Abstract
BackgroundMicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear.MethodsMiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model.ResultsSerum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis.ConclusionsAs a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.
Highlights
MicroRNAs are involved in tumor progression by regulating tumor cells and tumor microenvironment
Since it has recently been reported that the cytotoxic effect of ABT-199 on tumor cells rely on survival signals from tumor microenvironment [11], microenvironmentrelated biomarkers may become potential predictors of ABT-199 efficacy on B-cell lymphoma
Serum miR21 was elevated in B-cell lymphoma and indicated lymphoma progression Comparing with healthy volunteers, serum miR21 was significantly increased in patients with diffuse large B-cell lymphoma (DLBCL)
Summary
MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes. Besides genetic abnormalities of malignant cells themselves, the aberrant status of tumor microenvironment plays a pivotal role on disease progression [4]. As the main components of microenvironment, tumor vessels prevent the attack of chemotherapy on tumor cells [5]. Tumor angiogenesis mediated by immune cells is involved in the development of drug resistance in lymphoma [6, 7]. Direct interaction of immunosuppressive regulatory T (Treg) cells with vascular endothelial cells contributes to the regulation of anti-lymphoma responses [8, 9]. Since it has recently been reported that the cytotoxic effect of ABT-199 on tumor cells rely on survival signals from tumor microenvironment [11], microenvironmentrelated biomarkers may become potential predictors of ABT-199 efficacy on B-cell lymphoma
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