BackgroundThe possibility to combine Low Intensity UltraSound (LIUS) and Nanoparticles (NP) could represent a promising strategy for drugs delivery in tumors difficult to treat overcoming resistance to therapies. On one side the NP can carry drugs that specifically target the tumors on the other the LIUS can facilitate and direct the delivery to the tumor cells. In this study, we investigated whether Very Low Intensity UltraSound (VLIUS), at intensities lower than 120 mW/cm2, might constitute a novel strategy to improve delivery to tumor cells. Thus, in order to verify the efficacy of this novel modality in terms of increase selective uptake in tumoral cells and translate speedily in clinical practice, we investigated VLIUS in three different in vitro experimental tumor models and normal cells adopting three different therapeutic strategies.MethodsVLIUS at different intensities and exposure time were applied to tumor and normal cells to evaluate the efficiency in uptake of labeled human ferritin (HFt)-based NP, the delivery of NP complexed Firefly luciferase reported gene (lipoplex-LUC), and the tumor-killing of chemotherapeutic agent.ResultsSpecifically, we found that specific VLIUS intensity (120 mW/cm2) increases tumor cell uptake of HFt-based NPs at specific concentration (0.5 mg/ml). Similarly, VLIUS treatments increase significantly tumor cells delivery of lipoplex-LUC cargos. Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion. Noteworthy, VLIUS treatments are well tolerated in normal cells with not significant effects on cell survival, NPs delivery and drug-induced toxicity, suggesting a tumor specific fashion.ConclusionsOur data shed novel lights on the potential application of VLIUS for the design and development of novel therapeutic strategies aiming to efficiently deliver NP loaded cargos or anticancer drugs into more aggressive and unresponsive tumors niche.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1018-6) contains supplementary material, which is available to authorized users.
Mutations in the TP53 tumor suppressor gene are the most frequent genetic alteration in human cancers. These alterations are mostly missense point mutations that cluster in the DNA binding domain. There is growing evidence that many of these mutations generate mutant p53 proteins that have acquired new biochemical and biological properties. Through this gain of function activity, mutant p53 is believed to contribute to tumor malignancy. The purpose of our study was to explore mutant p53 as a target for novel anticancer treatments. To this aim, we inhibited mutant p53 expression by RNA interference in three different cancer cell lines endogenously expressing mutant p53 proteins, and evaluated the effects on the biological activities through which mutant p53 exerts gain of function. We found that depletion of mutant p53 reduces cell proliferation, in vitro and in vivo tumorigenicity, and resistance to anticancer drugs. Our results demonstrate that mutant p53 knocking down weakens the aggressiveness of human cancer cells, and provides further insight into the comprehension of mutant p53 gain of function activity in human tumor.
Abstract. The involvement of p53 protein in cell differentiation has been recently suggested by some observations made with tumor cells and the correlation found between differentiation and increased levels of p53. However, the effect of p53 on differentiation is in apparent contrast with the normal development of p53-null mice. To test directly whether p53 has a function in cell differentiation, we interfered with the endogenous wt-p53 protein of nontransformed cells of two different murine histotypes: 32D myeloid progenitors, and C2C12 myoblasts. A drastic inhibition of terminal differentiation into granulocytes or myotubes, respectively, was observed upon expression of dominant-negative p53 proteins. This inhibition did not alter the cell cycle withdrawal typical of terminal differentiation, nor p21 (wAF1/cIP1) upregulation, indicating that interference with endogenous p53 directly affects cell differentiation, independently of the p53 activity on the cell cycle. We also found that the endogenous wt-p53 protein of C2C12 cells becomes transcriptionally active during myogenesis, and this activity is inhibited by p53 dominant-negative expression. Moreover, we found that p53 DNA-binding and transcriptional activities are both required to induce differentiation in p53-negative K562 cells. Taken together, these data strongly indicate that p53 is a regulator of cell differentiation and it exerts this role, at least in part, through its transcriptional activity.
Tumor phenotype is a result of the complex interactions between malignant cells and sorrounding stroma. However, the mechanisms by which cancer cells and fibroblasts, the most abundant and active part of the tumor stroma, interact remain to be elucidated. The K303R mutation of estrogen-receptor (ERα) was identified in 50% of invasive breast tumors and associated with poorer survival outcomes. Here, we show that human cancer-associated fibroblasts (CAFs) stimulated proliferation and migration of wild-type (WT) ERα stably transfected breast cancer cells and to a higher extent in cells expressing the K303R ERα hyperactive receptor. We identified, for the first time, leptin, a known cytokine involved in breast cancer development, as a determinant for CAFs tumor-promoting activities in both WT and K303R ERα-expressing cells. Indeed, we found an increase in leptin receptor isoforms expression, and in its signalling activation in K303R-expressing cells compared to WT ERα clones. These data correlated well with the amplified effects of leptin on cell growth, motility and invasiveness in mutant cells. Mutant expression generated a leptin hypersensitive phenotype also in vivo. Lastly, K303R ERα cell-secreted factors stimulated CAFs proliferation and migration and their ability to secrete leptin. We demonstrated that the epidermal growth factor is the paracrine factor by which breast cancer cells affect CAFs phenotype. Thus, our work uncovers a bidirectional cross-talk between breast cancer cells and ‘educated’ CAFs, which leads via leptin signaling to increased tumor progression. The blockade of these intercellular communications might represent an effective strategy for molecular targeted therapies in breast cancer.
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