It is unclear how the loss of TGF-b signaling components affects metastatic abilities in clear cell renal cell carcinoma (ccRCC). In this study, we identified that low TGFBR3 expression in ccRCC cells enhanced primary tumor formation and lung metastasis. In the presence of TGFBR3, TGF-b2 decreased the aldehyde dehydrogenase (ALDH)-positive ccRCC cell population, in which renal cancer-initiating cells are enriched. Loss of TGFBR3 also enhanced cell migration in cell culture and induced expression of several mesenchymal markers in a TGF-b-independent manner. Increased lamellipodium formation by FAK-PI3K signaling was observed with TGFBR3 downregulation, and this contributed to TGF-b-independent cell migration in ccRCC cells. Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-b-dependent and independent pathways. Overall design: Target genes for TGF-b2 and TGFBR3 in ccRCC cells were identified.
Decreased TGFBR3/betaglycan expression enhances the metastatic abilities of renal cell carcinoma cells through TGF-β-dependent and -independent mechanisms.
Cell line, Subject
View SamplesTumor microenvironment plays a pivotal role in cancer progression; however, little is known regarding how differences in the microenvironment affect characteristics of cancer cells. Here, we investigated the effects of tumor microenvironment on cancer cells by using mouse tumor models. After 3 cycles of inoculation and extraction of human pancreatic cancer cells, including SUIT-2 and Panc-1 cells, from tumors, distinct cancer cell lines were established; 3P cells from the pancreas obtained using the orthotopic tumor model, and 3sc cells from subcutaneous tissue obtained using the subcutaneous tumor model. On cell re-inoculation of these cells, the 3sc cells and, more prominently, the 3P cells, exhibited higher tumorigenic activity than the parental cells. The 3P cells specifically exhibited low E-cadherin expression and high invasiveness, suggesting that they were endowed with the highest malignant characteristics. RNA-sequence analysis demonstrated that distinct signaling pathways were activated in each cell line and that the 3P cells acquired a cancer stem cell-like phenotype. Among cancer stem cell-related genes, those specifically expressed in the 3P cells, including NES, may be potential new targets for cancer therapy. The mechanisms underlying the development of highly malignant cancer cell lines were investigated. Individual clones within the parental cells varied in tumor-forming ability, indicating the presence of cellular heterogeneity. Moreover, the gene expression profile of each clone changed after orthotopic inoculation. The present study thus suggests that both selection and education processes are involved in the development of highly malignant cancer cells. Overall design: Expression of mRNA in the highly malignant sublines of SUIT-2 and Panc-1 cells xenografted into mice.
Pancreatic tumor microenvironment confers highly malignant properties on pancreatic cancer cells.
Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program.
Specimen part, Cell line
View SamplesWe demonstrate that activation of Ras and TGF- pathways strengthens the binding of p63 to its genomic sites and modulates the expression of p63 target genes.
Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program.
Cell line
View SamplesLoss or reduction in function of tumor suppressor genes contributes to tumorigenesis. We identified a novel homozygous deletion of DACH1 in gliomas.
Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells.
Specimen part, Cell line
View SamplesWe searched for roles of ZEB1 during EMT by RNA-seq in breast cancer cells. Overall design: Expression of mRNA in a basal type breast cancer cell line MDA-231-D transfected with ZEB1/ZEB2 siRNAs and stimulated with TGF-beta for 24 h.
ZEB1-regulated inflammatory phenotype in breast cancer cells.
Specimen part, Cell line, Subject
View SamplesR-spondin1 (Rspo1) is a member of a secreted protein family which has pleiotropic functions in development and stem cell growth. Rspo1 knock-out mice are sex-reversed, but some remain sub-fertile, so, they are unable to nurse their pups. A lack of Rspo1 expression in mammary epithelial cells results in an absence of duct side-branching development and defective alveolar formation. In this study we propose to characterize the molecular functions involved to mammary gland phenotype due to Rspo1 knock out. By transcriptional profiling, we have identified gene misregulated in mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of genes characterising mesenchymal tissue was observed in the absence of alterations to the structure of mammary epithelial tissue. Mammary epithelial cell characterization, by immunohistochemistry approach, revealed a persistence of virgin markers which sign a delay in their differentiation. Moreover serial transplantation experiments show that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our data have also highlighted that in mammary gland during pregnancy the expression of Rspo1s partners, Lgr4 and RNF43, are negatively regulated and Tgf- signaling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt in mammary development at mid-pregnancy due to loss of further differentiated function.
Phenotypic and Molecular Alterations in the Mammary Tissue of R-Spondin1 Knock-Out Mice during Pregnancy.
Sex, Specimen part
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