Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.

Proliferation and migration are important biological responses of mesangial cells to injury. Platelet-derived growth factor (PDGF) is a prime candidate to mediate these responses in glomerular disease. PDGF and its receptor (PDGFR) are upregulated in the mesangium during glomerular injury. We have recently shown that PDGF activates phosphatidylinositol 3-kinase (PI-3-kinase) in cultured mesangial cells. The role of this enzyme and other more distal signaling pathways in regulating migration and proliferation of mesangial cells has not yet been addressed. In this study, we used two inhibitors of PI-3-kinase, wortmannin (WMN) and LY-294002, to investigate the role of this enzyme in these processes. Pretreatment of mesangial cells with WMN and LY-294002 dose-dependently inhibited PDGF-induced PI-3-kinase activity assayed in antiphosphotyrosine immunoprecipitates. WMN pretreatment also inhibited the PI-3-kinase activity associated with anti-PDGFRβ immunoprecipitates prepared from mesangial cells treated with PDGF. Pretreatment of the cells with different concentrations of WMN resulted in a dose-dependent inhibition of PDGF-induced DNA synthesis. Both WMN and LY-294002 inhibited PDGF-stimulated migration of mesangial cells in a dose-dependent manner. It has recently been shown that PI-3-kinase physically interacts with Ras protein. Because Ras is an upstream regulator of the kinase cascade leading to the activation of mitogen-activated protein kinase (MAPK), we determined whether activation of PI-3-kinase is necessary for activation of MAPK. Pretreatment of mesangial cells with WMN and LY-294002 significantly inhibited PDGF-induced MAPK activity as measured by immune complex kinase assay of MAPK immunoprecipitates. Furthermore, PD-098059, an inhibitor of MAPK-activating kinase inhibited PDGF-induced MAPK activity and resulted in significant reduction of mesangial cell migration in response to PDGF. These data indicate that MAPK is a downstream target of PI-3-kinase and that both these enzymes are involved in regulating proliferation and migration of mesangial cells.

The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease.

The benefit of liver transplantation (LT) is determined not only by the severity of illness, but also by the likelihood of posttransplantation survival. Current models are unable to accurately predict which patients will have the best posttransplant survival. We hypothesized that the Charlson Comorbidity Index (CCI), which includes nine comorbidities, could be used to predict survival after LT. We performed a retrospective study of 624 patients undergoing LT, with a median follow-up time of 4.3 yr. Data on pretransplant comorbidities were collected, along with potential confounders such as age, gender, etiology, and severity of liver disease. Proportional hazards analysis was performed to determine the independent effect of each variable on posttransplantation survival, and to recalibrate the CCI for use in the liver transplant population. A total of 40% of patients had 1 or more comorbidities prior to transplantation. In the multivariate analysis, CCI was an independent predictor of posttransplantation survival (hazard ratio [HR] 1.21 per unit, P Ͻ 0.001). When the individual components of the CCI were analyzed, coronary disease (HR 2.33), diabetes (HR 1.38), chronic obstructive pulmonary disease (COPD) (HR 2.67), connective tissue disease (HR 2.32), and renal insufficiency (HR 1.61) were all independent predictors of posttransplant survival. The CCI was recalibrated using a simplified weighting system to create the CCI-orthotopic LT (OLT), which improved the likelihood ratio chi-squared value from 15 to 24 for predicting posttransplantation survival. In conclusion, survival after LT is diminished in patients with pretransplantation coronary disease, diabetes, COPD, connective tissue disease, and renal insufficiency. We demonstrate the usefulness of a modified comorbidity index, the CCI-OLT, for predicting posttransplantation survival. Liver Transpl 13:1515Transpl 13: -1520Transpl 13: , 2007

No abstract

Interleukin (IL)-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL-4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient-depleted environment, IL-4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient-depletion stress, IL-4 activates mitogen-activated protein kinases (MAPKs), including Erk, p38 and JNK. Using MAP-signaling-specific inhibitors, it was shown that IL-4-induced proliferation is mediated by JNK activation. In fact, JNK-inhibitor-V stunted IL-4-mediated cell proliferation. Furthermore, it was found that IL-4 induces survivin up-regulation in nutrient-depleted cancer cells. Using survivin-shRNAs, it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL-4-mediated proliferation. In addition, the significance of survivin up-regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL-4 could induce proliferation in cancer cells from multiple origins: MDA-MB-231 (breast), A253 (head and neck), and SKOV-3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL-4 triggers a simultaneous activation of the JNK-pathway and the up-regulation of survivin turning on a cancer proliferation mechanism.

Background: An underlying cause is found in only 7% to 30% of patients with chronic idiopathic axonal polyneuropathy (CIAP). Diabetes mellitus, inherited disorders, toxin exposure, and primary amyloidosis are the most common identified causes of sensory neuropathies affecting both large and small myelinated fibers. Undiagnosed impaired fasting glucose metabolism has been associated with CIAP at a higher frequency rate than in the general population. This increased prevalence rate was identified using the 2-hour oral glucose tolerance test (2h-OGTT) and a previous version of the American Diabetes Association (ADA) guidelines. Objectives: To determine the prevalence of abnormal fasting glucose metabolism in patients with CIAP and to compare the value of determining fasting plasma glucose levels using revised (2003) ADA criteria with the 2h-OGTT for predicting abnormal fasting glucose metabolism. Patients: In this 24-month retrospective study, 100 consecutive patients were identified with no known cause for CIAP, including diabetes mellitus, between January 2003 and January 2005. All had both a fasting plasma glucose test and a 2h-OGTT in addition to a complete neurological examination. Neurophysiological studies, computer-assisted sensory examination, and quantitative sudomotor axonal reflex testing were used to classify CIAP into subtypes according to nerve fiber involvement. Results: The prevalence of undiagnosed abnormal fasting glucose metabolism was found to be nearly 2-fold higher (62%) in patients with CIAP than in similar age-matched general population groups (33%). Using the 2003 revised ADA criteria, 39 patients (39%) had abnormal fasting plasma glucose metabolism (36 with impaired fasting glucose, 3 with diabetes mellitus), while the 2h-OGTT provided an even higher diagnostic rate of 62% (62 patients; PϽ.001) of impaired fasting glucose metabolism (38 with impaired glucose tolerance, 24 with diabetes mellitus). The abnormal glucose metabolism rates were found to be similar across the 3 subtypes (sensorimotor, pure sensory, and small-fiber neuropathy) of CIAP (P=.60, .72, and .61). Conclusions: This study adds to emerging evidence that abnormal glucose metabolism may be a risk factor for CIAP. Even with revised (2003) ADA criteria, the 2h-OGTT provides additional diagnostic information to the health care professional in the evaluation of CIAP. Subtypes of CIAP are equally likely to have abnormal glucose metabolism.

RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a prometastatic phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelial–mesenchymal transition, motility, and invasion by cancer cells. Genetic modulation or pharmacologic inhibition of RHAMM activity was sufficient and necessary for metastatic phenotypes induced by RB loss in prostate cancer. Mechanistic studies in this setting established that RHAMM stabilized F-actin polymerization by controlling ROCK signaling. Collectively, our findings show how RB loss drives metastatic capacity and highlight RHAMM as a candidate therapeutic target for treating advanced prostate cancer.