The impact of oocyte death on mouse primordial follicle formation and ovarian reserve.

Background: Ovaries, the source of oocytes, maintain the numbers of primordial follicles, develop oocytes for fertilization and embryonic development. Although it is well known that about two-thirds of oocytes are lost during the formation of primordial follicles through cyst fragmentation and the aggregation of oocytes within the cyst, the mechanism responsible for this remains unclear. Methods: We provide an overview of cell death that is associated with the oocyte cyst breakdown and primordial follicle assembly along with our recent findings for mice that had been treated with a TNFα ligand inhibitor. Main Findings: It is generally accepted that apoptosis is the major mechanism responsible for the depletion of germ cells. In fact, a gene deficiency or the overexpression of apoptosis regulators can have a great effect on follicle numbers and/or fertility. Apoptosis, however, may not be the only cause of the large-scale oocyte attrition during oocyte cyst breakdown, and other mechanisms, such as aggregation, may also be involved in this process. Conclusion: The continued study of oocyte death during primordial follicle formation could lead to the development of novel strategies for manipulating the primordial follicle pool, leading to improved fertility by enhancing the ovarian reserve.

ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition.

Previous studies have revealed that, at the initial step of carcinogenesis, transformed cells are often eliminated from epithelia via cell competition with the surrounding normal cells. In this study, we performed cell competition-based high-throughput screening for chemical compounds using cultured epithelial cells and confocal microscopy. PLX4720 was identified as a hit compound that promoted apical extrusion of RasV12-transformed cells surrounded by normal epithelial cells. Knockdown/knockout of ZAK, a target of PLX4720, substantially enhanced the apical elimination of RasV12 cells in vitro and in vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cells in vivo and suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competition-promoting chemical drug facilitates apical elimination of transformed cells in vivo, providing a new dimension in cancer preventive medicine.

Obesity Suppresses Cell-Competition-Mediated Apical Elimination of RasV12-Transformed Cells from Epithelial Tissues.

Recent studies have revealed that newly emerging transformed cells are often eliminated from epithelial tissues via cell competition with the surrounding normal epithelial cells. This cancer preventive phenomenon is termed epithelial defense against cancer (EDAC). However, it remains largely unknown whether and how EDAC is diminished during carcinogenesis. In this study, using a cell competition mouse model, we show that high-fat diet (HFD) feeding substantially attenuates the frequency of apical elimination of RasV12-transformed cells from intestinal and pancreatic epithelia. This process involves both lipid metabolism and chronic inflammation. Furthermore, aspirin treatment significantly facilitates eradication of transformed cells from the epithelial tissues in HFD-fed mice. Thus, our work demonstrates that obesity can profoundly influence competitive interaction between normal and transformed cells, providing insights into cell competition and cancer preventive medicine.

Validation of the Risk Score of the Mortality and Lower Limb Loss Considering Ambulatory Status after Surgical Revascularization in Maintaining Patients with Dialysis.

Surgical revascularization is performed to preserve limb and to maintain functional status of patients with critical limb ischemia (CLI). The PREVENT III risk score helps to predict the postoperative course of CLI. However, this score is not available to estimate the risk of amputation or death properly in patients with hemodialysis (HD) and tissue loss (HD: 4 points, Tissue loss: 3 points), because they are classified as a high-risk group. Therefore, we investigated 213 patients with revascularized HD for CLI and proposed prognosis amputation or death for patients with HD risk score (PAD for HD risk score). PAD for HD risk score (non-ambulation: 3 points, ulcer/gangrene: 2 points, GNRI<92: 2 points, CRP>0.3 mg/dl: 1 point, Age≥75: 1 point) is more accurate for the prediction of amputation or death than the PREVENT III risk score (area under the curve [AUC]: 0.79 [95% confidence interval: CI: 0.71-0.87], p<0.01 vs. AUC: 0.63 [95%CI: 0.56-0.71]). The patients were stratified into three groups by total score in ascending order. The rate of 1-year amputation-free survival and independent ambulatory status were significantly different among three groups. PAD for HD risk score is useful for rehabilitation planning in patients with HD and CLI. (This is a translation of J Jpn Coll Angiol 2016; 56: 85-91.).

Plectin is a novel regulator for apical extrusion of RasV12-transformed cells.

Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.

Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes.

Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. During this process, normal epithelial cells can recognize and actively eliminate transformed cells, a process called epithelial defence against cancer (EDAC). Here, we show that mitochondrial membrane potential is diminished in RasV12-transformed cells when they are surrounded by normal cells. In addition, glucose uptake is elevated, leading to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which positively regulates elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, involving filamin, drives the Warburg-effect-like metabolic alteration. Moreover, using a cell-competition mouse model, we demonstrate that PDK-mediated metabolic changes promote the elimination of RasV12-transformed cells from intestinal epithelia. These data indicate that non-cell-autonomous metabolic modulation is a crucial regulator for cell competition, shedding light on the unexplored events at the initial stage of carcinogenesis.