This study evaluates the performance of the Bruker positron emission tomograph (PET) insert combined with a BioSpec 70/30 USR magnetic resonance imaging (MRI) scanner using the manufacturer acceptance protocol and the NEMA NU 4–2008 for small animal PET. The PET insert is made of 3 rings of 8 monolithic LYSO crystals (50 × 50 × 10 mm ³ ) coupled to silicon photomultipliers (SiPM) arrays, conferring an axial and transaxial FOV of 15 cm and 8 cm. The MRI performance was evaluated with and without the insert for the following radiofrequency noise, magnetic field homogeneity and image quality. For the PET performance, we extended the NEMA protocol featuring system sensitivity, count rates, spatial resolution and image quality to homogeneity and accuracy for quantification using several MRI sequences (RARE, FLASH, EPI and UTE). The PET insert does not show any adverse effect on the MRI performances. The MR field homogeneity is well preserved (Diameter Spherical Volume, for 20 mm of 1.98 ± 4.78 without and −0.96 ± 5.16 Hz with the PET insert). The PET insert has no major effect on the radiofrequency field. The signal-to-noise ratio measurements also do not show major differences. Image ghosting is well within the manufacturer specifications (<2.5%) and no RF noise is visible. Maximum sensitivity of the PET insert is 11.0% at the center of the FOV even with simultaneous acquisition of EPI and RARE. PET MLEM resolution is 0.87 mm (FWHM) at 5 mm off-center of the FOV and 0.97 mm at 25 mm radial offset. The peaks for true/noise equivalent count rates are 410/240 and 628/486 kcps for the rat and mouse phantoms, and are reached at 30.34/22.85 and 27.94/22.58 MBq. PET image quality is minimally altered by the different MRI sequences. The Bruker PET insert shows no adverse effect on the MRI performance and demonstrated a high sensitivity, sub-millimeter resolution and good image quality even during simultaneous MRI acquisition.

Extracellular vesicles (EVs) like exosomes and shed microvesicles are generated by many different cells. However, among all the cells, cancer cells are now recognized to secrete more EVs than healthy cells. Tumor-derived EVs can be isolated from biofluids such as blood, urine, ascitic fluid, and saliva. Their numerous components (nucleic acids, proteins, and lipids) possess many pleiotropic functions involved in cancer progression. The tumor-derived EVs generated under the influence of tumor microenvironment play distant roles and promote cellular communication by directly interacting with different cells. Moreover, they modulate extracellular matrix remodeling and tumor progression. Tumor-derived EVs are involved in pre-metastatic niche formation, dependent on the EV-associated protein receptors, and in cancer chemoresistance as they transfer drug-resistance-related genes to recipient cells. Recent advances in preclinical and clinical fields suggest their potential use as biomarkers for diagnosis and prognosis as well as for drug delivery in cancer. In this Review, we discuss EV characteristics and pro-tumor capacities, and highlight the future crucial impact of tumor-derived EVs in pancreatic cancer diagnosis and prognosis.

Ovarian cancer remains one of the most fatal cancers due to a lack of robust screening methods of detection at early stages. Extracellular matrix (ECM) mediates interactions between cancer cells and their microenvironment via specific molecules. Lumican, a small leucine-rich proteoglycan (SLRP), maintains ECM integrity and inhibits both melanoma primary tumor development, as well as metastatic spread. The aim of this study was to analyze the effect of lumican on tumor growth of murine ovarian epithelial cancer. C57BL/6 wild type mice (n = 12) and lumican-deficient mice (n = 10) were subcutaneously injected with murine ovarian epithelial carcinoma ID8 cells, and then sacrificed after 18 days. Analysis of tumor volumes demonstrated an inhibitory effect of endogenous lumican on ovarian tumor growth. The ovarian primary tumors were subjected to histological and immunohistochemical staining using anti-lumican, anti-αv integrin, anti-CD31 and anti-cyclin D1 antibodies, and then further examined by label-free infrared spectral imaging (IRSI), second harmonic generation (SHG) and Picrosirius red staining. The IR tissue images allowed for the identification of different ECM tissue regions of the skin and the ovarian tumor. Moreover, IRSI showed a good correlation with αv integrin immunostaining and collagen organization within the tumor. Our results demonstrate that lumican inhibits ovarian cancer growth mainly by altering collagen fibrilogenesis.

