Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Rat visceral yolk sac (VYS) and placenta mitochondrial features during the placentation period.

The transference of the nutritional function from the VYS to the chorioallantoic placenta during middle pregnancy is a key event for the activation of embryo oxidative metabolism. However, the metabolic adaptations occurring in these tissues during this critical period have not been studied to date. Herein, we investigate the VYS and placenta mitochondrial adaptations throughout gestational days 11, 12 and 13. The results reflect that, during the placentation period, mitochondrial proliferation predominates over differentiation in placenta. Besides, VYS development and mitochondriogenesis show a slowdown despite maintaining the mitochondrial OXPHOS capacities, hence becoming a supporting tissue until the placenta functions are completely available.

Mitochondrial differentiation and oxidative phosphorylation system capacity in rat embryo during placentation period.

Mitochondrial biogenesis and function are essential for proper embryo development; however, these processes have not been further studied during the placentation period, when important oxidative metabolism activation is taking place. Thus, the aim of the present study was to investigate the oxidative phosphorylation system (OXPHOS) enzymatic activities as well as the expression of genes involved in the coordinated regulation of both mitochondrial and nuclear genomes (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, nuclear respiratory factors 1 and 2, mitochondrial single-strand DNA-binding protein, mitochondrial transcription factor A), and mitochondrial function (cytochrome c oxidase subunit IV, cytochrome c oxidase subunit I and beta-ATP phosphohydrolase) in rat embryo throughout the placentation period (gestational days 11, 12 and 13). Our results reflect that embryo mitochondria were enhancing their OXPHOS potential capacities, pointing out that embryo mitochondria become more differentiated during the placentation period. Besides, the current findings show that the mRNAs of the nuclear genes involved in mitochondrial biogenesis were downregulated, whereas their protein content together with the mitochondrial DNA expression were upregulated throughout the period studied. These data indicate that the molecular regulation of the mitochondrial differentiation process during placentation involves a post-transcriptional activation of the nuclear-encoded genes that would lead to an increase in both the nuclear- and mitochondrial-encoded proteins responsible for the mitochondrial biogenic process. As a result, embryo mitochondria would reach a more differentiated stage with a more efficient oxidative metabolism that would facilitate the important embryo growth during the second half of the pregnancy.

Sex-related differences in energy balance in response to caloric restriction.

Sex-related differences in energy balance were studied in young Wistar rats fed standard chow pellets either ad libitum or in restricted amounts (60% of ad libitum intake) for 100 days. Caloric intake, indirect calorimetry, organ and adipose tissue weights, energy efficiency, liver mitochondrial respiration rate, and brown adipose tissue (BAT) uncoupling protein-1 (UCP1) content were measured. Ad libitum-fed females showed greater oxygen consumption (Vo(2)) and carbon dioxide production (Vco(2)) and lower energy efficiency than males. Caloric restriction induced a chronic drop of Vo(2) and Vco(2) in females but not in males over the period studied. Restricted females showed a better conservation of metabolic active organ mass and a greater decrease in adipose depots than restricted males. Moreover, changes of BAT size and UCP1 content suggest that BAT may be the main cause responsible for sex differences in the response of energy balance to caloric restriction. In conclusion, our results indicate that females under caloric restriction conditions deactivate facultative thermogenesis to a greater degree than males. This ability may have obvious advantages for female survival and therefore the survival of the species when food is limiting.

Morphofunctional changes in the mitochondrial subpopulations of conceptus tissues during the placentation process.

To establish the role of mitochondrial subpopulations in the mitochondrial maturation process, we studied morphological and functional changes in the mitochondria of different mammalian conceptus tissues during the organogenic and the placentation processes. Mitochondrial subpopulations of three different conceptus tissues, embryo and visceral yolk sac placenta on gestational days 11, 12 and 13 and placenta on days 12 and 13, were examined morphologically by transmission electron microscopy. Cytochrome oxidase activity and protein levels were also measured in each mitochondrial subpopulation. The results indicate two different mitochondrial subpopulation profiles: a homogeneous one, which corresponds to immature mitochondria, and a heterogeneous one, which represents the mature mitochondria. The three tissues studied show different morphologic and metabolic patterns of mitochondrial maturation during the placentation process, rendering them suitable as experimental models to establish the possible relationship between mitochondrial maturation and the mitochondrial subpopulations.