UMR 2587, CNRS-Pierre Fabre, Institut des Sciences et Technologies du Médicament de Toulouse (ISTMT), Toulouse, France.
PLoS One. 2012;7(5):e36762. doi: 10.1371/journal.pone.0036762. Epub 2012 May 24.
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.
转移性黑色素瘤是最具侵袭性的皮肤癌。最近，已经鉴定出肿瘤细胞具有不同表型的亚群。其中，被认为具有干细胞样特性的 ABCB5 表达细胞具有增强的致瘤性。此外，ABCB5(+)细胞被认为通过 ABCB5 的潜在外排功能参与化疗耐药性。然而，这些细胞在用于黑色素瘤化疗的药物作用下的命运仍有待阐明。在这里，我们研究了抗黑色素瘤治疗对 ABCB5 表达细胞的影响。使用黑色素瘤异种移植模型（WM266-4），我们在体内观察到在用替莫唑胺治疗后，ABCB5 表达细胞增多，导致肿瘤明显消退。在对接受达卡巴嗪治疗的患者的临床样本进行的初步研究中进一步证实了这些结果。在体外，我们表明，当暴露于达卡巴嗪（转移性黑色素瘤的参考治疗药物）和维莫非尼（一种新的突变激酶 V600E BRAF 抑制剂以及其他各种化疗药物）时，ABCB5 表达细胞选择性存活。我们的结果表明，抗黑色素瘤化疗可能通过选择表达 ABCB5 的肿瘤细胞亚群参与化疗耐药性的获得。这对于理解抗黑色素瘤治疗后观察到的复发具有重要意义，并加强了 ABCB5 和 ABCB5 表达细胞作为黑色素瘤潜在治疗靶点的重要性。
