BACKGROUND: Fast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells. METHODS: 4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice. RESULTS: OXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways. CONCLUSION: In summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: In England, many hypertensives are not detected by primary medical care. Higher detection is associated with lower premature mortality. We aimed to summarise recent evidence on detection and interventions to improve detection in order to inform policies to improve care. DESIGN: Data sources: systematic review of articles published since 2000. Searches of Medline and Embase were undertaken. Eligibility criteria: published in English, any study design, the setting was general practice and studies included patients aged 18 or over. EXCLUSION CRITERIA: screening schemes, studies in primary care settings other than general practice, discussion or comment pieces. PARTICIPANTS: adult patients of primary medical care services. SYNTHESIS: study heterogeneity precluded a statistical synthesis, and papers were described in summary tables. RESULTS: Seventeen quantitative and one qualitative studies were included. Detection rates varied by gender and ethnic group, but longitudinal studies indicated an improvement in detection over time. Patient socioeconomic factors did not influence detection, but living alone was associated with lower detection. Few health system factors were associated with detection, but in two studies higher numbers of general practitioners per 1000 population were associated with higher detection. Three studies investigated interventions to improve detection, but none showed evidence of effectiveness. LIMITATIONS: The search was limited to studies published from 2000, in English. There were few studies of interventions to improve detection, and a meta-analysis was not possible. CONCLUSIONS AND IMPLICATIONS: Levels of detection of hypertension by general practices may be improving, but large numbers of people with hypertension remain undetected. Improvement in detection is therefore required, but guidance for primary medical care is not provided by the few studies of interventions included in this review. Primary care teams should continue to use low-cost, practical approaches to detecting hypertension until evidence from new studies of interventions to improve detection is available.
9th ed. 12, 750 s. : il.
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
691 s. : il., tab.
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
