ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.
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Wilson BJ, Saab KR, Ma J, Schatton T, Putz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH
ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.
Cancer Res. 2014 Aug 1;74(15):4196-207. doi: 10.1158/0008-5472.CAN-14-0582. Epub 2014 Jun 16.
- PubMed ID
- 24934811 [ View in PubMed]
- Abstract
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 IL1beta secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1beta/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.