Chlenski Alexandre, Dobratic Marija, Salwen Helen R, Applebaum Mark, Guerrero Lisa J, Miller Ryan, DeWane Gillian, Solomaha Elena, Marks Jeremy D, Cohn Susan L
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
Biological Sciences Division, Biophysics Core Facility, University of Chicago, Chicago, IL, USA.
Oncotarget. 2016 Nov 22;7(47):77696-77706. doi: 10.18632/oncotarget.12773.
SPARC is a matrix protein that mediates interactions between cells and the microenvironment. In cancer, SPARC may either promote or inhibit tumor growth depending upon the tumor type. In neuroblastoma, SPARC is expressed in the stromal Schwannian cells and functions as a tumor suppressor. Here, we developed a novel in vivo model of stroma-rich neuroblastoma using non-tumorigenic SHEP cells with modulated levels of SPARC, mixed with tumorigenic KCNR cells. Tumors with stroma-derived SPARC displayed suppressed growth, inhibited angiogenesis and increased lipid accumulation. Based on the described chaperone function of SPARC, we hypothesized that SPARC binds albumin complexed with fatty acids and transports them to tumors. We show that SPARC binds albumin with Kd=18.9±2.3 uM, and enhances endothelial cell internalization and transendothelial transport of albumin in vitro. We also demonstrate that lipids induce toxicity in neuroblastoma cells and show that lipotoxicity is increased when cells are cultured in hypoxic conditions. Studies investigating the therapeutic potential of SPARC are warranted.
SPARC是一种介导细胞与微环境之间相互作用的基质蛋白。在癌症中，根据肿瘤类型，SPARC可能促进或抑制肿瘤生长。在神经母细胞瘤中，SPARC在基质雪旺细胞中表达，并作为一种肿瘤抑制因子发挥作用。在此，我们使用具有调节水平SPARC的非致瘤性SHEP细胞与致瘤性KCNR细胞混合，开发了一种富含基质的神经母细胞瘤新型体内模型。具有基质来源SPARC的肿瘤表现出生长受抑制、血管生成受抑制和脂质积累增加。基于所描述的SPARC伴侣功能，我们假设SPARC结合与脂肪酸复合的白蛋白并将它们转运至肿瘤。我们表明SPARC以Kd = 18.9±2.3 μM的亲和力结合白蛋白，并在体外增强内皮细胞对白蛋白的内化和跨内皮运输。我们还证明脂质在神经母细胞瘤细胞中诱导毒性，并表明当细胞在缺氧条件下培养时脂毒性增加。对SPARC治疗潜力的研究是有必要的。
