Abstract | BACKGROUND: METHODS: We evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays. RESULTS:
5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations. CONCLUSION: Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity.
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Authors | Murray J Cutler, Erica L Lowthers, Cynthia L Richard, Dagmar M Hajducek, Paul A Spagnuolo, Jonathan Blay |
Journal | BMC cancer
(BMC Cancer)
Vol. 15
Pg. 882
(Nov 10 2015)
ISSN: 1471-2407 [Electronic] England |
PMID | 26552750
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CXCL12 protein, human
- CXCR4 protein, human
- Chemokine CXCL12
- Hyaluronan Receptors
- Receptors, CXCR4
- Irinotecan
- DPP4 protein, human
- Dipeptidyl Peptidase 4
- Fluorouracil
- Camptothecin
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Topics |
- Animals
- Camptothecin
(administration & dosage, analogs & derivatives)
- Carcinogenesis
(drug effects)
- Cell Lineage
- Cell Movement
(drug effects)
- Chemokine CXCL12
(biosynthesis, genetics)
- Colonic Neoplasms
(drug therapy, genetics, pathology)
- Dipeptidyl Peptidase 4
(biosynthesis, genetics)
- Fluorouracil
(administration & dosage)
- Gene Expression Regulation, Neoplastic
(drug effects)
- HT29 Cells
- Humans
- Hyaluronan Receptors
(genetics)
- Irinotecan
- Mice
- Neoplasm Metastasis
- Receptors, CXCR4
(biosynthesis, genetics)
- Xenograft Model Antitumor Assays
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