Melanoma chemotherapy leads to the selection of ABCB5-expressing cells.
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.
UMR 2587, CNRS-Pierre Fabre, Institut des Sciences et Technologies du Médicament de Toulouse (ISTMT), Toulouse, France.
Marine
M
Chartrain
Joëlle
J
Riond
Aline
A
Stennevin
Isabelle
I
Vandenberghe
Bruno
B
Gomes
Laurence
L
Lamant
Nicolas
N
Meyer
Jean Edouard
JE
Gairin
Nicolas
N
Guilbaud
Jean Philippe
JP
Annereau
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D018365:Neoplasm, Residual; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003606:Dacarbazine