The relationship between expression of VIMENTIN and CD146 genes in breast cancer

Objectives CD146 is an adhesive molecule that was originally reported on malignant melanoma cells as a protein crucial for cell adhesion. It is now known that high expression of the CD146 protein is not only characteristic of melanoma, but it occurs on a number of cancers, contributing to worse prognosis and increased aggressiveness. Independent in vitro studies in breast cancer have shown that CD146 protein alone can induce a change in epithelial to mesenchymal transcriptional profile, which is the basis of the tumor aggressiveness and metastasis. Methods In the following work, the correlation coefficients were analyzed between the genes of the mesenchymal profile and the CD146 gene in 10 independent transcriptomic data of breast cancer patients. Results The analysis confirmed the relationship between CD146 expression and mesenchymal profile genes, pointing VIMENTIN as the gene which expression is most strongly correlated with the CD146, suggesting that both genes, CD146 and VIM may be directly controlled by the same mechanism or regulate one another. Conclusions The analysis points a potential route for research on the CD146 gene expression, which may lead to understanding of its regulation in breast cancer, contributing to the development of new therapeutic strategies targeting highly metastatic breast cancer cells.

Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism

ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

Spata19 Inactivation as a Cause of Oligospermia

Background: Spermatogenesis associated 19 (Spata19) was introduced as a testis-specific gene that was probably involved in spermatogenesis cell apoptosis. Therefore, this study aimed to investigate the effect of Spata19 inactivation on sperm count. Materials and Methods: We generated global Spata19 knockout mice by CRISPR/Cas9 nickase technology. Disability was validated in three levels of DNA, RNA, and protein using PCR, RT-PCR, and immunohistochemistry. Histological studies were performed for testis. Sperm characteristics were also assessed with CASA software. Results: Spata19 knockout mice had a 43 nucleotides deletion in exon 4 of this gene. The presence and absence of Spata19 were confirmed in normal and knockout mice, respectively. The presence of Spata19 in normal NMRI mice was detected in the brain, heart, and thymus by semi-nested RT-PCR and in Leydig cells by immunohistochemistry. Histological studies revealed a decrease in sperm count in knockout mice. Also, CASA parameters were significantly reduced (P<0.05). Conclusion: These data indicate that Spata19 inactivation is a cause of oligospermia, and its role could be beyond an adhesive molecule.

Human Bone Marrow Mesenchymal Stem/Stromal Cells Exposed to an Inflammatory Environment Increase the Expression of ICAM-1 and Release Microvesicles Enriched in This Adhesive Molecule: Analysis of the Participation of TNF-α and IFN-γ

Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory capacity; therefore, they have been used in different clinical protocols in which it is necessary to decrease the immune response. This capacity is mainly regulated by TNF-α and IFN-γ, and it has been observed that cell-cell contact, mainly mediated by ICAM-1, is important for MSCs to carry out efficient immunoregulation. Therefore, in the present work, we analyzed the effect of TNF-α alone or in combination with IFN-γ on the expression of ICAM-1. Besides, given the importance of cell contact in the immunoregulatory function of MSCs, we analyzed whether these cells release ICAM-1+ microvesicles (MVs). Our results show for the first time that TNF-α is capable of increasing the early expression of ICAM-1 in human BM-MSCs. Also, we observed that TNF-α and IFN-γ have a synergistic effect on the increase in the expression of ICAM-1. Furthermore, we found that BM-MSCs exposed to an inflammatory environment release MVs enriched in ICAM-1 (MVs-ICAM-1high). The knowledge generated in this study will contribute to the improvement of in vitro conditioning protocols that favor the therapeutic effect of these cells or their products.

Intercellular adhesive molecule-1 (ICAM-1) in proliferative diabetic retinopathy

Purpose: To determine the level of intercellular adhesion molecule-1 (ICAM-1) in vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and its affecting factors including HbA1c level, duration of diabetes mellitus (DM) and insulin usage. Methods: A cross-sectional study was conducted in Cipto Mangunkusumo National General Central Hospital, Jakarta, Indonesia from June 2015 to August 2016. Thirty-three consecutive vitreous samples harvested from PDR patients underwent vitrectomy. The level of vitreous ICAM-1 was determined by enzyme-linked immunosorbent assay. Results: Based on the glycemic status, vitreous ICAM-1 level in the uncontrolled glycemic group (21.61 ng/ml) was lower than controlled glycemic group (24.20 ng/ml). Patients with DM for more than 10 years had higher level of vitreous ICAM-1 (26.30 ng/ml). Vitreous ICAM-1 level in DM patients with insulin was higher than those without insulin (27.07 ng/ml vs. 24.17 ng/ml). There was no statistically significant difference between vitreous ICAM-1 levels among all groups (p > 0.05). Conclusion: The concentration of vitreous ICAM-1 may not be influenced by glucose control and conventional insulin therapy.