Identification of redox-sensitive transcription factors as markers of malignant pleural mesothelioma.

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer

Impact of ABC transporters in osteosarcoma and ewing’s sarcoma: Which are involved in chemoresistance and which are not?

The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing’s sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing’s sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms

“Three-bullets” loaded mesoporous silica nanoparticles for combined photo/chemotherapy

This contribution reports the design, preparation, photophysical and photochemical characterization, as well as a preliminary biological evaluation of mesoporous silica nanoparticles (MSNs) covalently integrating a nitric oxide (NO) photodonor (NOPD) and a singlet oxygen (1O2) photosensitizer (PS) and encapsulating the anticancer doxorubicin (DOX) in a noncovalent fashion. These MSNs bind the NOPD mainly in their inner part and the PS in their outer part in order to judiciously exploit the different diffusion radius of the cytotoxic NO and 1O2. Furthermore this silica nanoconstruct has been devised in such a way to permit the selective excitation of the NOPD and the PS with light sources of different energy in the visible window. We demonstrate that the individual photochemical performances of the photoactive components of the MSNs are not mutually affected, and remain unaltered even in the presence of DOX. As a result, the complete nanoconstruct is able to deliver NO and 1O2 under blue and green light, respectively, and to release DOX under physiological conditions. Preliminary biological results performed using A375 cancer cells show a good tolerability of the functionalized MSNs in the dark and a potentiated activity of DOX upon irradiation, due to the effect of the NO photoreleased

Características biológicas de cepas de Herpesvirus bovino 1 y 5 utilizando el modelo experimental conejo

Los Herpesvirus bovinos (BoHV) pueden infectar tanto a mustélidos como a conejos y esta última especie ha sido utilizada como modelo de laboratorio para la infección por BoHV-1 y 5. El objetivo de este trabajo fue estudiar la patogenicidad de diferentes cepas argentinas de BoHV-1 y BoHV-5 utilizando el modelo experimental conejo. Se utilizaron conejos de raza neozelandesa que se inocularon por vía intranasal e intravaginal. Los animales inoculados por vía intranasal con cepas de BoHV-5 desarrollaron signos nerviosos en el 83% de los casos, mientras que BoHV-1.1 causó signos nerviosos en el 57% de los animales y BoHV-1.2 no provocó signos clínicos evidentes. El BoHV-5 causó síntomas nerviosos solo en los animales jóvenes mientras que BoHV-1 solo lo hizo ocasionalmente y también en individuos jóvenes. Los conejos inoculados por vía intravaginal no mostraron signos clínicos ni lesiones aparentes en los órganos estudiados; la infección se demostró por seroconversión serológica. El conejo resultó adecuado para estudiar la sintomatología y las lesiones producidas en los distintos órganos, fundamentalmente en el sistema nervioso central. El modelo resultó de utilidad por ser económico, de muy fácil manejo y permitió reconocer diferencias en el comportamiento biológico de las cepas de BoHV-1 y BoHV-5 estudiadas.Bovine Herpesvirus (BoHV) can infect both rabbits and mustelids. Rabbit has been used as a laboratory model for infection with BoHV-1 and 5. The objective of this research was to study the pathogenicity of different Argentinian BoHV-1 and BoHV-5 strains by using the rabbit experimental model. New Zealand rabbits were inoculated by intranasal and intravaginal ways. The animals inoculated intranasally with strains of BoHV-5 developed neurological signs in 83% of the cases. BoHV-1.1 caused neurological signs in 57% of the animals and BoHV-1.2 did not cause clear clinical signs. BoHV-5 caused nervous signs in young animals while BoHV-1 did so occasionally in young rabbits. Animales inoculated intravaginally showed no apparent clinical signs or apparent lesions in the studied organs. The infection was demonstrated by serological seroconversion. The rabbit was appropriate to study the clinical signs and the lesions produced in the different organs, primarily in the central nervous system. The model was useful for being inexpensive and very easy to use, and it enabled to identify differences in the biological behavior of the studied BoHV-1 and BoHV-5 strains

Endothelial heme dynamics drive cancer cell metabolism by shaping the tumor microenvironment

The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy

Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition

The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-022-03321-8