ABSTRACT
Although deregulation of the Wnt signalling pathway has been implicated in urothelial cell carcinoma (UCC), the functional significance is unknown. To test its importance, we have targeted expression of an activated form of ß-catenin to the urothelium of transgenic mice using Cre-Lox technology (UroIICRE(+) ß-catenin(exon3/+)). Expression of this activated form of ß-catenin led to the formation of localized hyperproliferative lesions by 3 months, which did not progress to malignancy. These lesions were characterized by a marked increase of the phosphatase and tensin homologue (PTEN) tumour suppressor protein. This appears to be a direct consequence of activating Wnt signalling in the bladder as conditional deletion of the adenomatous polyposis coli (Apc) gene within the adult bladder led rapidly to coincident ß-catenin and PTEN expression. This PTEN expression blocked proliferation. Next, we combined PTEN deficiency with ß-catenin activation and found that this caused papillary UCC. These tumours had increased pAKT signalling and were dependent on mammalian target of rapamycin (mTOR). Importantly, in human UCC, there was a significant correlation between high levels of ß-catenin and pAKT (and low levels of PTEN). Taken together these data show that deregulated Wnt signalling has a critical role in promoting UCC, and suggests that human UCC that have high levels of Wnt and PI3 kinase signalling may be responsive to mTOR inhibition.
Subject(s)
Carcinoma, Papillary/metabolism , Cell Transformation, Neoplastic/metabolism , PTEN Phosphohydrolase/metabolism , Urinary Bladder Neoplasms/chemically induced , beta Catenin/metabolism , Adenomatous Polyposis Coli Protein/genetics , Animals , Cell Proliferation , Cohort Studies , Female , Humans , Hyperplasia/chemically induced , Male , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/analysis , Proto-Oncogene Proteins c-akt/metabolism , Sequence Deletion , TOR Serine-Threonine Kinases/metabolism , Urinary Bladder/metabolism , Urothelium/metabolism , Wnt Proteins/metabolismABSTRACT
PIP: Population aging has started late in Romania but has increased rapidly in the last few decades. The share of the population aged 60 and over reached 17% in 1992 and the decline in fertility after 1989 will considerably increase this share in the future. The author provides a detailed analysis of the present economic and social situation of the elderly in Romania. Factors such as the economic crisis, and particularly the deterioration of the standard of living, the very low income (pension) level, the high rate of inflation, and the lack of appropriate medical care have pushed most of the aged population into poverty. According to recent surveys, 1.5 million people out of the 3.8 million aged 60 and over live below the poverty line.^ieng
Subject(s)
Aged , Birth Rate , Income , Inflation, Economic , Population Dynamics , Poverty , Socioeconomic Factors , Adult , Age Factors , Demography , Developed Countries , Economics , Europe , Europe, Eastern , Fertility , Population , Population Characteristics , RomaniaABSTRACT
PIP: The author analyzes trends in permanent emigration from Romania since the fall of the Ceaucescu government at the end of 1989. Emigrant characteristics are described.^ieng
