title: Drug-tolerant cancer cells show reduced tumor-initiating capacity: depletion of CD44 cells and evidence for epigenetic mechanisms.
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.
authors.affiliation: Department of Molecular Carcinogenesis, the University of Texas M.D. Anderson Cancer Center, Smithville, Texas, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jichao
authors.initials: J
authors.lastname: Qin
authors.forename: Hangwen
authors.initials: H
authors.lastname: Li
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Tammy
authors.initials: T
authors.lastname: Calhoun-Davis
authors.forename: Luis Della
authors.initials: LD
authors.lastname: Coletta
authors.forename: Jim
authors.initials: J
authors.lastname: Klostergaard
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Skora
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Bi
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D005047:Etoposide; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; D019311:Staurosporine; D017239:Paclitaxel