Oncotarget

Research Papers:

Resistance of leukemia cells to cytarabine chemotherapy is mediated by bone marrow stroma, involves cell-surface equilibrative nucleoside transporter-1 removal and correlates with patient outcome

Patricia Macanas-Pirard, Richard Broekhuizen, Alfonso González, Claudia Oyanadel, Daniel Ernst, Patricia García, Viviana P. Montecinos, Felipe Court, Mauricio Ocqueteau, Pablo Ramirez and Bruno Nervi _

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Oncotarget. 2017; 8:23073-23086. https://doi.org/10.18632/oncotarget.14981

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Abstract

Patricia Macanas-Pirard1, Richard Broekhuizen1,7, Alfonso González2, Claudia Oyanadel3, Daniel Ernst1, Patricia García4,7, Viviana P. Montecinos1, Felipe Court5, Mauricio Ocqueteau1, Pablo Ramirez6, Bruno Nervi1,7

1Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

2Facultad de Medicina, Universidad San Sebastián, Center for Aging and Regeneration (CARE), Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile

3Facultad de Ciencia, Universidad San Sebastián, Fundación Ciencia y Vida, Santiago, Chile

4Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

5Department of Physiology, Millennium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile

6Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Región de los Ríos, Chile

7Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile

Correspondence to:

Bruno Nervi, email: bnervi@med.puc.cl

Keywords: leukemia, cytarabine-resistance, ENT1, bone marrow stroma, biomarker

Received: May 23, 2016     Accepted: January 06, 2017     Published: February 01, 2017

ABSTRACT

The interaction between acute myeloid leukemia cells (AML) with the bone marrow stroma cells (BMSCs) determines a protective environment that favors tumor development and resistance to conventional chemotherapy. We showed that BMSCs secrete soluble factors that protect AML cells from Ara-C induced cytotoxicity. This leukemia chemoresistance is associated with a decrease in the equilibrative nucleoside transporter (ENT1) activity by inducing removal of ENT1 from the cell surface. Reduction of cell proliferation was also observed with activation of AKT and mTOR-dependent cell survival pathways, which may also contribute to the tumor chemoprotection. Analysis of primary BMSC cultures has demonstrated that AML patients with stroma capable to confer Ara-C resistance in vitro compared to AML patients without this stroma capacity were associated with a worse prognosis. The two year overall survival rate was 0% versus 80% respectively (p=0.0001). This is the first report of a chemoprotection mechanism based on the removal of a drug transporter from the cell surface and most importantly the first time that a stroma phenotype has correlated with prognostic outcome in cancer.


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