A new tumor suppressor role for the Notch pathway in bladder cancer

Ράμπιας, Θεόδωρος; Vgenopoulou, Paraskevi; Avgeris, Margaritis; Polyzos, Alexander; Stravodimos, Konstantinos; Valavanis, Christos; Scorilas, Andreas; Klinakis, Apostolos

doi:10.1038/nm.3678

Cited by 162 publications

(144 citation statements)

References 35 publications

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“…Furthermore, we have demonstrated the proof of concept that these findings can be translated into a therapeutic strategy for patients with bladder cancer by studying the effects of a NOTCH2 inactivating antibody, NRR2Mab. Our results are particularly timely as they build on three recent reports suggesting that NOTCH is a tumor suppressor in bladder cancer (12)(13)(14).…”

Section: Introductionsupporting

confidence: 55%

Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy

Hayashi

Gust

Wyatt

et al. 2016

Clinical Cancer Research

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Purpose: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1. Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer.Experimental design: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo.Results: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model. Conclusions:We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer.

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Section: Introductionsupporting

confidence: 55%

Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy

Hayashi

Gust

Wyatt

et al. 2016

Clinical Cancer Research

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“…It may be fruitful to target this broader Notch pathway to gain a more panoramic understanding of the important role of Notch in SCCs. A nice example is a recent research on the tumor suppressor role of Notch pathway in bladder cancer, revealed by the characterization of multiple components of Notch pathway 100. We have recently characterized a Notch‐modifying enzyme Xxylt1 101 that is frequently amplified in specific cancer types lacking loss‐of‐function XXYLT1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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“…Interestingly, Notch signaling previously has been reported to function as both a tumor suppressor and an oncogene (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The dependency of Notch1 function in cancer may be tissue specific and context dependent (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Loss-offunction mutations in Notch receptors support their tumor-suppressive role in multiple malignances, including bladder cancer and squamous cell carcinoma (22)(23)(24).…”

Section: Significancementioning

confidence: 99%

“…The dependency of Notch1 function in cancer may be tissue specific and context dependent (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Loss-offunction mutations in Notch receptors support their tumor-suppressive role in multiple malignances, including bladder cancer and squamous cell carcinoma (22)(23)(24). Constitutive activation of the Notch receptors through gene rearrangements or mutations leads to Notch receptors' oncogenic function in 55-60% of patients with T-cell acute lymphoblastic leukemia (26,27).…”

Section: Significancementioning

confidence: 99%

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova

Riedinger

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

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A new tumor suppressor role for the Notch pathway in bladder cancer

Cited by 162 publications

References 35 publications

Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy

Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

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