TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination.

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8-positive cells' dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment.

Quantitative Gd-DOTA-based aerosol deposition mapping in the lungs of asthmatic rats using 3D UTE-MRI.

Asthma is a chronic respiratory disease, commonly treated with inhaled therapy. Better understanding of the mechanisms of aerosol deposition is required to improve inhaled drug delivery. Three-dimensional ultrashort echo time (UTE) MRI acquisitions at 1.5 T were combined with spontaneous nose-only inhalation of aerosolized gadolinium (Gd) to map the aerosol deposition and to characterize signal enhancement in asthmatic rat lungs. The rats were sensitized to ovalbumin (OVA) to develop asthmatic models and challenged before imaging by nebulization of OVA to trigger asthmatic symptoms. The negative controls were not sensitized or challenged by nebulization of saline. The animal lungs were imaged before and after administration of Gd-based aerosol in freely breathing rats, by using a T1 -weighted 3D UTE sequence. A contrast-enhanced quantitative analysis was performed to assess regional concentration. OVA-sensitized rats had lower signal enhancement and lower deposited aerosol concentration. Their enhancement dynamics showed large inter-subject variability. The signal intensity was homogeneously enhanced for controls while OVA-sensitized rats showed heterogeneous enhancement. Contrast-enhanced 3D UTE was applied with aerosolized Gd to efficiently measure spatially resolved deposition in asthmatic lungs. The small administered dose (around 1 µmol/kg body weight) and the use of standard clinical MRI suggest a potential application for the exploration of asthma.

High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology.

OBJECTIVES: We have developed a relevant preclinical model associated with a specific imaging protocol dedicated to onco-pharmacology studies in mice. MATERIALS AND METHODS: We optimized both the animal model and an ultrasound imaging procedure to follow up longitudinally the lung tumor growth in mice. Moreover we proposed to measure by photoacoustic imaging the intratumoral hypoxia, which is a crucial parameter responsible for resistance to therapies. Finally, we compared ultrasound data to x-ray micro computed tomography and volumetric measurements to validate the relevance of this approach on the NCI-H460 human orthotopic lung tumor. RESULTS: This study demonstrates the ability of ultrasound imaging to detect and monitor the in vivo orthotopic lung tumor growth by high resolution ultrasound imaging. This approach enabled us to characterize key biological parameters such as oxygenation, perfusion status and vascularization of tumors. CONCLUSION: Such an experimental approach has never been reported previously and it would provide a nonradiative tool for assessment of anticancer therapeutic efficacy in mice. Considering the absence of ultrasound propagation through the lung parenchyma, this strategy requires the implantation of tumors strictly located in the superficial posterior part of the lung.