Proteoglycans (PG) play an important role in maintaining the extracellular matrix (ECM) integrity. Lumican, a small leucine rich PG, is one such actor capable of regulating such properties. In this study, the integrity of the dermis of lumican-deleted Lum^–/– vs. wild-type mice was investigated by conventional histology and by infrared spectral histology (IRSH). Infrared spectroscopy is a non-invasive, rapid, label-free and sensitive technique that allows to probe molecular vibrations of biomolecules present in a tissue. Our IRSH results obtained on control (WT, n = 3) and Lum^–/– (n = 3) mice showed that different histological structures were identified by using K-means clustering and validated by hematoxylin eosin saffron (HES) staining. Furthermore, an important increase of the dermis thickness was observed in Lum^–/– compared to WT mice. In terms of structural information, analysis of the spectral images also revealed an intra-group homogeneity and inter-group heterogeneity. In addition, type I collagen contribution was evaluated by HES and picrosirius red staining as well as with IRSH. Both techniques showed a strong remodeling of the ECM in Lum^–/– mice due to the looseness of collagen fibers in the increased dermis space. These results confirmed the impact of lumican on the ECM integrity. The loss of collagen fibers organization due to the absence of lumican can potentially increase the accessibility of anti-cancer drugs to the tumor. These results are qualitatively interesting and would need further structural characterization of type I collagen fibers in terms of size, organization, and orientation.

Regenerative vascular medicine research has positioned mesenchymal stromal cells (MSCs) as a leading candidate to treat ischemic diseases. Recent studies have highlighted the emerging role of small extracellular vesicles (sEVs) produced by MSCs in their own potential. This study explores a strategy to improve the angiogenic potential of MSCs through the acquisition of endothelial features. Umbilical cord Wharton's jelly MSCs were cultured in fetal bovine serum‐free endothelial growth medium under hypoxic conditions (SH‐MSCs). sEVs were characterised by a multimodal approach: visualisation, count and particle size distribution, sEVs surface antigen, proangiogenic potential and ability to internalise into recipient cells. Compared with MSCs, SH‐MSCs exhibited significant morphological and phenotypical change characterised by the up‐regulation of CD31 and CD144 mRNA as well as a marked increase in sEVs secretion. MSC‐ and SH‐MSC‐derived sEVs had the capacity to internalise into endothelial cells, myoblasts and macrophages; exhibited a strong proangiogenic effect in vitro, particularly in promoting endothelial cell proliferation and pseudotube formation, likely due to an enriched cargo of angiogenic factors. These results highlight the dual benefit of hypoxia conditioning and endothelial differentiation of MSCs to optimise the angiogenic potential of their secreted sEVs, thus paving the way for innovative regenerative therapies in ischemic diseases.

L'adénocarcinome canalaire pancréatique (ACP) est un cancer très agressif caractérisé par une réaction desmoplasique importante. Les peptides dérivés de l'élastine (PDEs) régulent de nombreux processus et VG-6 et AG-9 en font l’étude sur le développement de l’ACP. La protéine ribosomale SA (RPSA) est un nouveau récepteur associé à ces PDEs. La communication intercellulaire entre les cellules tumorales et son microenvironnement par les vésicules extracellulaires (VE) favorise les changements de phénotype. Le lien entre ces différents acteurs et leur implication dans la progression de l’ACP restait inconnu. Nous avons montré les effets pro-tumoraux des PDEs sur la progression de l’ACP in vivo en utilisant un modèle murin de xénogreffe (MIA PaCa-2/eGFP-FLuc+). L’imagerie multimodale a permis un suivi longitudinal tumoral in vivo. AG-9 exacerbe la croissance tumorale par l’augmentation de la vascularisation tumorale. De plus, nous avons montré le potentiel pro-tumoral des VEs dérivées d’ACP et de l'influence du microenvironnement sur la progression tumorale. In vitro, les VE dérivées de l’ACP générées via AG-9 sont présentes en plus grand nombre et à long terme stimulent la prolifération des cellules cancéreuses. Traitées ou non, les VEs dérivées d’ACP stimulent la prolifération et la migration des cellules tumorales et favorisent la prolifération, la sécrétion de protéases et la formation de pseudo-tubes des cellules endothéliales. Nous avons enfin observé avec succès la biodistribution in vivo des VEs dérivées d’ACP (FLuc+) et de leur capacité à cibler les tumeurs. Cette biodistribution était différente selon le contexte du microenvironnement suggérant un « homing » métastastique modulé. AG-9 pourrait être utilisé pour délivrer des agents anti-tumoraux in situ via RPSA, reconnus comme marqueurs de mauvais pronostic. Les VEs sont des candidats potentiels pour l'administration ciblée de médicaments modulant la progression tumorale.