Omental cancer-associated fibroblast-derived exosomes with low microRNA-29c-3p promote ovarian cancer peritoneal metastasis.

Ovarian cancer (OC) is characterized by frequent widespread peritoneal metastasis. Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote omentum metastasis in OC patients. However, the role of exosomes derived from omental CAFs in metastasis remains unclear. We isolated exosomes from primary omental normal fibroblasts (NFs) and CAFs from OC patients (NF-Exo and CAF-Exo, respectively) and assessed their effect on metastasis. In mice bearing orthotopic OC xenografts, CAF-Exo treatment led to more rapid intraperitoneal tumor dissemination and shorter animal survival. Similar results were observed in mice undergoing intraperitoneal injection of tumor cells. Among the miRNAs downregulated in CAF-Exo, miR-29c-3p in OC tissues was associated with metastasis and survival in patients. Moreover, increasing miR-29c-3p in CAF-Exo significantly weakened the metastasis-promoting effect of CAF-Exo. Based on RNA sequencing, expression assays, and luciferase assays, matrix metalloproteinase 2 (MMP2) was identified as a direct target of miR-29c-3p. These results verify the significant contribution of exosomes from omental CAFs to OC peritoneal metastasis, which could be partially due to the relief of MMP2 expression inhibition mediated by low exosomal miR-29c-3p.

TIE2-high cervical cancer cells promote tumor angiogenesis by upregulating TIE2 and VEGFR2 in endothelial cells.

Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2), the receptor for angiopoietins, has been found highly expressed in cervical cancer and associated with poor prognosis. However, the potential role of tumoral TIE2 in cervical cancer angiogenesis and the underlying mechanisms remain unexplored. Here, based on multicolor immunofluorescence of 64 cervical cancer tissues, we found that TIE2 level in cervical cancer cells was positively related to shorter survival and higher microvessel density in tumor. In vitro and in vivo experiments verified that TIE2-high cervical cancer cells could promote tumor angiogenesis. TIE2-high tumor cells induced an amplified expression of TIE2 and vascular endothelial growth factor receptor 2(VEGFR2) in HUVECs to promote angiogenesis via TIE2 -AKT/MAPK signals, which could be reversed or partially reversed by TIE2, AKT or MAPK inhibitors and activated by angiopoietin-1 and angiopoietin-2. In conclusion, TIE2-high cervical cancer cells promote tumor angiogenesis by upregulating TIE2 and VEGFR2 in endothelial cells via TIE2-AKT/MAPK axis inside tumor cells.

Tumor cell-derived exosomes deliver TIE2 protein to macrophages to promote angiogenesis in cervical cancer.

Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2)-expressing macrophages (TEMs) are an angiogenesis-promoting subset of tumor-associated macrophages that have been demonstrated to be increased in solid tumors and associated with the progression of cervical cancer. However, the induction mechanism of TEMs remains unclear. Here, based on multicolor immunofluorescence of 58 cervical cancer tissues and the GEPIA database, we found that TEMs were increased in TIE2-high cervical cancer and related to shorter survival. In vitro and in vivo experiments verified that exosomes derived from TIE2-high cervical cancer cells transferred TIE2 protein directly to macrophages, thereby inducing TEMs. Similar to primary TEMs, TEMs induced by tumor-derived exosomes promoted angiogenesis, could be induced by angiopoietin-2, and possessed an M2-like phenotype. In conclusion, exosomes derived from TIE2-high cervical cancer cells induce TEMs by directly transporting TIE2 to promote tumor angiogenesis.

Association of smoking with risk of stroke in middle-aged and older Chinese: Evidence from the China National Stroke Prevention Project.

Although the impacts of smoking on health are well established, it is unclear on how they affect the Chinese population aged ≥40 years. This study aimed to investigate the association between smoking and risk of stroke in middle-aged and older Chinese adults, based on the data from the China National Stroke Prevention Project.A community-based cross-sectional study with 12,704 (5681 men, 7023 women) Chinese adults aged ≥40 years was conducted to examine the association of smoking with stroke. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Among the study population, a total of 524 stroke survivors were identified. The age-adjusted prevalence of stroke was 4.06% for both sexes, 2.95% for women, and 5.38% for men. The multivariate-adjusted ORs (95% CI) of stroke associated with current cigarette smoking and former cigarette smoking were 1.67 (1.24-2.25) and 1.93 (1.29-2.87), respectively. Compared with those who were never-smokers, the multivariate-adjusted OR of stroke (95% CI) were 1.48 (0.96 to -2.29), 1.75 (1.20-2.56), and 2.37 (1.20 to -4.68) for those who smoked 1 to 10, 11 to 20, and ≥21 cigarettes per day; and 0.51 (0.19 to -1.42), 1.90 (1.36 to -2.67), and 2.01 (1.17 to -3.46) for those who smoked 1 to 19, 20 to 39, and ≥40 years, respectively (both P < .001 for linear trends). Among former smokers, the multivariable-adjusted ORs of stroke by duration of smoking cessation (compared with never smokers) for <5, 5 to 19, and ≥20 years were 3.47 (1.42-8.49), 3.37 (1.95-5.80), and 0.95 (0.49-1.84), respectively (P = .009 for linear trend). The increased odds of stroke with smoking were more evident among participants who were men, >60 years old, or without family history of stroke than their counterparts.This study suggests the increased odds of stroke in current cigarette smokers with a graded increase in prevalent risk that depended on how many cigarettes and how many years were smoked. Moreover, quitting smoking appears to decrease this excess risk substantially.