Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

Acute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemias, characterized by hyperproliferation of progenitors that are committed to terminal differentiation into granulocytes. Despite recent clinical studies using arsenic trioxide, anthracyclines and anti-CD33 monoclonal antibodies, all-trans retinoic acid (ATRA)-based therapy represents, until today, the standard cure of APL patients. Studies on both APL blasts and APL-derived cell lines have elucidated that the treatment with ATRA promotes the completion of their maturation to neutrophils throughout a complex network that includes the degradation of the PML/RAR-alpha fusion protein and the activation of RAR-alpha-mediated gene transcription. Even if the underlying mechanism by which ATRA interacts with its receptor located on specific DNA sequences is well known, the events mediated by the ATRA target genes, able to elicit the integrated signaling networks that promote maturation of tumoral promyelocytes, are currently studied to identify specific targets for new therapies of APL. Stemming from the above reported consideration, the proposed review will focus on the possible role of the multidomain protein Vav1 as a target molecule in treatment of APL. This proposal arises from evidences demonstrating that, in addition to promote the acquisition of a mature phenotype by normal hematopoietic cells, Vav1 is a crucial molecule in the completion of the differentiation program to neutrophils of APL-derived cells induced by ATRA. Indeed, it was demonstrated that the down-modulation of Vav1 prevents, and the Vav1 over-expression potentiates, the ability of ATRA to induce the acquisition of a mature phenotype by tumoral promyelocytes

PLCB2 (phospholipase C, beta 2)

Review on PLCB2 (phospholipase C, beta 2), with data on DNA, on the protein encoded, and where the gene is implicated

Vav1 sustains the in vitro differentiation of normal and tumor precursors to insulin producing cells induced by all-trans retinoic acid (ATRA)

All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional beta-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to beta-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional beta-cells

Level and correlates of physical activity and sedentary behavior in patients with type 2 diabetes: a cross-sectional analysis of the italian diabetes and exercise study-2

OBJECTIVE: Patients with type 2 diabetes usually show reduced physical activity (PA) and increased sedentary (SED)-time, though to a varying extent, especially for low-intensity PA (LPA), a major determinant of daily energy expenditure that is not accurately captured by questionnaires. This study assessed the level and correlates of PA and SED-time in patients from the Italian Diabetes and Exercise Study_2 (IDES_2). METHODS: Three-hundred physically inactive and sedentary patients with type 2 diabetes were enrolled in the IDES_2 to be randomized to an intervention group, receiving theoretical and practical exercise counseling, and a control group, receiving standard care. At baseline, LPA, moderate-to-vigorous-intensity PA (MVPA), and SED-time were measured by accelerometer. Physical fitness and cardiovascular risk factors and scores were also assessed. RESULTS: LPA was 3.93±1.35 hours∙day-1, MVPA was 12.4±4.6 min∙day-1, and SED-time was 11.6±1.2 hours∙day-1, with a large range of values (0.89-7.11 hours∙day-1, 0.6-21.0 min∙day-1, and 9.14-15.28 hours∙day-1, respectively). At bivariate analysis, LPA and MVPA correlated with better cardiovascular risk profile and fitness parameters, whereas the opposite was observed for SED-time. Likewise, values of LPA, MVPA, and SED-time falling in the best tertile were associated with optimal or acceptable levels of cardiovascular risk factors and scores. At multivariate analysis, age, female gender, HbA1c, BMI or waist circumference, and high-sensitivity C reactive protein (for LPA and SED-time only) were negatively associated with LPA and MPA and positively associated with SED-time in an independent manner. CONCLUSIONS: Physically inactive and sedentary patients with type 2 diabetes from the IDES_2 show a low level of PA, though values of LPA, MVPA, and SED-time vary largely. Furthermore, there is a strong correlation of these measures with glycemic control, adiposity and inflammation, thus suggesting that even small improvements in LPA, MVPA, and SED-time might be associated with significant improvement in cardiovascular risk profile

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

Beyond its possible relationship with stemness of tumor cells, CD133/prominin is a highly glycosylated trans-membrane protein that correlates with tumor size, metastasis and clinical stage of triple negative breast cancers (TNBC), that represent 20% of all breast tumors and have a particularly worse clinical outcome than other tumor subtypes [1]. The correlation between the levels of CD133 expression and the biology of breast tumor cells was studied in CD133low and CD133high cell subpopulations isolated from MDA-MB-231 cells (ER-, PR-, HER2-). High expression of CD133 characterizes a small percentage of cells with larger adhesion area, lower proliferation rate, higher invasion capability and increased expression of proteins involved in metastasis and drug resistance of breast cancers. PLC-b2 expression, that plays a crucial role in malignancy of breast tumor cells [2, 3], inversely correlates with the levels of CD133 and has a role in inducing the CD133high cells to CD133low cells conversion. The forced up-regulation of PLC-b2 counteracts the invasiveness of CD133high MDAMB- 231, suggesting that, in TNBC, the de-regulation of this PLC isozyme is responsible of the switch from an early to a mature tumoral phenotype also by reducing the expression of CD133. These data might contribute to identify unexplored key steps in TNBC malignancy, to be considered for potential therapeutic strategies

