No abstract

Despite the high mortality from metastatic cancer, therapeutic targets to prevent metastasis are limited. Efforts to identify genetic aberrations that predispose tumors to metastasis have been mostly unsuccessful. To understand the nature of candidate targets for metastatic disease, we performed an in silico screen to identify drugs that can inhibit a gene expression signature associated with epithelial-mesenchymal transition (EMT). Compounds discovered through this method, including those previously identified, appeared to restrict metastatic capacity through a common mechanism, the ability to modulate the fluidity of cell membranes. Treatment of breast cancer cell lines with the putative antimetastasis agents reduced membrane fluidity, resulting in decreased cell motility, stem celllike properties, and EMT in vitro, and the drugs also inhibited spontaneous metastasis in vivo. When fluidity was unchanged, the antimetastasis compounds could no longer restrict metastasis, indicating a causal association between fluidity and metastasis. We further demonstrate that fluidity can be regulated by cellular cholesterol flux, as the cholesterol efflux channel ABCA1 potentiated metastatic behaviors in vitro and in vivo. The requirement for fluidity was further supported by the finding in breast cancer patients that ABCA1 was overexpressed in 41% of metastatic tumors, reducing time to metastasis by 9 years. Collectively, our findings reveal increased membrane fluidity as a necessary cellular feature of metastatic potential that can be controlled by many currently available drugs, offering a viable therapeutic opportunity to prevent cancer metastasis.

Background The hippocampus and hippocampal subfields have been found to be diversely affected in Alzheimer’s Disease (AD) and early stages of Alzheimer’s disease by neuroimaging studies. However, our knowledge is still lacking about the trajectories of the hippocampus and hippocampal subfields atrophy with the progression of Alzheimer’s disease. Objective To identify which subfields of the hippocampus differ in the trajectories of Alzheimer’s disease by magnetic resonance imaging (MRI) and to determine whether individual differences on memory could be explained by structural volumes of hippocampal subfields. Methods Four groups of participants including 41 AD patients, 43 amnestic mild cognitive impairment (aMCI) patients, 35 subjective cognitive decline (SCD) patients and 42 normal controls (NC) received their structural MRI brain scans. Structural MR images were processed by the FreeSurfer 6.0 image analysis suite to extract the hippocampus and its subfields. Furthermore, we investigated relationships between hippocampal subfield volumes and memory test variables (AVLT-immediate recall, AVLT-delayed recall, AVLT-recognition) and the regression model analyses were controlled for age, gender, education and eTIV. Results CA1, subiculum, presubiculum, molecular layer and fimbria showed the trend toward significant volume reduction among four groups with the progression of Alzheimer’s disease. Volume of left subiculum was most strongly and actively correlated with performance across AVLT measures. Conclusion The trend changes in the hippocampus subfields and further illustrates that SCD is the preclinical stage of AD earlier than aMCI. Future studies should aim to associate the atrophy of the hippocampal subfields in SCD with possible conversion to aMCI or AD with longitudinal design.