Notch signaling in pediatric malignancies

Zweidler‐McKay, Patrick A.

doi:10.1007/s11912-008-0071-2

Cited by 30 publications

(26 citation statements)

References 50 publications

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“…Notch signaling is involved in many developmental systems, including but not limited to neurogenesis, angiogenesis, hematopoiesis, and myogenesis (3). Notch signaling members include multiple transmembrane receptors and ligands that function through direct cell surface contact.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Belyea

Naini

Bentley

et al. 2011

Clinical Cancer Research

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Purpose Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and remains refractory to combined-modality therapy in patients with high risk disease. In skeletal myogenesis, Notch signaling prevents muscle differentiation and promotes proliferation of satellite cell progeny. Given its physiologic role in myogenesis and oncogenic role in other human cancers, we hypothesized that aberrant Notch signaling may contribute to RMS tumorigenesis and present novel therapeutic opportunities. Experimental Design Human RMS cell lines and tumors were evaluated by immunoblot, IHC, and RT-PCR to measure Notch ligand, receptor, and target gene expression. Manipulation of Notch signaling was accomplished using genetic and pharmacologic approaches. In vitro cell growth, proliferation, and differentiation were assessed using colorimetric MTT and BrdU assays, and biochemical/morphologic changes after incubation in differentiation-promoting media, respectively. In vivo tumorigenesis was assessed using xenograft formation in SCID/beige mice. Results Notch signaling is upregulated in human RMS cell lines and tumors compared to primary skeletal muscle, especially in the embryonal (eRMS) subtype. Inhibition of Notch signaling using Notch1 RNAi or γ-secretase inhibitors reduced eRMS cell proliferation in vitro. Hey1 RNAi phenocopied Notch1 loss and permitted modest myogenic differentiation, while over-expression of an activated Notch moiety, ICN1, promoted eRMS cell proliferation and rescued pharmacologic inhibition. Finally, Notch inhibition using RNAi or γ-secretase inhibitors blocked tumorigenesis in vivo. Conclusions Aberrant Notch-Hey1 signaling contributes to eRMS by impeding differentiation and promoting proliferation. The efficacy of Notch pathway inhibition in vivo supports the development of Notch-Hey1 axis inhibitors in the treatment of eRMS.

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Section: Introductionmentioning

confidence: 99%

“…In contrast, the Notch signaling pathway functions as a tumor suppressor in some type of malignancies including B cell leukemia (3). The role of Notch signaling in tumorigenesis likely varies in different cell types and depends in part on tissue contexts (3, 10). …”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Belyea

Naini

Bentley

et al. 2011

Clinical Cancer Research

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“…The NICD-RBP-J-MAML complex induces transcription of Notch effectors such as the Hes and Hey family members, which are themselves transcription factors that go on to regulate the expression of downstream Notch targets. 8,9 The Notch ligand DLL4 is essential for vascular formation. 10,11 When DLL4 is inhibited in developing mouse retinas or in xenograft tumor models such as colon and lung carcinoma, excessive proliferation of nonfunctional vasculature occurs.…”

Section: Introductionmentioning

confidence: 99%

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Stewart

Zhou

Zweidler‐McKay

et al. 2011

Blood

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Delta-like ligand 4 (DLL4) is essential for the formation of mature vasculature. However, the role of DLL4-Notch signaling in pericyte/vascular smooth muscle cell (vSMC) development is poorly understood. We sought to determine whether DLL4-Notch signaling is involved in pericyte/vSMC formation in vitro and during vasculogenesis in vivo using 2 Ewing sarcoma mouse models. Inhibition of DLL4 with the antibody YW152F inhibited pericyte/vSMC marker expression by bone marrow (BM) cells in vitro. Conversely, transfection of 10T1/2 cells with the active domains of Notch receptors led to increased expression of pericyte/vSMC markers. Furthermore, the blood vessels of Ewing sarcoma tumors from mice treated with YW152F had reduced numbers of BM-derived pericytes/vSMCs, fewer open lumens, and were less functional than the vessels in tumors of control-treated mice. Tumor growth was also inhibited. These data demonstrate a specific role for DLL4 in the formation of BM-derived pericytes/vSMCs and indicate that DLL4 may be a novel therapeutic target for the inhibition of vasculogenesis.

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“…The group analyzed by Das Gupta contained a relatively higher proportion of T-ALL cases, which is characteristic for the Indian subcontinent. The involvement of Notch and PI3K/Akt signaling in the development of some B-lineage acute lymphoblastic leukemia cases is emerging in the literature [39,40,43]. Diversity of CD71 expression among lymphoblastic leukemias originating from the B-lineage observed in this study might indicate different levels of PI3K/Akt/mTOR pathway activity in this group [44].…”

Section: Discussionmentioning

confidence: 63%

“…In this context, high expression of CD71 on T-cell malignancies is not surprising as the importance of Notch signaling for T cell development has been well established [37]. Gain of function mutations of NOTCH [39,40] as well as inactivating mutations of the suppressor PTEN and increased activity of PI3K/Akt pathway have been frequently identified in T cell ALL [41].…”

Section: Discussionmentioning

confidence: 99%

Cytometric evaluation of transferrin receptor 1 (CD71) in childhood acute lymphoblastic leukemia

Płoszyńska

Rückemann-Dziurdzińska

Jóźwik

et al. 2012

Folia Histochem Cytobiol.

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Abstract:Transferrin receptor 1 (CD71) is a transmembrane glycoprotein responsible for cellular iron uptake. Higher expression of CD71 has been identified as a negative prognostic marker for numerous solid tumor types and for some lymphomas. The aim of this study was to evaluate CD71 expression on acute lymphoblastic leukemia (ALL) cells and to follow its possible clinical correlations. Sixty one patients, aged 1-17 years and diagnosed with ALL, were enrolled in the study. CD71 expression was analyzed on the bone marrow blastic cells by flow cytometry. CD71 expression on the leukemic blasts was diversified; in most patients, all blastic cells showed expression of CD71, but levels of expression varied. CD71 expression was statistically higher on T-lineage leukemias. Within the B lineage ALL, a significant difference in CD71 expression existed between precursor B ALL and mature B-ALL, which showed higher CD71 expression. CD71 expression positively correlated with Hgb concentration at diagnosis. Initial risk group assessment and therapy response were not correlated with CD71 expression, although disease free and overall survival times tended to be shorter in patients with B-lineage leukemias with initial high CD71 expression.

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Notch signaling in pediatric malignancies

Cited by 30 publications

References 50 publications

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Cytometric evaluation of transferrin receptor 1 (CD71) in childhood acute lymphoblastic leukemia

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