Dose-response association between cigarette smoking and gastric cancer risk: a systematic review and meta-analysis

This study aims at providing an accurate and up-to-date quantification of the dose-response association between cigarette smoking and gastric cancer (GC) risk, overall and by subsite. We conducted a systematic review and meta-analysis of case-control and cohort studies on the association between cigarette smoking and GC risk published up to January 2023. We estimated pooled relative risks (RR) of GC and its subsites according to smoking status, intensity, duration, and time since quitting. Among 271 eligible articles, 205 original studies were included in this meta-analysis. Compared with never smokers, the pooled RR for GC was 1.53 (95% confidence interval; CI 1.44-1.62; n = 92) for current and 1.30 (95% CI 1.23-1.37; n = 82) for former smokers. The RR for current compared with never smokers was 2.08 (95% CI 1.66-2.61; n = 21) for gastric cardia and 1.48 (95% CI 1.33-1.66; n = 8) for distal stomach cancer. GC risk nonlinearly increased with smoking intensity up to 20 cigarettes/day (RR:1.69; 95% CI 1.55-1.84) and levelled thereafter. GC risk significantly increased linearly with increasing smoking duration (RR: 1.31; 95% CI 1.25-1.37 for 20 years) and significantly decreased linearly with increasing time since quitting (RR: 0.65; 95% CI 0.44-0.95 for 30 years since cessation). The present meta-analysis confirms that cigarette smoking is an independent risk factor for GC, particularly for gastric cardia. GC risk increases with a low number of cigarettes up to 20 cigarettes/day and increases in a dose-dependent manner with smoking duration

PLC-βeta2 plays a phenotype dependent role in the malignant potential induced by hypoxia in breast cancer cells

Hypoxia plays a crucial role in malignant progression of solid tumors, including breast cancer, since neoplastic cells adapt to low oxygen availability by modulating the expression of genes involved in survival, proliferation, metabolic reprogramming, stem cell maintenance, EMT, angiogenesis, invasion and metastasis (1). Among the signaling molecules deregulated in breast tumors, the beta2 isoform of the phosphoi- nositide-dependent phospholipase C (PLC-β2) is expressed in the large majority of primary invasive tumors from all histological subtypes in which it strongly correlates with malignancy and with a poor prognosis (2). PLC-β2 is also expressed in breast tumor- derived cells, in which it improves proliferation and motility and sustains invasion capability (3). A decreased PLC-β2 expression is induced by hypoxia in the BT-474 and MCF7 cell lines, that is correlated with the hypoxia-induced modulation of the EMT markers E-cadherin and Vimentin, as well as of the stem cell marker CD133. In contrast, hypoxia induced the increase of PLC-β2 levels in MDA-MB-231 cells, in which it supports the hypoxia-related reorganization of actin cytoskeleton. In all examined cell lines, the prevention of the effects of hypoxia on PLC-β2 also reduced the recovery of HIF-1α, in turn able to exert a phenotype-related role in modulating EMT and expression of CD133 during the cell response to low oxygen. Our data highlighted a peculiar effect of low oxygen availability on PLC-β2 expression in breast tumor cells with different phenotypes and allocate PLC-β2 in the complex and interconnected transcriptional activity induced by hypoxia. Our results also suggest that the forced modulation of PLC-β2 programmed on the basis of the tumor phenotype may prevent malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia

Correlation between the surface expression of CD133 and the phenotype of breast tumor cells

Originally considered a marker of hematopoietic stem cells, CD133/prominin is a highly glycosylated trans-membrane protein expressed in various tissues, such as breast, in which it seems to regulate ductal branching but not regenerative capacity [1]. CD133 is also expressed in various solid tumors, including breast cancer, in which CD133-positivity seems to identify a restricted subgroup of tumor stem cells [2]. CD133 expression was heterogeneous in different breast carcinomas but, in triple- negative (ER-, PR-, HER2-) invasive ductal breast carcinoma, CD133 correlates with tumor size, metastasis and clinical stage [3]. In order to establish a correlation between the surface recognition of CD133 and the phenotype of tumor cells, the highly invasive breast-derived MDA-MB-231 cells (ER-, PR-, HER2-) were subjected to immunomagnetic separation of CD133+ and CD133- subpopulations, which were analyzed for malignant properties. In comparison to CD133- cells, the expression of CD133 characterizes cells with a larger adhesion area, lower proliferation rate and reduced migration speed. This phenotype correlates with altered expression of malignancy-associated proteins and with a peculiar pattern of PLC, in turn involved in proliferation and motility of breast tumor cells (4-6). This suggests that, in triple negative ductal breast tumor-derived cells, the expression of CD133 characterizes a small subset of cells with a less undifferentiated phenotype. The reduced expression of CD133 at membrane level may constitute a marker of the switch of tumor cells from a less malignant to a mature phenotype since it correlates with the de-regulation of proteins involved in cell proliferation, motility and invasion