Phthalates are a huge class of chemicals with a wide spectrum of industrial uses, from the manufacture of plastics to food contact applications, children’s toys, and medical devices. People and animals can be exposed through different routes (i.e., ingestion, inhalation, dermal, or iatrogenic exposure), as these compounds can be easily released from plastics to water, food, soil, air, making them ubiquitous environmental contaminants. In the last decades, phthalates and their metabolites have proven to be of concern, particularly in products for pregnant women or children. Moreover, many authors reported high concentrations of phthalates in soft drinks, mineral waters, wine, oil, ready-to-eat meals, and other products, as a possible consequence of their accumulation along the food production chain and their accidental release from packaging materials. However, due to their different physical and chemical properties, phthalates do not have the same human and environmental impacts and their association to several human diseases is still under debate. In this review we provide an overview of phthalate toxicity, pointing out the health and legal issues related to their occurrence in several types of food and beverage.

Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM.

Extracellular adenosine mediates diverse anti-inflammatory, angiogenic and vasoactive effects, and has become an important therapeutic target for cancer, which has been translated into clinical trials. This study was designed to comprehensively assess adenosine metabolism in prostate and breast cancer cells. We identified cellular adenosine turnover as a complex cascade, comprising (1) the ectoenzymatic breakdown of ATP via sequential ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1, officially known as ENPP1), ecto-5′-nucleotidase (CD73, also known as NT5E), and adenosine deaminase reactions, and ATP re-synthesis through a counteracting adenylate kinase and members of the nucleoside diphosphate kinase (NDPK, also known as NME/NM23) family; (2) the uptake of nucleotide-derived adenosine via equilibrative nucleoside transporters; and (3) the intracellular adenosine phosphorylation into ATP by adenosine kinase and other nucleotide kinases. The exposure of cancer cells to 1% O2 for 24 h triggered an ∼2-fold upregulation of CD73, without affecting nucleoside transporters, adenosine kinase activity and cellular ATP content. The ability of adenosine to inhibit the tumor-initiating potential of breast cancer cells via a receptor-independent mechanism was confirmed in vivo using a xenograft mouse model. The existence of redundant pathways controlling extracellular and intracellular adenosine provides a sufficient justification for reexamination of the current concepts of cellular purine homeostasis and signaling in cancer. This article has an associated First Person interview with the first author of the paper.

Glioblastoma (GBM) stem cells (GSCs), which contribute to GBM unfavorable prognosis, show high expression levels of ATP/P2X7 receptors (P2X7R). Here, we reported that cells exposure to 2’(3’)-O-(4-benzoylbenzoyl)-ATP (BzATP), a P2X7R agonist, up-regulated the expression of markers associated to epithelial-to-mesenchymal transition (EMT), a process likely contributing to GSC malignancy, and increased GSC migration/invasiveness like the known EMT inducer, Transforming Growth Factor β1 (TGFβ1). These effects were coupled to phosphorylation of SMAD2, a downstream effector in the TGFβ pathway, suggesting its involvement in P2X7R-mediated activity in GSCs. All BzATP effects, including a decrease in the caspase 3/7 activity in GSC medium, were mostly counteracted by the P2X7R antagonist A438079. Finally, BzATP increased the subunit expression of two main human P2X7R splice variants, the full-length P2X7A and the truncated P2X7B, lacking the carboxylic tail, which have different functional properties depending on their arrangement. Since up-regulation of A/B subunits might favor their assembly into a heterotrimeric P2X7R with great sensitivity towards agonists and cell energy support, this is in line with increased EMT markers expression, cell migration/invasion and GSC survival observed following P2X7R stimulation. As in GBM microenvironment extracellular ATP levels may activate P2X7R, our data suggest a P2X7R role in GBM recurrence/invasiveness.

The low-density-lipoprotein receptors represent a family of pleiotropic cell surface receptors involved in lipid homeostasis, cell migration, proliferation and differentiation. The family shares common structural features but also has significant differences mainly due to tissue-specific interactors and to peculiar proteolytic processing. Among the receptors in the family, recent studies place low-density lipoprotein receptor-related protein 8 (LRP8) at the center of both neurodegenerative and cancer-related pathways. From one side, its overexpression has been highlighted in many types of cancer including breast, gastric, prostate, lung and melanoma; from the other side, LRP8 has a potential role in neurodegeneration as apolipoprotein E (ApoE) and reelin receptor, which are, respectively, the major risk factor for developing Alzheimer’s disease (AD) and the main driver of neuronal migration, and as a γ-secretase substrate, the main enzyme responsible for amyloid formation in AD. The present review analyzes the contributions of LDL receptors, specifically of LRP8, in both cancer and neurodegeneration, pointing out that depending on various interactions and peculiar processing, the receptor can contribute to both proliferative and neurodegenerative processes.