Open AccessSelective depletion of metastatic stem cells as therapy for human colorectal cancer
Author(s) -
Céspedes María Virtudes,
Unzueta Ugutz,
Aviñó Anna,
Gallardo Alberto,
Álamo Patricia,
Sala Rita,
SánchezChardi Alejandro,
Casanova Isolda,
Mangues María Antònia,
LopezPousa Antonio,
Eritja Ramón,
Villaverde Antonio,
Vázquez Esther,
Mangues Ramón
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708772
Subject(s) - library science , humanities , geography , cartography , ethnology , history , art , computer science
Abstract Selective elimination of metastatic stem cells (Met SC s) promises to block metastatic dissemination. Colorectal cancer ( CRC ) cells overexpressing CXCR 4 display trafficking functions and metastasis‐initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22‐ GFP ‐H6‐FdU) that selectively delivers Floxuridine to CXCR 4 + cells. In contrast to free oligo‐FdU, intravenous T22‐ GFP ‐H6‐FdU selectively accumulates and internalizes in CXCR 4 + 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 CXCR 4 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 CXCR 4 + cancer cells, and validates metastatic stem cells (Met SC s) as targets for clinical therapy.