No abstract

Extracellular vesicles (EVs) are membrane-surrounded structures that transmit biologically important molecules from the releasing to target cells, thus providing a novel intercellular communication mechanism. Since EVs carry their cargo in a protected form and their secretion is generally increased in tumorigenesis, EVs hold a great potential for early cancer diagnosis. By 3D culturing, we provide evidence that colorectal cancer (CRC) patient-derived organoids, representing a state-of-the-art established and essential approach for studying human CRC, is a suitable model for EV analysis. When testing the effects of major factors promoting CRC progression on EV release in the organoid model, we observed that Apc mutation, leading to uncontrolled Wnt activation and thus to tumorigenesis in the vast majority in CRC patients, critically induces EV release by activating the Wnt pathway. Furthermore, the extracellular matrix component collagen, known to accumulate in tumorigenesis, enhances EV secretion as well. Importantly, we show that fibroblast-derived EVs induce colony formation of CRC organoid cells under hypoxia. In contrast, there was no major effect of tumor cell-derived EVs on the activation of fibroblasts. Collectively, our results with CRC and Apc -mutant adenoma organoids identify Apc mutation and collagen deposition as critical factors for increasing EV release from tumors. Furthermore, we provide evidence that stromal fibroblast-derived EVs contribute to tumorigenesis under unfavorable conditions in CRC. Electronic supplementary material The online version of this article (10.1007/s00018-019-03052-1) contains supplementary material, which is available to authorized users.

No abstract

It has been demonstrated recently in several solid tumors that thrombocytosis at diagnosis may correlate with tumor invasion, metastatic progression and worse outcome. Several details of the pathomechanism of the relationship of thrombocytosis and cancer have been elucidated; however, the complete process is not clearly understood. Several hypotheses have been proposed. Recently, it was suggested that in ovarian cancer elevated IL-6 production by the tumor may induce increased megakaryopoiesis via hepatic thrombopoietin production leading to thrombocytosis. The importance of the prognostic power of elevated platelet count is still debated in gastrointestinal cancer. The aims of this review were to evaluate the prognostic significance of thrombocytosis in gastrointestinal tumors, to see whether clinical practice confirmed the hypotheses and to reveal the causes of the inconsistent findings.

The elevated expression of claudins (CLDN) and E-cadherin (CDH-1) was found to correlate with poor prognostic features. Our aim was to perform a comprehensive analysis to assess their potential to predict prognosis in breast cancer. The expression of , and E-cadherin at the mRNA level was evaluated in correlation with survival in datasets containing expression measurements of 1809 breast cancer patients. The breast cancer tissues of 197 patients were evaluated with tissue microarray technique and immunohistochemical method for CLDN-1-5, -7, and E-cadherin protein expression. An additional validation set of 387 patients was used to test the accuracy of the resulting prognostic score. Based on the bioinformatic screening of publicly-available datasets, the metagene of CLDN-3, -4, -7, and E-cadherin was shown to have the most powerful predictive power in the survival analyses. An immunohistochemical protein profile consisting of CLDN-2, -4, and E-cadherin was able to predict outcome in the most effective manner in the training set. Combining the overlapping members of the above two methods resulted in the claudin-4 and E-cadherin score (CURIO), which was able to accurately predict relapse-free survival in the validation cohort (P = 0.029). The multivariate analysis, including clinicopathological variables and the CURIO, showed that the latter kept its predictive power (P = 0.040). Furthermore, the CURIO was able to further refine prognosis, separating good versus poor prognosis subgroups in luminal A, luminal B, and triple-negative breast cancer intrinsic subtypes. In breast cancer, the CURIO provides additional prognostic information besides the routinely utilized diagnostic approaches and factors. (Cancer Sci 2011; 102: 2248-2254

Together our data show that detection and characterization of EVs directly in pancreatic juice is feasible and may prove to be a valuable source of potential biomarkers of pancreatic cancer.

No abstract

IntroductionOperation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP).ObjectivesOur aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.Materials and methodsWistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured.ResultsLess significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group.ConclusionNIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.