Selective depletion of metastatic stem cells as therapy for human colorectal cancer
Abstract 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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708772 |
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| author | María Virtudes Céspedes Ugutz Unzueta Anna Aviñó Alberto Gallardo Patricia Álamo Rita Sala Alejandro Sánchez‐Chardi Isolda Casanova María Antònia Mangues Antonio Lopez‐Pousa Ramón Eritja Antonio Villaverde Esther Vázquez Ramón Mangues |
| author_facet | María Virtudes Céspedes Ugutz Unzueta Anna Aviñó Alberto Gallardo Patricia Álamo Rita Sala Alejandro Sánchez‐Chardi Isolda Casanova María Antònia Mangues Antonio Lopez‐Pousa Ramón Eritja Antonio Villaverde Esther Vázquez Ramón Mangues |
| author_sort | María Virtudes Céspedes |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-22f73e7198844bf5873e6fa6e08b45a4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-22f73e7198844bf5873e6fa6e08b45a42025-08-20T03:46:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-09-01101012210.15252/emmm.201708772Selective depletion of metastatic stem cells as therapy for human colorectal cancerMaría Virtudes Céspedes0Ugutz Unzueta1Anna Aviñó2Alberto Gallardo3Patricia Álamo4Rita Sala5Alejandro Sánchez‐Chardi6Isolda Casanova7María Antònia Mangues8Antonio Lopez‐Pousa9Ramón Eritja10Antonio Villaverde11Esther Vázquez12Ramón Mangues13Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauInstitut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauCIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauInstitut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauServei de Microscòpia, Universitat Autònoma de BarcelonaInstitut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauInstitut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauCIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN)Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant PauAbstract 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.https://doi.org/10.15252/emmm.201708772colorectal cancerCXCR4 receptormetastatic stem cellsprotein nanoconjugatetargeted drug delivery |
| spellingShingle | María Virtudes Céspedes Ugutz Unzueta Anna Aviñó Alberto Gallardo Patricia Álamo Rita Sala Alejandro Sánchez‐Chardi Isolda Casanova María Antònia Mangues Antonio Lopez‐Pousa Ramón Eritja Antonio Villaverde Esther Vázquez Ramón Mangues Selective depletion of metastatic stem cells as therapy for human colorectal cancer EMBO Molecular Medicine colorectal cancer CXCR4 receptor metastatic stem cells protein nanoconjugate targeted drug delivery |
| title | Selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| title_full | Selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| title_fullStr | Selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| title_full_unstemmed | Selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| title_short | Selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| title_sort | selective depletion of metastatic stem cells as therapy for human colorectal cancer |
| topic | colorectal cancer CXCR4 receptor metastatic stem cells protein nanoconjugate targeted drug delivery |
| url | https://doi.org/10.15252/emmm.201708772 |
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