Conventional chemotherapy eliminates the bulk of colorectal cancer (CRC) following surgery. However, recurrence may occur due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to the chemotherapeutic agents. The residual effects of chemotherapy on such surviving cancer cells, and the possible implication for subsequent evolution of metastatic disease, are not well understood. We evaluated the expression and function of the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12. The major CRC chemotherapeutics 5-fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, doxorubicin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on surviving viable cells from HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry revealed that the decline in CXCR4 was associated with a significant loss of CXCR4+ cells. Elevations in CD26 were observed across the entire cell population and were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. CD26-annexin V-propidium iodide co-staining confirmed that CD26 was elevated only on live cells. 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 showed that drug treatment and elevated CD26 was most closely associated with enrichment of the CD44+CD133- cell population, suggesting benefits of standard chemotherapy may be derived from selective elimination of cell populations by the combination of complementary drugs 5-fluorouracil and oxaliplatin. 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.
Citation Format: Murray J. Cutler, Erica L. Lowthers, Cynthia L. Richard, Dagmar M. Hajducek, Paul A. Spagnuolo, Jonathan Blay. Chemotherapeutic agents attenuate subsequent CXCL12-induced migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B06.