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Notch Signaling in Neuroblastoma and Renal Cell Carcinoma

Sjölund, Jonas LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:8.
Abstract
The Notch signaling pathway governs cell functions essential for normal development and organogenesis. Aberrant Notch signaling has been implicated in tumorigenesis by perturbing control of proliferation, differentiation, apoptosis, migration and angiogenesis.

Neuroblastoma is an embryonal tumor derived from cells of the sympathetic nervous system, arrested at an immature stage of differentiation. Notch signaling is thought to play an important role during the development of the sympathetic nervous system, and prior studies have indicated that dysregulated Notch signaling might be associated with the perturbed differentiation that characterize neuroblastoma cells. Here we show that the histone deacetylase inhibitor valproic acid... (More)
The Notch signaling pathway governs cell functions essential for normal development and organogenesis. Aberrant Notch signaling has been implicated in tumorigenesis by perturbing control of proliferation, differentiation, apoptosis, migration and angiogenesis.

Neuroblastoma is an embryonal tumor derived from cells of the sympathetic nervous system, arrested at an immature stage of differentiation. Notch signaling is thought to play an important role during the development of the sympathetic nervous system, and prior studies have indicated that dysregulated Notch signaling might be associated with the perturbed differentiation that characterize neuroblastoma cells. Here we show that the histone deacetylase inhibitor valproic acid induced differentiation of neuroblastoma cells, in conjunction with activation of Notch-1 signaling. In addition, we also noted that the expression of the Notch target HES-1 was primarily regulated by ERK-MAP kinase signaling in a neuroblastoma cell line.

Clear cell renal cell carcinoma (CCRCC) is characterized by activation of the hypoxia inducible factor (HIF) pathway due to functional loss of the von Hippel-Lindau tumor suppressor gene. However, cooperating oncogenic events parallel to the HIF pathway remains poorly described. Our results presented here imply a growth-promoting role for Notch signaling in CCRCC cells, seemingly independent of HIF-regulated cellular events. Treatment of nude mice bearing CCRCC xenografts, with daily injections of a Notch inhibitor (γ-secretase inhibitor) in cycles of 3 days followed by 4 days without treatment, retarded tumor growth and minimized the adverse effects commonly associated with γ-secretase inhibition. In addition, analysis of primary CCRCC samples revealed that Notch-1 and Jagged-1 were expressed at significantly higher levels compared to normal kidney tissue samples. Finally, we found that inhibition of Notch signaling decreased the migratory potential of CCRCC cells. This effect might be linked to a cross-talk between Notch and TGF-β signaling in CCRCC cells. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Eberhart, Charles G., Johns Hopkins University School of Medicine
organization
publishing date
type
Thesis
publication status
published
subject
keywords
differentiation, clear cell renal cell carcinoma, neuroblastoma, TGF-beta, migration, γ-secretase, valproic acid, cancer, Notch, ERK, von Hippel-Lindau, hypoxia
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:8
pages
60 pages
publisher
Molecular Tumour Biology
defense location
Main lecture hall, Pathology building, Malmö University Hospital
defense date
2008-02-15 09:15
ISSN
1652-8220
ISBN
978-91-85897-61-2
language
English
LU publication?
yes
id
abafd141-06dc-40ae-b0c4-5972fc194c62 (old id 949628)
date added to LUP
2008-01-29 15:25:35
date last changed
2016-09-19 08:44:46
@phdthesis{abafd141-06dc-40ae-b0c4-5972fc194c62,
  abstract     = {The Notch signaling pathway governs cell functions essential for normal development and organogenesis. Aberrant Notch signaling has been implicated in tumorigenesis by perturbing control of proliferation, differentiation, apoptosis, migration and angiogenesis.<br/><br>
	Neuroblastoma is an embryonal tumor derived from cells of the sympathetic nervous system, arrested at an immature stage of differentiation. Notch signaling is thought to play an important role during the development of the sympathetic nervous system, and prior studies have indicated that dysregulated Notch signaling might be associated with the perturbed differentiation that characterize neuroblastoma cells. Here we show that the histone deacetylase inhibitor valproic acid induced differentiation of neuroblastoma cells, in conjunction with activation of Notch-1 signaling. In addition, we also noted that the expression of the Notch target HES-1 was primarily regulated by ERK-MAP kinase signaling in a neuroblastoma cell line.<br/><br>
	Clear cell renal cell carcinoma (CCRCC) is characterized by activation of the hypoxia inducible factor (HIF) pathway due to functional loss of the von Hippel-Lindau tumor suppressor gene. However, cooperating oncogenic events parallel to the HIF pathway remains poorly described. Our results presented here imply a growth-promoting role for Notch signaling in CCRCC cells, seemingly independent of HIF-regulated cellular events. Treatment of nude mice bearing CCRCC xenografts, with daily injections of a Notch inhibitor (γ-secretase inhibitor) in cycles of 3 days followed by 4 days without treatment, retarded tumor growth and minimized the adverse effects commonly associated with γ-secretase inhibition. In addition, analysis of primary CCRCC samples revealed that Notch-1 and Jagged-1 were expressed at significantly higher levels compared to normal kidney tissue samples. Finally, we found that inhibition of Notch signaling decreased the migratory potential of CCRCC cells. This effect might be linked to a cross-talk between Notch and TGF-β signaling in CCRCC cells.},
  author       = {Sjölund, Jonas},
  isbn         = {978-91-85897-61-2},
  issn         = {1652-8220},
  keyword      = {differentiation,clear cell renal cell carcinoma,neuroblastoma,TGF-beta,migration,γ-secretase,valproic acid,cancer,Notch,ERK,von Hippel-Lindau,hypoxia},
  language     = {eng},
  pages        = {60},
  publisher    = {Molecular Tumour Biology},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Notch Signaling in Neuroblastoma and Renal Cell Carcinoma},
  volume       = {2008:8},
  year         = {2008},
}