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TGF-B signaling in Neuroblastoma and Renal Cell Carcinoma

Boström, Anna-Karin LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:17.
Abstract
The tubular cells of the adult kidney are normally mitotically quiescent, in stark contrast to the massive regenerative capacity of the injured renal epithelium. In Paper I we characterized a new cell population of progenitor cells using ALDH as a selection marker. These cells are situated in the proximal tubular epithelium and are called proximal tubular progenitor cells (PTPCs). Gene expression analysis of the PTPCs together with functional and immunohistochemical studies revealed that these cells might be responsible for the regeneration of damaged tubular epithelium.

Clear cell RCC (ccRCC) is the most common type of RCC and is characterized by loss of function of the tumor suppressor gene von Hippel-Lindau (VHL). In Paper II... (More)
The tubular cells of the adult kidney are normally mitotically quiescent, in stark contrast to the massive regenerative capacity of the injured renal epithelium. In Paper I we characterized a new cell population of progenitor cells using ALDH as a selection marker. These cells are situated in the proximal tubular epithelium and are called proximal tubular progenitor cells (PTPCs). Gene expression analysis of the PTPCs together with functional and immunohistochemical studies revealed that these cells might be responsible for the regeneration of damaged tubular epithelium.

Clear cell RCC (ccRCC) is the most common type of RCC and is characterized by loss of function of the tumor suppressor gene von Hippel-Lindau (VHL). In Paper II and III we investigated the role of Notch and TGF-β signaling in ccRCC. Here we reported a cross talk between the two pathways and demonstrated a correlation between elevated TGF-β activity and worse prognosis in ccRCC patients. This correlation, in corroboration with functional migration and proliferation data, suggested that ccRCC cells have escaped the cytostatic effects of TGF-β signaling and that TGF-β instead increases the metastatic potential of ccRCCs.

Sarcomatoid areas can occasionally be found in all types of renal malignancies and patients displaying sarcomatoid features have a very poor prognosis. In Paper IV we analyzed six ccRCC cases with sarcomatoid areas and show that sarcomatoid RCC demonstrate an enhanced expression of epithelial-to-mesenchymal transition (EMT)-related markers as compared to the ccRCC counterparts and that TGF-β might be the driving force behind this process.

Neuroblastoma (NB) is a tumor arising the sympathetic nervous system in children and high-risk NBs are characterized by increased MYC-N/MYC activity. In Paper V we examined the protein response upon activation of the micro-RNA cluster miR-17-92 in NB using quantitative mass spectrometry. We showed that activation of the miR-17-92 cluster affected multiple oncogenic pathways including key effectors of the TGF-β signaling cascade. We report a connection between elevated expression of miR-17-92, low TGF-β signaling, and decreased patient survival. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • M.D, Ph.D Moch, Holger, Institute of Surgical Pathology, Zurich, Switzerland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Renal Cell Carcinoma, ATN, Regeneration, Notch, TGF-B, EMT, Neuroblastoma, MYCN, miR-17-92
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:17
pages
146 pages
publisher
Center for Molecular Pathology, Faculty of Medicine
defense location
Main lecture hall, Pathology building, Skåne University Hospital, Malmö
defense date
2012-03-02 09:15
ISSN
1652-8220
ISBN
978-91-86871-79-6
language
English
LU publication?
yes
id
61ed2312-87bf-4bd5-8674-9f6d7e466e90 (old id 2339761)
date added to LUP
2012-02-14 11:18:55
date last changed
2016-09-19 08:44:50
@phdthesis{61ed2312-87bf-4bd5-8674-9f6d7e466e90,
  abstract     = {The tubular cells of the adult kidney are normally mitotically quiescent, in stark contrast to the massive regenerative capacity of the injured renal epithelium. In Paper I we characterized a new cell population of progenitor cells using ALDH as a selection marker. These cells are situated in the proximal tubular epithelium and are called proximal tubular progenitor cells (PTPCs). Gene expression analysis of the PTPCs together with functional and immunohistochemical studies revealed that these cells might be responsible for the regeneration of damaged tubular epithelium.<br/><br>
Clear cell RCC (ccRCC) is the most common type of RCC and is characterized by loss of function of the tumor suppressor gene von Hippel-Lindau (VHL). In Paper II and III we investigated the role of Notch and TGF-β signaling in ccRCC. Here we reported a cross talk between the two pathways and demonstrated a correlation between elevated TGF-β activity and worse prognosis in ccRCC patients. This correlation, in corroboration with functional migration and proliferation data, suggested that ccRCC cells have escaped the cytostatic effects of TGF-β signaling and that TGF-β instead increases the metastatic potential of ccRCCs. <br/><br>
Sarcomatoid areas can occasionally be found in all types of renal malignancies and patients displaying sarcomatoid features have a very poor prognosis. In Paper IV we analyzed six ccRCC cases with sarcomatoid areas and show that sarcomatoid RCC demonstrate an enhanced expression of epithelial-to-mesenchymal transition (EMT)-related markers as compared to the ccRCC counterparts and that TGF-β might be the driving force behind this process.<br/><br>
Neuroblastoma (NB) is a tumor arising the sympathetic nervous system in children and high-risk NBs are characterized by increased MYC-N/MYC activity. In Paper V we examined the protein response upon activation of the micro-RNA cluster miR-17-92 in NB using quantitative mass spectrometry. We showed that activation of the miR-17-92 cluster affected multiple oncogenic pathways including key effectors of the TGF-β signaling cascade. We report a connection between elevated expression of miR-17-92, low TGF-β signaling, and decreased patient survival.},
  author       = {Boström, Anna-Karin},
  isbn         = {978-91-86871-79-6},
  issn         = {1652-8220},
  keyword      = {Renal Cell Carcinoma,ATN,Regeneration,Notch,TGF-B,EMT,Neuroblastoma,MYCN,miR-17-92},
  language     = {eng},
  pages        = {146},
  publisher    = {Center for Molecular Pathology, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {TGF-B signaling in Neuroblastoma and Renal Cell Carcinoma},
  volume       = {2012:17},
  year         = {2012},
}