Side Population Cells from Human Melanoma Tumors Reveal Diverse Mechanisms for Chemoresistance

Journal of Investigative Dermatology (2012) 132, 2440–2450; doi:10.1038/jid.2012.161; published online 24 May 2012

Yuchun Luo1, Lixia Z Ellis1, Katiuscia Dallaglio1,2, Moe Takeda1, William A Robinson3, Steven E Robinson3, Weimin Liu1, Karl D Lewis3, Martin D McCarter4, Rene Gonzalez3, David A Norris1,5, Dennis R Roop1,2, Richard A Spritz6, Natalie G Ahn7 and Mayumi Fujita
Department of Dermatology, University of Colorado, Mail Stop 8127, 12801 E. 17th Avenue, Room 4124, Aurora, Colorado 80045, USA.

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-?B, ?6-?4-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.