IGF, PI3K and HIF-2 in Normal and Tumor Development

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Cells adapt to oxygen shortage, hypoxia, by inducing a transcriptional shift governed mainly by Hypoxia Inducible Factor (HIF)-1 and HIF-2. In various cancer forms, including neuroblastoma, high expression of HIF-2α correlates with disseminated disease and poor outcome. It has become evident that HIF-1 and HIF-2 are differentially regulated over time and by oxygen levels. HIF-2α is expressed in a subset of perivascularly located neuroblastoma cells in vivo and appear to be co-expressed with markers of early sympathetic nervous system development, while HIF-1α expression is restricted to necrotic and hypoxic tumor areas.
Here, we demonstrate that HIF-2α is regulated at the transcriptional level by the IGF and PI3K signaling pathways, two pathways commonly deregulated in human cancer. In addition, the expression of HIF-2α and IGF-II correlates in neuroblastoma specimens and cell lines, and the finding that HIF-2α and IGF-II are co-expressed in sympathetic neuroblasts during early human development (embryonic week 6.5) suggest that neuroblastoma cells are arrested at a differentiation stage corresponding to when sympathetic chain ganglia begin to coalesce.
We further show that the differential regulation of HIF-1α and HIF-2α in neuroblastoma partly can be explained by specific IGF and PI3K-mTOR signaling. While HIF-1α is exclusively regulated at the translational level via mTOR complex 1 (mTORC1) at hypoxia, HIF-2α is regulated at the transcriptional level by mTORC2, providing an opportunity to specifically target the HIF-2α-driven aggressive phenotype in neuroblastoma.
At last, PI3K is composed of a regulatory and a catalytic domain, and we highlight the complexity of this signaling pathway by identifying the catalytic subunit, p110δ, responsible for c-Kit mediated cell transformation, and the process of kinase-dependent and –independent activation.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Translational Medicine
Supervisors/Advisors
  • Påhlman, Sven, Supervisor
  • Jögi, Annika, Supervisor
Award date2013 Jun 14
Publisher
ISBN (Print)978-91-87449-37-6
Publication statusPublished - 2013

Bibliographical note

Defence details

Date: 2013-06-14
Time: 09:00
Place: CRC Main Lecture Hall, University Hospital MAS, Jan Waldenströms gata 35, Malmö

External reviewer(s)

Name: Giaccia, Amato
Title: [unknown]
Affiliation: Department of Radiation Oncology, Stanford University, Stanford, USA

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The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Molecular Medicine (013031200)

Subject classification (UKÄ)

  • Cancer and Oncology

Keywords

  • Neuroblastoma
  • Hypoxia
  • Insulin-like Growth Factor
  • PI3K
  • HIF-2alpha
  • Cancer
  • Development

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