Like a set of bookends, cellular, molecular, and genetic changes of the beginnings of life mirror those of one of the most common cause of death--metastatic cancer. Epithelial to mesenchymal transition (EMT) is an important change in cell phenotype which allows the escape of epithelial cells from the structural constraints imposed by tissue architecture, and was first recognized by Elizabeth Hay in the early to mid 1980's to be a central process in early embryonic morphogenesis. Reversals of these changes, termed mesenchymal to epithelial transitions (METs), also occur and are important in tissue construction in normal development. Over the last decade, evidence has mounted for EMT as the means through which solid tissue epithelial cancers invade and metastasize. However, demonstrating this potentially rapid and transient process in vivo has proven difficult and data connecting the relevance of this process to tumor progression is still somewhat limited and controversial. Evidence for an important role of MET in the development of clinically overt metastases is starting to accumulate, and model systems have been developed. This review details recent advances in the knowledge of EMT as it occurs in breast development and carcinoma and prostate cancer progression, and highlights the role that MET plays in cancer metastasis. Finally, perspectives from a clinical and translational viewpoint are discussed.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.21223

Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression.

Like a set of bookends, cellular, molecular, and genetic changes of the beginnings of life mirror those of one of the most common cause of death—metastatic cancer. Epithelial to mesenchymal transition (EMT) is an important change in cell phenotype which allows the escape of epithelial cells from the structural constraints imposed by tissue architecture, and was first recognized by Elizabeth Hay in the early to mid 1980's to be a central process in early embryonic morphogenesis. Reversals of these changes, termed mesenchymal to epithelial transitions (METs), also occur and are important in tissue construction in normal development. Over the last decade, evidence has mounted for EMT as the means through which solid tissue epithelial cancers invade and metastasize. However, demonstrating this potentially rapid and transient process in vivo has proven difficult and data connecting the relevance of this process to tumor progression is still somewhat limited and controversial. Evidence for an important role of MET in the development of clinically overt metastases is starting to accumulate, and model systems have been developed. This review details recent advances in the knowledge of EMT as it occurs in breast development and carcinoma and prostate cancer progression, and highlights the role that MET plays in cancer metastasis. Finally, perspectives from a clinical and translational viewpoint are discussed

Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression

The many ways of Wnt in cancer.

Homeobox genes comprise a large and essential family of developmental regulators that are vital for all aspects of growth and differentiation. Although many studies have reported their deregulated expression in cancer, few studies have established direct functional roles for homeobox genes in carcinogenesis. Nonetheless, most cases of deregulated homeobox gene expression in cancer conform to a simple rule: those that are normally expressed in undifferentiated cells are upregulated in cancer, whereas those that are normally expressed in differentiated tissues are downregulated in cancer.

Deregulated homeobox gene expression in cancer: cause or consequence?

Wilms' tumour, or nephroblastoma, is a common childhood tumour that is intimately linked to early kidney development and is often associated with persistent embryonic renal tissue and other kidney abnormalities. WT1, the first gene found to be inactivated in Wilms' tumour, encodes a transcription factor that functions as both a tumour suppressor and a critical regulator of renal organogenesis. Our understanding of the roles of WT1 in tumour formation and organogenesis have advanced in parallel, providing a striking example of the intersection between tumour biology, cellular differentiation and normal organogenesis.

Wilms' tumour: connecting tumorigenesis and organ development in the kidney.

Wilms’ tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649–5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF.

/pdf/gene-expression-in-wilms-tumor-mimics-the-earliest-committed-1t270ilb26.pdf

Gene Expression in Wilms’ Tumor Mimics the Earliest Committed Stage in the Metanephric Mesenchymal-Epithelial Transition

Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.

CTNNB1 mutations and overexpression of Wnt/β-catenin target genes in WT1-mutant Wilms' tumors

Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78MX1 protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects.

/pdf/cell-type-specific-over-expression-of-chromosome-21-genes-in-4gjgiq7iwl.pdf

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

Using vehicle-to-grid (V2G) technology to balance power load fluctuations is gaining attention from governments and commercial enterprises. We address a valuable research gap from a new perspective by examining whether electrochemical energy storage can completely replace V2G technology in terms of balancing grid load fluctuations. Specifically, we evaluate the benefits of power grid from the perspective of electrochemical energy storage replacement and explore the practical application potential to determine whether V2G technology can benefit both power grids and electric vehicles (EVs). The research results are mixed. The positive results are as follows: a) Power grid companies and EVs can achieve a win-win strategy, and V2G technology can transfer 2.7 % to 4.3 % of charging load from peak to off-peak periods at a city level; b) Based on simulations, the transferable electricity through V2G increases from 50 MWh in 2019 to 330 MWh each day in Beijing. The negative results are as follows: a) The transferred electricity achieved through V2G is extremely small compared with the EV charging load, and this low ratio cannot be improved effectively over time; b) A more flexible charging price or lower cost for power batteries and electrochemical storage cannot significantly help improve the relatively limited transferable load. The results show that the daily transferable electricity is stable at 330MWh. 

Meirong Guo

Papers

Gene Expression in Wilms’ Tumor Mimics the Earliest Committed Stage in the Metanephric Mesenchymal-Epithelial Transition

CTNNB1 mutations and overexpression of Wnt/β-catenin target genes in WT1-mutant Wilms' tumors

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

An economic evaluation of electric vehicles balancing grid load fluctuation, new perspective on electrochemical energy storage alternative