ABCB5 Maintains Melanoma-Initiating Cells through a Proinflammatory Cytokine Signaling Circuit

The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux ha...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2014-08, Vol.74 (15), p.4196-4207
Main Authors: WILSON, Brian J, SAAB, Karim R, FRANK, Markus H, JIE MA, SCHATTON, Tobias, PÜTZ, Pablo, QIAN ZHAN, MURPHY, George F, GASSER, Martin, WAAGA-GASSER, Ana Maria, FRANK, Natasha Y
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
Cell Line, Tumor
Dermatology
Gene Expression
Heterografts
Humans
Interleukin-1beta - metabolism
Interleukin-8 - metabolism
Medical sciences
Melanoma - immunology
Melanoma - metabolism
Melanoma - pathology
Mice
Mice, Inbred NOD
Mice, SCID
Microarray Analysis
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplastic Stem Cells - immunology
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Pharmacology. Drug treatments
Receptors, Interleukin-8A - immunology
Receptors, Interleukin-8A - metabolism
Signal Transduction
Transfection
Tumors
Tumors of the skin and soft tissue. Premalignant lesions
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Summary:The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells, ABCB5 controls IL1β secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1β/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-14-0582