Melanoma chemotherapy leads to the selection of ABCB5-expressing cells

PLoS One. 2012;7(5):e36762. doi: 10.1371/journal.pone.0036762. Epub 2012 May 24.

Abstract

Metastatic melanoma is the most aggressive skin cancer. Recently, phenotypically distinct subpopulations of tumor cells were identified. Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties. In addition, ABCB5(+) cells are thought to participate to chemoresistance through a potential efflux function of ABCB5. Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified. Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells. Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression. These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine. In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs. Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5. This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Mice
  • Mice, Nude
  • Neoplasm, Residual
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • ABCB5 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Dacarbazine