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Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic-Cell-Induced Bone Marrow Angiogenesis.

ABSTRACT: The critical role of angiogenesis for solid tumor growth and metastatic spread has been well established. In contrast, even though increased vascularity has been commonly observed in bone marrows of patients with hematological malignancies (liquid tumors), the pathophysiology of leukemia-induced angiogenesis in the bone marrow remains elusive. This paper demonstrates the usage of a microengineered 3D biomimetic model to study leukemic-cell-induced bone marrow angiogenesis. Rational design of the 3D angiogenesis chip incorporating endothelial cells (ECs), leukemic cells, and bone marrow stromal fibroblasts provide an efficient biomimetic means to promote and visualize early angiogenic processes. Morphological features of angiogenesis induced by three different leukemic cell lines (U937, HL60, and K562) are investigated and compared. Quantitative measurements of angiogenic factors secreted from monocultures and cocultures of leukemic cells with bone marrow stromal fibroblasts suggest a synergistic relationship between ECs, leukemic cells, and bone marrow stromal fibroblasts for angiogenic induction, and also confirm the necessity of conducting functional angiogenic assays in proper 3D biomimetic cell culture systems like the one developed in this work.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC4890157 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic-Cell-Induced Bone Marrow Angiogenesis.

Zheng Yi Y Sun Yubing Y Yu Xinwei X Shao Yue Y Zhang Ping P Dai Guohao G Fu Jianping J

Advanced healthcare materials 20160229 9

The critical role of angiogenesis for solid tumor growth and metastatic spread has been well established. In contrast, even though increased vascularity has been commonly observed in bone marrows of patients with hematological malignancies (liquid tumors), the pathophysiology of leukemia-induced angiogenesis in the bone marrow remains elusive. This paper demonstrates the usage of a microengineered 3D biomimetic model to study leukemic-cell-induced bone marrow angiogenesis. Rational design of the ...[more]

PMID: 26924785

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Project description:BackgroundDuring acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs).MethodsBM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten.ResultsIn the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection.ConclusionsTreatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation.

Dataset Information

Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic-Cell-Induced Bone Marrow Angiogenesis.

Publications

Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic-Cell-Induced Bone Marrow Angiogenesis.

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