ABSTRACT
BACKGROUND: Angiogenesis strongly reflects poor breast cancer outcome and an important contributor to breast cancer (BC) metastasis; therefore, anti-angiogenic intervention is a potential tool for cancer treatment. However, currently used antibodies against vascular endothelial growth factor A (VEGFA) or inhibitors that target the VEGFA receptor are not effective due to weak penetration and low efficiency. Herein, we assessed the anti-BC angiogenic role of muscone, a natural bioactive musk constituent, and explored possible anti-cancer mechanisms of this compound. METHODS: CCK-8, EdU, scratch and Transwell assessments were employed to detect the muscone-mediated regulation of breast cancer (BC) and human umbilical vein endothelial cells (HUVECs) proliferation and migration. Tube formation, matrigel plug assay and zebrafish assay were employed for assessment of regulation of tumor angiogenesis by muscone. In vivo xenograft mouse model was constructed to compare microvessel density (MVD), vascular leakage, vascular maturation and function in muscone-treated or untreated mice. RNA sequencing was performed for gene screening, and Western blot verified the effect of the VEGFA-VEGFR2 pathway on BC angiogenic inhibition by muscone. RESULTS: Based on our findings, muscone suppressed BC progression via tumor angiogenic inhibition in cellular and animal models. Functionally, muscone inhibited BC cell proliferation and migration as well as tumor cell-conditioned medium-based endothelial cell proliferation and migration. Muscone exhibited a strong suppressive influence on tumor vasculature in cellular and animal models. It abrogated tumor cell growth in a xenograft BC mouse model and minimized tumor microvessel density and hypoxia, and increased vascular wall cell coverage and perfusion. Regarding the mechanism of action, we found that muscone suppressed phosphorylation of members of the VEGF/PI3K/Akt/MAPK axis, and it worked synergistically with a VEGFR2 inhibitor, an Akt inhibitor, and a MAPK inhibitor to further inhibit tube formation. CONCLUSION: Overall, our results demonstrate that muscone may proficiently suppress tumor angiogenesis via modulation of the VEGF/PI3K/Akt/MAPK axis, facilitating its candidacy as a natural small molecule drug for BC treatment.
ABSTRACT
Predicting and interpreting the spatial location and causes of traffic accidents is one of the current hot topics in traffic safety. This research purposed a multi-dimensional long-short term memory neural network model (MDLSTM) to fit the non-linear relationships between traffic accident characteristics and land use properties, which are further interpreted to form local and general rules. More variables are taken into account as the input land use properties and the output traffic accident characteristics. Five types of traffic accident characteristics are simultaneously predicted with higher accuracy, and three levels of interpretation, including the hidden factor-traffic potential, the potential-determine factors, which varies between grid cells, and the general rules across the whole study area are analyzed. Based on the model, some interesting insights were revealed including the division line in the potential traffic accidents in Shenyang (China). It is also purposed that the relationship between land use and accidents differ from previous researches in the neighboring and regional aspects. Neighboring grids have strong spatial connections so that the relationship of accidents in a continuous area is relatively similar. In a larger region, the spatial location is found to have a great influence on the traffic accident and has a strong directionality.
