Selective AKT inhibition by MK-2206 represses colorectal cancer-initiating stem cells

Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemo
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.
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Metadaten
Author:Patrizia Malkomes, Ilaria Lunger, Alexander Lütticke, Elsie Oppermann, Nadine Hätscher, Hubert Serve, Katharina Holzer, Wolf Otto Bechstein, Michael A. Rieger
URN:urn:nbn:de:hebis:30:3-457152
DOI:http://dx.doi.org/10.1245/s10434-016-5218-z
ISSN:1534-4681
ISSN:1068-9265
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27059026
Parent Title (English):Annals of surgical oncology
Publisher:Springer
Place of publication:Berlin [u. a.]
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/04/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/02/20
Tag:Becton Dickinson; Conventional Chemotherapeutic; SW480 Cell; Sphere Formation Assay; Tumorsphere Formation
Volume:23
Issue:9
Pagenumber:2849
First Page:2857
Last Page:9
Note:
© The Author(s) 2016. Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
HeBIS PPN:431860068
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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