Small extracellular vesicle TGF-ß in cancer progression and immune evasion.

Transforming growth factor-ß (TGF-ß) is a well-known cytokine that controls various processes in normal physiology and disease context. Strong preclinical and clinical literature supports the crucial roles of the TGF-ß in several aspects of cancer biology. Recently emerging evidence reveals that the release of TGF-ß from tumor/immune/stromal cells in small extracellular vesicles (sEVs) plays an important part in tumor development and immune evasion. Hence, this review aims to address the packaging, release, and signaling pathways of TGF-ß carried in sEVs (sEV-TGF-ß) in cancer, and to explore its underpinning roles in tumor development, growth, progression, metastasis, etc. We also highlight key progresses in deciphering the roles of sEV-TGF-ß in subverting anti-tumor immune responses. The paper ends with a focus on the clinical significance of TGF-ß carried in sEVs and draws attention to its diagnostic, therapeutic, and prognostic importance.

Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to Trastuzumab

Objective(s) Exosomal HER2 has been evidenced to interfere with antibody-induced anti-tumor effects. However, whether the blockade of HER2+ exosomes release would affect antibody-mediated tumor inhibition has yet to be investigated. Methods Exosomes derived from BT-474, SK-BR3 and SK-OV3 (HER2-overexpressing tumor cells) and MDA-MB-231 cells (HER2 negative) were purified and characterized by bicinchoninic acid (BCA) assay, western blotting and Transmission electron microscopy (TEM). Inhibition of exosome release was achieved by neutral sphingomyelinase-2 (nSMase-2) inhibitor, GW4869. The effects of exosome blockade on the anti-proliferative effects, apoptosis induction, and antibody-mediated cellular cytotoxicity (ADCC) activity of Trastuzumab were examined using MTT, flow cytometry, and LDH release assays. Also, the effects of exosome inhibition on the surface expression and endocytosis/internalization of HER2 were studied by flow cytometry. Results Purified exosomes derived from HER2 overexpressing cancer cells were positive for HER2 protein. Blockade of exosome release was able to significantly improve apoptosis induction, anti-proliferative and ADCC responses of Trastuzumab dose dependently. The pretreatment of Trastuzumab/purified NK cells, but not PBMCs, with HER2+ exosomes could also decrease the ADCC effects of Trastuzumab. Exosome inhibition also remarkably downregulated surface HER2 levels in a time-dependent manner, but does not affect its endocytosis/internalization. Conclusion Based on our findings, HER2+ exosomes may benefit tumor progression by dually suppressing Trastuzumab-induced tumor growth inhibition and cytotoxicity of NK cells. It seems that concomitant blocking of exosome release might be an effective approach for improving the therapeutic effects of Trastuzumab, and potentially other HER2-directed mAbs (AU)

Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to Trastuzumab.

OBJECTIVE(S): Exosomal HER2 has been evidenced to interfere with antibody-induced anti-tumor effects. However, whether the blockade of HER2+ exosomes release would affect antibody-mediated tumor inhibition has yet to be investigated. METHODS: Exosomes derived from BT-474, SK-BR3 and SK-OV3 (HER2-overexpressing tumor cells) and MDA-MB-231 cells (HER2 negative) were purified and characterized by bicinchoninic acid (BCA) assay, western blotting and Transmission electron microscopy (TEM). Inhibition of exosome release was achieved by neutral sphingomyelinase-2 (nSMase-2) inhibitor, GW4869. The effects of exosome blockade on the anti-proliferative effects, apoptosis induction, and antibody-mediated cellular cytotoxicity (ADCC) activity of Trastuzumab were examined using MTT, flow cytometry, and LDH release assays. Also, the effects of exosome inhibition on the surface expression and endocytosis/internalization of HER2 were studied by flow cytometry. RESULTS: Purified exosomes derived from HER2 overexpressing cancer cells were positive for HER2 protein. Blockade of exosome release was able to significantly improve apoptosis induction, anti-proliferative and ADCC responses of Trastuzumab dose dependently. The pretreatment of Trastuzumab/purified NK cells, but not PBMCs, with HER2+ exosomes could also decrease the ADCC effects of Trastuzumab. Exosome inhibition also remarkably downregulated surface HER2 levels in a time-dependent manner, but does not affect its endocytosis/internalization. CONCLUSION: Based on our findings, HER2+ exosomes may benefit tumor progression by dually suppressing Trastuzumab-induced tumor growth inhibition and cytotoxicity of NK cells. It seems that concomitant blocking of exosome release might be an effective approach for improving the therapeutic effects of Trastuzumab, and potentially other HER2-directed mAbs. In addition, the exosome secretion pathway possibly contributes to the HER2 trafficking to plasma membrane, since the blockade of exosome secretion decreased surface HER2 levels.

