title: Side population cells from human melanoma tumors reveal diverse mechanisms for chemoresistance.
abstract: Side population (SP) cells are identified as cells capable of excluding the fluorescent Hoechst dye and anticancer drugs, and it represents hematopoietic stem cells and chemoresistant cells from several solid tumors. In this study, we confirmed the presence of SP cells in tumors from melanoma patients. Melanoma SP cells overexpressed ATP-binding-cassette (ABC) transporters, ABCB1 and ABCB5. We generated a direct in vivo xenograft model, and demonstrated that SP cells were resistant to paclitaxel, a substrate of ABCB1, both in vitro and in vivo. However, melanoma SP cells were also resistant to temozolomide, which is not a substrate for ABC transporters, through IL-8 upregulation. In addition, gene profiling studies identified three signaling pathways (NF-κB, α6-β4-integrin, and IL-1) as differentially upregulated in melanoma SP cells, and there was a significant increase of PCDHB11 and decrease of FUK and TBX2 in these cells. Therefore, we provide evidence that SP is an enriched source of chemoresistant cells in human melanomas, and suggest that the selected genes and signaling pathways of SP cells may be a potential target for effective melanoma therapies. To our knowledge, this is a previously unreported study to isolate SP cells from melanoma patients and to investigate the gene expression profiling of these cells.
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Lixia Z
authors.initials: LZ
authors.lastname: Ellis
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA; Charles C Gates Regenerative Medicine and Stem Cell Biology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Dallaglio
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Moe
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Robinson
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: McCarter
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA; Denver Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Norris
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA; Charles C Gates Regenerative Medicine and Stem Cell Biology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.affiliation: Human Medical Genetics Program, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado, USA.
authors.forename: Natalie G
authors.initials: NG
authors.lastname: Ahn
authors.affiliation: Department of Dermatology, University of Colorado Denver, Aurora, Colorado, USA; Charles C Gates Regenerative Medicine and Stem Cell Biology, University of Colorado Denver, Aurora, Colorado, USA; Denver Veterans Affairs Medical Center, Denver, Colorado, USA. Electronic address: mayumi.fujita@ucdenver.edu.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujita
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004396:Coloring Agents; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use; D058985:Side-Population Cells / Q000473:pathology* / Q000502:physiology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D000077204:Temozolomide; D015854:Up-Regulation / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004396:Coloring Agents; D016209:Interleukin-8; D003606:Dacarbazine; D017239:Paclitaxel; D000077204:Temozolomide