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A lentiviral CXCR4 overexpression and knockdown model in colorectal cancer cell lines reveals plerixafor-dependent suppression of SDF-1α-induced migration and invasion

Background: The development of distant metastasis is associated with poor outcome in patients with colorectal cancer (CRC). The stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) have pivotal roles in the chemotaxis of migrating tumor cells during metastasis. Thu...

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Main Authors: Heckmann, Doreen (Author) , Maier-Laufs, Stephanie (Author) , Maier, Patrick (Author) , Zucknick, Manuela (Author) , Giordano, Frank Anton (Author) , Veldwijk, Marlon Romano (Author) , Eckstein, Volker (Author) , Wenz, Frederik (Author) , Zeller, W. Jens (Author) , Frühauf, Stefan (Author) , Allgayer, Heike (Author)
Format: Article (Journal)
Language:English
Published: [October 2011]
In: Onkologie
Year: 2011, Volume: 34, Issue: 10, Pages: 502-508
ISSN:1423-0240
DOI:10.1159/000332390
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1159/000332390
Verlag, lizenzpflichtig, Volltext: https://www.karger.com/Article/FullText/332390
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Author Notes:Doreen Heckmann, Stephanie Laufs, Patrick Maier, Manuela Zucknick, Frank A. Giordano, Marlon R. Veldwijk, Volker Eckstein, Frederik Wenz, W. Jens Zeller, Stefan Fruehauf, Heike Allgayer
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Summary:Background: The development of distant metastasis is associated with poor outcome in patients with colorectal cancer (CRC). The stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) have pivotal roles in the chemotaxis of migrating tumor cells during metastasis. Thus, hampering the SDF-1/CXCR4 cross-talk is a promising strategy to suppress metastasis. Methods: We investigated the invasive behavior of the lentivirally CXCR4overexpressing CRC cell lines SW480, SW620 and RKO in chemotaxis and invasion assays toward an SDF-1α gradient. Low endogenous CXCR4 expression levels were determined by quantitative realtime polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS) analyses. Results: A lentiviral CXCR4 overexpression and knockdown model was established in these CRC cells. In transwell migration assays, CXCR4 overexpression favored chemotaxis and invasion of cells in all 3 lines depending on an SDF-1α gradient (p < 0.001 vs. untransduced cells). Functional CXCR4 knockdown using lentiviral short hairpin RNA (shRNA) vectors significantly decreased the migration behavior in CRC cell lines (p < 0.001), confirming a CXCR4-specific effect. Pharmacologic inhibition of the SDF-1α/CXCR4 interaction by the bicyclam Plerixafor<sup>TM</sup> at 100 µM significantly abrogated CXCR4-dependent migration and invasion through Matrigel<sup>TM</sup> (SW480, SW620, RKO; p < 0.05). Conclusion: Our results indicate that a CXCR4-antagonistic therapy might prevent tumor cell dissemination and metastasis in CRC patients, consequently improving survival.
Item Description:Gesehen am 28.09.2022
Physical Description:Online Resource
ISSN:1423-0240
DOI:10.1159/000332390

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