Selective depletion of metastatic stem cells as therapy for human colorectal cancer
Por:
Cespedes, MV, Unzueta, U, Avino, A, Gallardo, A, Alamo, P, Sala, R, Sanchez-Chardi, A, Casanova, I, Mangues, MA, Lopez-Pousa, A, Eritja, R, Villaverde, A, Vazquez, E, Mangues, R
Publicada:
1 oct 2018
Resumen:
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis-initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22-GFP-H6-FdU) that selectively delivers Floxuridine to CXCR4(+) cells. In contrast to free oligo-FdU, intravenous T22-GFP-H6-FdU selectively accumulates and internalizes in CXCR4(+) cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re-initiation capacity. Repeated T22-GFP-H6-FdU administration in cell line and patient-derived CRC models blocks intravasation and completely prevents metastases development in 38-83% of mice, while showing CXCR4 expression-dependent and site-dependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligo-FdU. T22-GFP-H6-FdU induces also higher regression of established metastases than free oligo-FdU, with negligible distribution or toxicity in normal tissues. This targeted drug delivery approach yields potent antimetastatic effect, through selective depletion of metastatic CXCR4(+) cancer cells, and validates metastatic stem cells (MetSCs) as targets for clinical therapy.
Filiaciones:
Cespedes, MV:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Unzueta, U:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Avino, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
CSIC, Inst Adv Chem Catalonia IQAC, Barcelona, Spain
Gallardo, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain
Alamo, P:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Sala, R:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Sanchez-Chardi, A:
Univ Autonoma Barcelona, Serv Microscopia, Barcelona, Spain
Casanova, I:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Mangues, MA:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Pharm, Barcelona, Spain
Lopez-Pousa, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona, Spain
Eritja, R:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
CSIC, Inst Adv Chem Catalonia IQAC, Barcelona, Spain
Villaverde, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Vazquez, E:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Mangues, R:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Gold, Green Published
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