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GSE45164
Homo sapiens
13 Downloadable Samples
Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Skin squamous cell carcinomas are among the most frequent human cancers. In this study we compared the expression profiles of 10 skin SCCs with a set of 3 normal human epidermis controls.
Publication Title
Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.
Sample Metadata Fields
Disease, Disease stage
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-JK, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.
Publication Title
Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J-kappa in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, with p53 activation providing a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblasts senescence, enhances CAF effector gene expression and, in vivo, promotes stromal and cancer cell expansion. Together, these findings support a CAF activation/stromal evolution model under convergent CSL/p53 control.
Publication Title
Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We report here that Notch1 expression is significantly reduced in a substantial fraction of human PCas, while it is unaffected or even increased in others. Global analysis of gene expression shows that increased Notch1 expression in PCa cells or samples, while counteracting to a significant extent the abnormal program of gene expression that is characteristically altered in clinically occurring tumors, enhances some other aberrant aspects of this program. In particular, down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity. While control of p21Cip1/WAF1 expression by increased Notch1 activity through a Smad3-dependent mechanism can explain the growth inhibitory effects, pro-oncogenic genes, like EPAS1 and CXCL6, are concomitantly up-regulated by Notch in PCa cell lines resistant to Notch1 growth inhibition, in agreement with enhanced tumorigenic behavior.
Publication Title
No associated publication
Sample Metadata Fields
Cell line
View Samples