Cancer exosomes and natural killer cells dysfunction: biological roles, clinical significance and implications for immunotherapy.

Tumor-derived exosomes (TDEs) play pivotal roles in several aspects of cancer biology. It is now evident that TDEs also favor tumor growth by negatively affecting anti-tumor immunity. As important sentinels of immune surveillance system, natural killer (NK) cells can recognize malignant cells very early and counteract the tumor development and metastasis without a need for additional activation. Based on this rationale, adoptive transfer of ex vivo expanded NK cells/NK cell lines, such as NK-92 cells, has attracted great attention and is widely studied as a promising immunotherapy for cancer treatment. However, by exploiting various strategies, including secretion of exosomes, cancer cells are able to subvert NK cell responses. This paper reviews the roles of TDEs in cancer-induced NK cells impairments with mechanistic insights. The clinical significance and potential approaches to nullify the effects of TDEs on NK cells in cancer immunotherapy are also discussed.

The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells.

Tumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide future treatment options, in particular DC-based vaccination strategy, and review advances in the design and discovery of exosome inhibitors. Understanding the exosomal content and the pathways by which TDEs are responsible for immune evasion may help to revise treatment rationales and devise novel therapeutic approaches to overcome the hurdles in cancer treatment.

Incidence patterns of gynecological sarcomas in Iran analysis of National Cancer Registry data between 2009 and 2014.

AIM: Gynecological sarcomas (GS) are rare malignant tumors arising in the female genital organs. Due to the low incidence and diverse histology, information on the epidemiology of these tumors is sparse. We aimed to investigate the incidence rates of GS in Iran that in our knowledge is the first report from Eastern Mediterranean Region. METHODS: In this retrospective study, all malignant tumors with a sarcoma morphology arising in the female genital organs diagnosed between 2009 and 2014 were extracted from the Iran National Cancer Registry dataset. All the cancer cases were categorized according to ICD-O-3 morphologic and topographic codes. Age-standardized incidence rates, age-specific incidence rates, morphologic and geographic distribution of all cases were analyzed and compared with other parts of the world. RESULTS: A total of 1174 cases were diagnosed over the period 2009-2014. The overall age-standardized incidence rate for all sites combined was 6.13 per million females. Analysis of trends in incidence did not show a significant change over time according to annual average percent change analysis (P-value = 0.300). The most common anatomical site was the uterus, accounting for 77% of all cases. The mean (±SD) age at diagnosis, irrespective of tumor site, was 52.3 (±15) years. In terms of morphology, leiomyosarcoma was the most frequently observed subtype, constituting 34% of all GS. Also, the highest ASIR was observed in women aged 60-64 years. CONCLUSION: Based on the findings, GS are relatively rare tumors that occur more in old women. The results of this study provide a comprehensive picture of GS incidence patterns in Iran for more investigation.

Effect of exercise-based cardiac rehabilitation following coronary artery bypass surgery on ventricular repolarization indices.

PURPOSE: Indices of ventricular repolarization heterogeneity are associated with future arrhythmias and sudden cardiac death. We investigated the effect of exercise-based cardiac rehabilitation (CR) on these indices in a sample of Iranian patients. METHODS: Patients (N 122), who had undergone coronary artery bypass surgery (CABGS), were enrolled in this cohort study. Sixty patients attended 15 or more sessions of CR (CR group) and the remaining 62 patients attended 5 or fewer sessions of CR (control group). A standard 12-lead electrocardiogram was recorded for each patient. QT interval dispersion (QTd), RR interval variability (RRV), and heart rate-corrected QTd (QTc-d) were measured 3 times as follow: just before surgery, at the beginning of the first session of the CR program, and at the end of the 15th session for the CR group or the last session for the control group. RESULTS: Following completion of the exercise-training program, the CR group showed a significant decrease in QTd (Δ = -49.4%, P < .0001) and QTc-d (Δ = 52.8%, P .0001), but not in the control group (Δ = 13.4% and 17.9%, respectively, P > .05 for both). In both groups, no statistically significant change in RRV was observed. After adjustment for variables such as age, gender, digoxin use, ß-blocker use, and prerehabilitation ejection fraction, CR remained the independent predictor of QTd and QTc-d. CONCLUSION: Results suggest that cardiac rehabilitation and exercise training programs significantly improve the indices of ventricular repolarization heterogeneity in patients with coronary artery disease who received CABGS.