Electromagnetic fields (EMFs) originating both from both natural and manmade sources permeate our environment. As people are continuously exposed to EMFs in everyday life, it is a matter of great debate whether they can be harmful to human health. On the basis of two decades of epidemiological studies, an increased risk for childhood leukemia associated with Extremely Low Frequency fields has been consistently assessed, inducing the International Agency for Research on Cancer to insert them in the 2B section of carcinogens in 2001. EMFs interaction with biological systems may cause oxidative stress under certain circumstances. Since free radicals are essential for brain physiological processes and pathological degeneration, research focusing on the possible influence of the EMFs-driven oxidative stress is still in progress, especially in the light of recent studies suggesting that EMFs may contribute to the etiology of neurodegenerative disorders. This review synthesizes the emerging evidences about this topic, highlighting the wide data uncertainty that still characterizes the EMFs effect on oxidative stress modulation, as both pro-oxidant and neuroprotective effects have been documented. Care should be taken to avoid methodological limitations and to determine the patho-physiological relevance of any alteration found in EMFs-exposed biological system.

CD133 and CXCR4 were evaluated in the NCI-60 cell lines to identify cancer stem cell rich populations. Screening revealed that, ovarian OVCAR-3, -4 and -5 and colon cancer HT-29, HCT-116 and SW620 over expressed both proteins. We aimed to isolate cells with stem cell features sorting the cells expressing CXCR4⁺CD133⁺ within ovarian cancer cell lines. The sorted population CD133⁺CXCR4⁺ demonstrated the highest efficiency in sphere formation in OVCAR-3, OVCAR-4 and OVCAR-5 cells. Moreover OCT4, SOX2, KLF4 and NANOG were highly expressed in CD133⁺CXCR4⁺ sorted OVCAR-5 cells. Most strikingly CXCR4⁺CD133⁺ sorted OVCAR-5 and -4 cells formed the highest number of tumors when inoculated in nude mice compared to CD133⁻CXCR4⁻, CD133⁺CXCR4⁻, CD133⁻CXCR4⁺ cells. CXCR4⁺CD133⁺ OVCAR-5 cells were resistant to cisplatin, overexpressed the ABCG2 surface drug transporter and migrated toward the CXCR4 ligand, CXCL12. Moreover, when human ovarian cancer cells were isolated from 37 primary ovarian cancer, an extremely variable level of CXCR4 and CD133 expression was detected. Thus, in human ovarian cancer cells CXCR4 and CD133 expression identified a discrete population with stem cell properties that regulated tumor development and chemo resistance. This cell population represents a potential therapeutic target.

Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. However, their efficacy is thought to be limited by feedback loops and crosstalk with other pathways leading to the development of drug resistance. As CXCR4–CXCL12–CXCR7 axis has been described to have a crucial role in renal cancer; the crosstalk between the mTOR pathway and the CXCR4–CXCL12–CXCR7 chemokine receptor axis has been investigated in human renal cancer cells. In SN12C and A498, the common CXCR4–CXCR7 ligand, CXCL12, and the exclusive CXCR7 ligand, CXCL11, activated mTOR through P70S6K and 4EBP1 targets. The mTOR activation was specifically inhibited by CXCR4 antagonists (AMD3100, anti-CXCR4-12G5 and Peptide R, a newly developed CXCR4 antagonist) and CXCR7 antagonists (anti-CXCR7-12G8 and CCX771, CXCR7 inhibitor). To investigate the functional role of CXCR4, CXCR7 and mTOR in human renal cancer cells, both migration and wound healing were evaluated. SN12C and A498 cells migrated toward CXCL12 and CXCL11; CXCR4 and CXCR7 inhibitors impaired migration and treatment with mTOR inhibitor, RAD001, further inhibited it. Moreover, CXCL12 and CXCL11 induced wound healing while was impaired by AMD3100, the anti CXCR7 and RAD001. In SN12C and A498 cells, CXCL12 and CXCL11 promoted actin reorganization characterized by thin spikes at the cell periphery, whereas AMD3100 and anti-CXCR7 impaired CXCL12/CXCL11-induced actin polymerization, and RAD001 treatment further reduced it. In addition, when cell growth was evaluated in the presence of CXCL12, CXCL11 and mTOR inhibitors, an additive effect was demonstrated with the CXCR4, CXCR7 antagonists and RAD001. RAD001-resistant SN12C and A498 cells recovered RAD001 sensitivity in the presence of CXCR4 and CXCR7 antagonists. In conclusion, the entire axis CXCR4–CXCL12–CXCR7 regulates mTOR signaling in renal cancer cells offering new therapeutic opportunities and targets to overcome resistance to mTOR inhibitors.