Renal cancer secretome induces migration of mesenchymal stromal cells

Abstract Background Advanced renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs’ migration to RCC remain unknown. Here, we aimed to comprehensively analyze RCC secretome to identify MSCs attractants. Methods Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T and KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. Results When compared with normal cells, CM from advanced RCC cell lines (Caki-1 and KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1 and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs’ transcriptional reprogramming, stimulating the expression of CD44, PTX3 and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs’ homing to the kidney. AREG emerged as an upregulator of MSCs’ transcription. Conclusions Advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs’ transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets. Graphical abstrac

Security theory and practice: The Age of Fear. 20 Years Lat er

From Introduction: "This issue is different from all previous ones. Thus, an introduction to it needs to be different from earlier ones. There has to be a place for reflection, which used to be included in an interview preceding academic articles. Clever readers will find out soon why this is so if they only think about the professional path of one of the editors. However, it is not the only reason. A special character of this issue is also due to the anniversary, the 20th already, of the September 11, 2001 attacks which have changed the world around us. They led it onto a new path which became the global war on international terrorism, or rather with terrorists and organisations bringing them together. The fight was joined by many states whose governments reached for armed forces, regarding this as the best tool for winning the war. They forgot that this was a way to eliminate only one generation of terrorists, but not the sources of the phenomenon which would motivate a generation after generation. For example, according to the wave theory of terrorism, those who did not participate directly in the struggle watched it carefully, and everybody felt its consequences, both as ongoing wars and their aftermath, changes in internal legislature perceived as limiting civil liberties, and terrorist attacks happening in various places. Attacks which were tragic and spectacular, but not with as many casualties as on September 11."(...