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

Pediatric T- and NK-cell lymphomas: new biologic insights and treatment strategies

T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK.

Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.Hug

Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas.

International audienceThe anaplastic lymphoma kinase (ALK), tyrosine kinase oncogene is implicated in a wide variety of cancers. In this study we used conditional onco-ALK (NPM-ALK and TPM3-ALK) mouse MEF cell lines (ALK+ fibroblasts) and transgenic models (ALK+ B-lymphoma) to investigate the involvement and regulation of angiogenesis in ALK tumor development. First, we observed that ALK expression leads to downregulation of miR-16 and increased Vascular Endothelial Growth Factor (VEGF) levels. Second, we found that modification of miR-16 levels in TPM3-ALK MEF cells greatly affected VEGF levels. Third, we demonstrated that miR-16 directly interacts with VEGF mRNA at the 3'-untranslated region and that the regulation of VEGF by miR-16 occurs at the translational level. Fourth, we showed that expression of both the ALK oncogene and hypoxia-induced factor 1α (HIF1α) is a prerequisite for miR-16 downregulation. Fifth, in vivo, miR-16 gain resulted in reduced angiogenesis and tumor growth. Finally, we highlighted an inverse correlation between the levels of miR-16 and VEGF in human NPM-ALK+ Anaplastic Large Cell Lymphomas (ALCL). Altogether, our results demonstrate, for the first time, the involvement of angiogenesis in ALK+ ALCL and strongly suggest an important role for hypoxia-miR-16 in regulating VEGF translation.Leukemia advance online publication, 22 July 2011; doi:10.1038/leu.2011.168