Abstract
Cancer stem cells (CSCs) possess high tumor-initiating capacity and have been reported to be resistant to therapeutics. Vice versa, therapy-resistant cancer cells seem to manifest CSC phenotypes and properties. It has been generally assumed that drug-resistant cancer cells may all be CSCs although the generality of this assumption is unknown. Here, we chronically treated Du145 prostate cancer cells with etoposide, paclitaxel and some experimental drugs (i.e., staurosporine and 2 paclitaxel analogs), which led to populations of drug-tolerant cells (DTCs). Surprisingly, these DTCs, when implanted either subcutaneously or orthotopically into NOD/SCID mice, exhibited much reduced tumorigenicity or were even non-tumorigenic. Drug-tolerant DLD1 colon cancer cells selected by a similar chronic selection protocol also displayed reduced tumorigenicity whereas drug-tolerant UC14 bladder cancer cells demonstrated either increased or decreased tumor-regenerating capacity. Drug-tolerant Du145 cells demonstrated low proliferative and clonogenic potential and were virtually devoid of CD44+ cells. Prospective knockdown of CD44 in Du145 cells inhibited cell proliferation and tumor regeneration, whereas restoration of CD44 expression in drug-tolerant Du145 cells increased cell proliferation and partially increased tumorigenicity. Interestingly, drug-tolerant Du145 cells showed both increases and decreases in many “stemness” genes. Finally, evidence was provided that chronic drug exposure generated DTCs via epigenetic mechanisms involving molecules such as CD44 and KDM5A. Our results thus reveal that 1) not all DTCs are necessarily CSCs; 2) conventional chemotherapeutic drugs such as taxol and etoposide may directly target CD44+ tumor-initiating cells; and 3) DTCs generated via chronic drug selection involve epigenetic mechanisms.
Highlights
The cancer stem cell (CSC) concept, that tumors contain stem-like cancer cells, was proposed decades ago and recently revived to explain the cellular heterogeneity in the tumor
Based on the assumptions that CSCs may have a special advantage of surviving therapeutics and are likely the cells that mediate drug resistance, we tested whether cancer cells that have survived CHRONIC drug treatment may all possess CSC properties
The resultant drug-tolerant cell (DTC) lines were designated as Du145-VP16, Du145-Paclitaxel, Du145-STS, Du145-WP1102, and Du145WP1103 cells, respectively
Summary
The cancer stem cell (CSC) concept, that tumors contain stem-like cancer cells, was proposed decades ago and recently revived to explain the cellular heterogeneity in the tumor. The CD44+CD24lo/2 breast CSCs are enriched in breast cancer patients who have received adjuvant chemotherapy [28] and more resistant to some chemotherapeutic drugs [29]. Chemoresistant colon cancer cells display CSC phenotypes [31] and CD133+ hepatic CSCs are chemoresistant due to preferential activation of the Akt pathway [32]. These new findings highlight potential involvement of CSCs in therapy resistance and in disease recurrence. It has been assumed that drug-resistant cancer cells may all be enriched in CSCs the general applicability of this assumption remains untested
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