TY  - JOUR
A1  - Malkomes, Patrizia
A1  - Lunger, Ilaria
A1  - Lütticke, Alexander
A1  - Oppermann, Elsie
A1  - Hätscher, Nadine
A1  - Serve, Hubert
A1  - Holzer, Katharina
A1  - Bechstein, Wolf Otto
A1  - Rieger, Michael A.
T1  - Selective AKT inhibition by MK-2206 represses colorectal cancer-initiating stem cells
T2  - Annals of surgical oncology
N2  - 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.
KW  - SW480 Cell
KW  - Becton Dickinson
KW  - Sphere Formation Assay
KW  - Conventional Chemotherapeutic
KW  - Tumorsphere Formation
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45715
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-457152
SN  - 1534-4681
SN  - 1068-9265
N1  - © 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.
VL  - 23
IS  - 9
SP  - 2857
EP  - 9
PB  - Springer
CY  - Berlin [u. a.]
ER  -