title: ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients.
abstract: Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy.
authors.affiliation: Transplantation Research Center, Children's Hospital, Boston, MA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Karim R
authors.initials: KR
authors.lastname: Saab
authors.forename: Robin
authors.initials: R
authors.lastname: Schanche
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.forename: Jason S
authors.initials: JS
authors.lastname: Gold
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000502:physiology; D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D053631:Interleukin Receptor Common gamma Subunit; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D005472:Fluorouracil