The metabolic cross‐talk between epithelial cancer cells and stromal fibroblasts in ovarian cancer progression: Autophagy plays a role

Cancer and stromal cells, which include (cancer‐associated) fibroblasts, adipocytes, and immune cells, constitute a mixed cellular ecosystem that dynamically influences the behavior of each component, creating conditions that ultimately favor the emergence of malignant clones. Ovarian cancer cells release cytokines that recruit and activate stromal fibroblasts and immune cells, so perpetuating a state of inflammation in the stroma that hampers the immune response and facilitates cancer survival and propagation. Further, the stroma vasculature impacts the metabolism of the cells by providing or limiting the availability of oxygen and nutrients. Autophagy, a lysosomal catabolic process with homeostatic and prosurvival functions, influences the behavior of cancer cells, affecting a variety of processes such as the survival in metabolic harsh conditions, the invasive growth, the development of immune and chemo resistance, the maintenance of stem‐like properties, and dormancy. Further, autophagy is involved in the secretion and the signaling of promigratory cytokines. Cancer‐associated fibroblasts can influence the actual level of autophagy in ovarian cancer cells through the secretion of pro‐inflammatory cytokines and the release of autophagy‐derived metabolites and substrates. Interrupting the metabolic cross‐talk between cancer cells and cancer‐associated fibroblasts could be an effective therapeutic strategy to arrest the progression and prevent the relapse of ovarian cancer.     

Targeting renal purinergic signalling for the treatment of lithium‐induced nephrogenic diabetes insipidus

Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium‐induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP‐activated P2Y₂ receptor in lithium‐induced NDI in rats and showed that P2Y₂ receptor knockout mice are significantly resistant to Li‐induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP‐activated P2Y₁₂ receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix^®) ameliorates Li‐induced NDI in rodents. Parallel in vitro studies showed that P2Y₁₂ receptor blockade by the reversible antagonist PSB‐0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y₂ or P2Y₁₂ receptors to counter AVP resistance in lithium‐induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti‐AVP effects to those that enhance the sensitivity of the kidney to AVP action.     

Enhanced expression of mucin 6 glycoprotein in cholangiocarcinoma tissue from patients in Thailand as a prognostic marker for survival

Background and Aim: Cholangiocarcinoma (CCA) is a mucin‐producing cancer that has poor prognosis. Mucin 6 (MUC6) is a mucin that is normally co‐expressed with the trefoil factor family‐2 (TFF2) trefoil peptide. Both MUC6 and TFF2 have been reported to be involved in the progression of many types of cancers. The aim of this study was to determine the expression of MUC6 and TFF2 in CCA tissues and associate these results with clinical data. Methods: MUC6 and TFF2 were detected in CCA tissues by immunohistochemistry. The correlations of MUC6 and TFF2 expressions with clinical data were analyzed. Results: We determined the significant co‐expression of both proteins in serial CCA tissues. The high expressions of MUC6 and TFF2 were demonstrated in 37% and 31% of patients, respectively. The expression levels decreased in the advanced stage of CCA when clinical metastasis was exhibited. The high expression of either protein showed a correlation with prolonged postoperative survival time, but only a high expression of MUC6 is significantly correlated with a 5‐year survival rate. A multivariate Cox regression analysis revealed that a low expression of MUC6, high expression of TFF2, age of patients >56 years, tumor size >5 cm, and poorly‐differentiated histological type were independent, poor prognostic indicators for CCA. Conclusion: MUC6 showed a good correlation with the survival of CCA patients. It may be of value to propose that MUC6 is a good prognostic marker for CCA management.     

Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker

Background  

Fibroblasts play important roles in several cancers. It was hypothesized that cholangiocarcinoma (CCA)-associated fibroblasts (Cfs) differ from non-tumorigenic liver fibroblasts (Lfs) in their gene expression profiles resulting in the capability to promote cancer. Periostin (PN) is a multi-functional protein and has emerged as a promising marker for tumor progression. The role of PN in CCA, however, has not yet been explored.     

Cellular localization of nucleolin determines the prognosis in cancers: a meta-analysis

Journal of Molecular Medicine - Nucleolin (NCL) is a multifunctional protein expressed in the nucleus, cytoplasm, and cell membrane. Overexpression of NCL has a controversial role as a poor...     

Ruptured abdominal aortic aneurysms in southern Saskatchewan: a 10-year mortality review

The Regina Qu'Appelle Health Region (RQHR) provides all tertiary vascular care for southern Saskatchewan and portions of southwestern Manitoba. The present study was undertaken to determine the regional mortality rates following rupture of an abdominal aortic aneurysm and to compare these rates with the published literature. A retrospective chart review was undertaken on all cases of ruptured abdominal aortic aneurysms (rAAA) presenting to the RQHR between March 1, 1996, and February 28, 2006. The demographic data and clinical outcomes were collected from hospital charts by a single reviewer. Over the 10-year study period, 101 cases of rAAA were presented to the RQHR. Patient demographics and comorbidities were comparable to other studies in the published literature. Thirty-seven percent of patients presented with systolic blood pressure below 90 mm Hg, and 7% had no recordable blood pressure. The overall mortality was 25%. Mortality risk was not statistically different between patients presenting within Regina (30%) and those referred from a distance of more than 35 km (21%, P = .353). Seven patients were treated palliatively, and 94 proceeded to open surgical repair. Within the group of patients undergoing surgery, there was a 19% mortality rate. The data show a low observed mortality rate for rAAA presenting to the RQHR. The favorable outcome of the patients is not associated with preselection bias of patients transported long distances to specialist vascular care.     

Type-I and type-III HTLV antibodies in hospitalized and out-patient Zairians

Sera from 182 Zairians (99 females and 83 males), aged 5 to 71 years, including maternity and child care consultants, out-patients suffering from minor injuries and patients hospitalized for tuberculosis, malaria or trauma, were analyzed for specific antibodies to HTLV-I and HTLV-III. Following pre-screening by the ELISA technique, reactive sera were further analyzed for specificity to HTLV-I or HTLV-III antigens by competition and/or Western blotting experiments. African sera, possibly because they have higher immunoglobulin levels than US and European sera, are highly reactive in ELISA systems and confirmatory assays are essential to rule out false-positive results. Confirmed antibody prevalence for HTLV-I was 13.2% (II females and 13 males) and increased with age, suggesting continuous exposure to the virus throughout life. Confirmed antibody prevalence for HTLV-III was 6.0% (8 females and 3 males) and showed a peak age range between 21 and 40 years, suggesting heterosexual transmission. Individuals positive for HTLV-I antibodies were not the same as individuals positive for HTLV-III antibodies, suggesting that infection with one virus did not increase susceptibility to infection by the other virus. Further investigations of the epidemiology and of the immunovirology of HTLV-III in Zaire, in relation to acquired immuno-deficiency syndrome (AIDS)-associated pathologies, should enlighten the question of the significant percentage of HTLV-III-infected individuals who do not manifest symptoms of AIDS.