Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes.
In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.
The goal of this study was to understand if exosomes derived from high-metastatic cells may influence the behavior of less aggressive cancer cells and the properties of the endothelium. We found that metastatic colon cancer cells are able to transfer their amoeboid phenotype to isogenic primary cancer cells through exosomes, and that this morphological transition is associated with the acquisition of a more aggressive behavior. Moreover, exosomes from the metastatic line (SW620Exos) exhibited higher ability to cause endothelial hyperpermeability than exosomes from the non metastatic line (SW480Exos). SWATH-based quantitative proteomic analysis highlighted that SW620Exos are significantly enriched in cytoskeletal-associated proteins including proteins activating the RhoA/ROCK pathway, known to induce amoeboid properties and destabilization of endothelial junctions. In particular, thrombin was identified as a key mediator of the effects induced by SW620Exos in target cells, in which we also found a significant increase of RhoA activity. Overall, our results demonstrate that in a heterogeneous context exosomes released by aggressive sub-clones can contribute to accelerate tumor progression by spreading malignant properties that affect both the tumor cell plasticity and the endothelial cell behavior.
It has been hypothesized that interstitial telomeric sequences (ITSs), i.e., repeated telomeric DNA sequences found at intrachromosomal sites in many vertebrates, could be correlated to chromosomal rearrangements and plasticity. To test this hypothesis, we hybridized a telomeric PNA probe through FISH on representative species of 2 primate infraorders, Strepsirrhini (Lemur catta, Otolemur garnettii, Nycticebus coucang) and Catarrhini (Erythrocebus patas, Cercopithecus petaurista, Chlorocebus aethiops, Colobus guereza), as well as on 1 species of the order Scandentia, Tupaia minor, used as an outgroup for primates in phylogenetic reconstructions. In almost all primate species analyzed, we found a telomeric pattern only. In Tupaia, the hybridization revealed many bright ITSs on at least 11 chromosome pairs, both biarmed and acrocentric. These ITS signals in Tupaia correspond to fusion points of ancestral human syntenic associations, but are also present in other chromosomes showing synteny to only a single human chromosome. This distribution pattern was compared to that of the heterochromatin regions detected through sequential C-banding performed after FISH. Our results in the analyzed species, compared with literature data on ITSs in primates, allowed us to discuss different mechanisms responsible for the origin and distribution of ITSs, supporting the correlation between rearrangements and ITSs.
By proteomic analysis we found an up-regulation of four carbonic anhydrase-3 (CA3) isoforms and a down-regulation of superoxide dismutase [Cu-Zn] (SODC) in quadriceps of sedentary X-linked muscular dystrophy (mdx) mice as compared with wild–type (WT) mice and the levels were significantly restored to WT values following low-intensity endurance exercise.
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