NOTCH pathway inactivation promotes bladder cancer progression.

@article{Maraver2015NOTCHPI,
  title={NOTCH pathway inactivation promotes bladder cancer progression.},
  author={Antonio Maraver and Pablo J. Fernandez-Marcos and Timothy P. Cash and Marinela M{\'e}ndez-Pertuz and Marta Due{\~n}as and Paolo Maietta and Paola Martinelli and M. {\'A}ngeles Mu{\~n}oz-Mart{\'i}n and M{\'o}nica Mart{\'i}nez-Fern{\'a}ndez and Marta Ca{\~n}amero and Giovanna Roncador and Jorge L. Mart{\'i}nez-Torrecuadrada and Dimitri A. Grivas and Jos{\'e} Luis de la Pompa and Alfonso Valencia and Jes{\'u}s M. Paramio and Francisco X. Real and Manuel Serrano},
  journal={The Journal of clinical investigation},
  year={2015},
  volume={125 2},
  pages={
          824-30
        }
}
NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial… 

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It is reported that the genetic inactivation of Notch in mice leads to downregulation of cell-cell and cell-ECM interaction components, including proteins previously implicated in interstitial cystitis/bladder pain syndrome, structural defects and mucosal sloughing, inflammation, and leaky urine-blood barrier.

Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer

A new concept for BC therapy is proposed, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.

WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma.

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References

SHOWING 1-10 OF 55 REFERENCES

Inactivation of p53 and Pten promotes invasive bladder cancer.

It is shown that combined deletion of p53 and Pten in bladder epithelium leads to invasive cancer in a novel mouse model, consistent with the ability of rapamycin to block bladder tumorigenesis in preclinical studies.

Alterations of the Notch pathway in lung cancer

It is shown that Notch signaling is altered in approximately one third of non–small-cell lung carcinomas (NSCLCs), which are the leading cause of cancer-related deaths, and it is suggested that it might represent a possible target for molecular therapies in these tumors.

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma

The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer.

It is shown that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate bladder cancer development and the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.

Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma

It is found that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.

Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia

Findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.

Immunohistochemical analysis of the role and relationship between Notch‐1 and Oct‐4 expression in urinary bladder carcinoma

Stromal expression of Notch‐1 may have a bad impact, possibly through up‐regulation of the active nuclear form of Oct‐4 in carcinoma cells, which may cooperate in the progression of bladder carcinoma by acquiring aggressive features, such as a liability for recurrence and dissemination.

Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia

These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

High expression of Notch ligand Jagged2 is associated with the metastasis and recurrence in urothelial carcinoma of bladder.

Jagged2 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas and played an important function on the bladder cancer cells' proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastases of bladder cancer.
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