cells in the G2 phase of the cell cycle compared to similarly treated control neotransfectants. After UVC irradiation, synchronized gelsolin-overexpressing UMUC2 cells had a prolonged S phase followed by delayed G2 accumulation compared to neotransfected UMUC2 cells as determined by cell cycle analysis. The levels of cyclin B1 and cdk1 histone H1 kinase activity in gelsolin transfectants remained low during S and early G2 phase and the production of diacylglycerol induced by UVC was reduced in gelsolin transfectants compared to neotransfectants. These observations suggest that gelsolin enhances G2 checkpoint function of cells through lipid metabolism, leading to UVC resistance. Considered together with recent evidence that radiation clastogenesis and chemical carcinogenesis are cell-cycle-dependent, down regulation of gelsolin may lead to the malignant transformation of human gastric or urinary bladder cancers by attenuating G2 checkpoint function.

Topics: Aphidicolin; Caffeine; CDC2 Protein Kinase; Cell Survival; Cyclin B; Cyclin B1; Diglycerides; DNA Damage; G2 Phase; Gelsolin; Gene Expression; Histones; Humans; Phosphorylation; Radiation Tolerance; S Phase; Stomach Neoplasms; Transfection; Tumor Cells, Cultured; Ultraviolet Rays; Urinary Bladder Neoplasms