Xiong Y, Russell D L, McDonald L T, Cowart L A, LaRue A C
Research Services, Ralph H Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Int J Cancer Res Mol Mech. 2017;3(1). doi: 10.16966/2381-3318.130. Epub 2017 Mar 8.
Adipocytes, apart from their critical role as the energy storage depots, contribute to the composition of the tumor microenvironment. Our previous studies based on a single hematopoietic stem cell (HSC) transplantation model, have revealed a novel source of adipocytes from HSCs monocyte/macrophage progenitors. Herein, we extend these studies to examine the role of HSC-derived adipocytes (HSC-Ad) in tumor progression. When cultured under adipogenic conditions, bone marrow-derived monocytic progenitors differentiated into adipocytes that accumulated oil droplets containing triglyceride. The adipokine array and ELISAs confirmed secretion of multiple adipokines by HSC-Ad. These adipocytes underwent further development when injected subcutaneously into C57Bl/6 mice. When co-injected with melanoma B16F1 cells or breast cancer E0771 cells into syngeneic C57Bl/6 mice, HSC-Ad not only accelerated both melanoma and breast tumor growth, but also enhanced vascularization in both tumors. Conditioned media from HSC-Ad supported B16F1 and E0771 cell proliferation and enhanced cell migration . Among the HSC-Ad secreted adipokines, insulin-like growth factor 1 (IGF-1) played an important role in E0771 cell proliferation. Hepatocyte growth factor (HGF) was indispensable for B16F1 cell migration, whereas HGF and platelet-derived growth factor BB (PDGF-BB) collectively contributed to E0771 cell migration. Expression levels of receptors for IGF-1, HGF, and PDGF-BB correlated with their differential roles in B16F1 and E0771 cell proliferation and migration. Our data suggest that HSC-Ad differentially regulate tumor behavior through distinct mechanisms.
脂肪细胞除了作为能量储存库发挥关键作用外，还对肿瘤微环境的组成有贡献。我们之前基于单一造血干细胞（HSC）移植模型的研究揭示了HSC单核细胞/巨噬细胞祖细胞是脂肪细胞的一个新来源。在此，我们扩展这些研究以考察HSC来源的脂肪细胞（HSC-Ad）在肿瘤进展中的作用。在成脂条件下培养时，骨髓来源的单核祖细胞分化为脂肪细胞，这些脂肪细胞积累了含有甘油三酯的油滴。脂肪因子阵列和酶联免疫吸附测定证实了HSC-Ad分泌多种脂肪因子。将这些脂肪细胞皮下注射到C57Bl/6小鼠体内后会进一步发育。当与黑色素瘤B16F1细胞或乳腺癌E0771细胞共同注射到同基因C57Bl/6小鼠体内时，HSC-Ad不仅加速了黑色素瘤和乳腺癌的生长，还增强了两种肿瘤的血管生成。HSC-Ad的条件培养基支持B16F1和E0771细胞增殖并增强细胞迁移。在HSC-Ad分泌的脂肪因子中，胰岛素样生长因子1（IGF-1）在E0771细胞增殖中起重要作用。肝细胞生长因子（HGF）对B16F1细胞迁移不可或缺，而HGF和血小板衍生生长因子BB（PDGF-BB）共同促进E0771细胞迁移。IGF-1、HGF和PDGF-BB受体的表达水平与其在B16F1和E0771细胞增殖及迁移中的不同作用相关。我们的数据表明，HSC-Ad通过不同机制差异调节肿瘤行为。
