Abstract
BackgroundColorectal 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.ResultsPathway 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-016-5218-z) contains supplementary material, which is available to authorized users.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide
Fluorescence-activated cell sorting (FACS) analysis showed a strong enrichment of CD133? cells in spheres (82.7 ± 7.5 %) in comparison to monolayer culture (16.9 ± 11 %; n = 6, data not shown)
Well-described pathways associated with CRC progression, such as ‘Wnt signaling’ (DKK, Axin, CCND1), ‘P53 signaling’ (PERP, SERPINB5), and ‘colorectal cancer’, including AKT (CCND1, TSC, Axin, MET) and transforming growth factor (TGF)-b signaling, were overrepresented in tumorspheres (Fig. 1d) and were potential targets for a tumor-initiating cells (TICs)-directed therapy
Summary
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. 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 TICdirected therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
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