Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 628# Zhenyuan Road, Shenzhen, Guangdong, China.
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, 74# Zhongshan 2nd Road, Guangzhou, Guangdong, China.
Stem Cell Res Ther. 2021 Jan 18;12(1):65. doi: 10.1186/s13287-020-02120-9.
Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer-related anemia is one of the main features of cancer cachexia and mostly results in a poor prognosis. The disadvantages of the current therapies are obvious, but few new treatments have been developed because the pathological mechanism remains unclear.
C57BL/6 mice were subcutaneously injected with Lewis lung carcinoma cells to generate a cancer-related anemia model. The treated group received daily intraperitoneal injections of SB505124. Blood parameters were determined with a routine blood counting analyzer. Erythroid cells and hematopoietic stem/progenitor cells were analyzed by flow cytometry. The microarchitecture changes of the femurs were determined by micro-computed tomography scans. Smad2/3 phosphorylation was analyzed by immunofluorescence and Western blotting. The changes in the hematopoietic stem cell niche were revealed by qPCR analysis of both fibrosis-related genes and hematopoietic genes, fibroblastic colony-forming unit assays, and lineage differentiation of mesenchymal stromal cells.
The mouse model exhibited hematopoietic suppression, marked by a decrease of erythrocytes in the peripheral blood, as well as an increase of immature erythroblasts and reduced differentiation of multipotent progenitors in the bone marrow. The ratio of bone volume/total volume, trabecular number, and cortical wall thickness all appeared to decrease, and the increased osteoclast number has led to the release of latent TGFβ and TGFβ signaling over-activation. Excessive TGFβ deteriorated the hematopoietic stem cell niche, inducing fibrosis of the bone marrow as well as the transition of mesenchymal stromal cells. Treatment with SB505124, a small-molecule inhibitor of TGFβ signaling, significantly attenuated the symptoms of cancer-related anemia in this model, as evidenced by the increase of erythrocytes in the peripheral blood and the normalized proportion of erythroblast cell clusters. Meanwhile, hindered hematopoiesis and deteriorated hematopoietic stem cell niche were also shown to be restored with SB505124 treatment.
This study investigated the role of TGFβ released by bone remodeling in the progression of cancer-related anemia and revealed a potential therapeutic approach for relieving defects in hematopoiesis.
癌症恶病质是一种消耗综合征，在晚期癌症患者中较为常见。癌症相关性贫血是癌症恶病质的主要特征之一，大多导致预后不良。目前治疗方法的缺点显而易见，但由于病理机制尚不清楚，很少有新的治疗方法被开发出来。
用 Lewis 肺癌细胞皮下注射 C57BL/6 小鼠，建立癌症相关性贫血模型。实验组每天腹腔注射 SB505124。用常规血细胞计数分析仪测定血液参数。用流式细胞术分析红系细胞和造血干/祖细胞。用微计算机断层扫描分析股骨微结构变化。用免疫荧光和 Western blot 分析 Smad2/3 磷酸化。通过纤维化相关基因和造血基因的 qPCR 分析、成纤维细胞集落形成单位测定和间充质基质细胞系分化，揭示造血干细胞龛的变化。
该小鼠模型表现出造血抑制，外周血红细胞减少，骨髓中未成熟红细胞增多，多能祖细胞分化减少。骨体积/总体积比、骨小梁数和皮质壁厚度均呈下降趋势，破骨细胞数增加导致潜在 TGFβ 的释放和 TGFβ 信号的过度激活。过多的 TGFβ 恶化了造血干细胞龛，导致骨髓纤维化和间充质基质细胞的转化。用 TGFβ 信号小分子抑制剂 SB505124 治疗，明显改善了该模型的癌症相关性贫血症状，外周血红细胞增多，网织红细胞簇比例正常。同时，SB505124 治疗也显示出阻止造血功能障碍和改善造血干细胞龛的作用。
本研究探讨了骨重塑释放的 TGFβ 在癌症相关性贫血进展中的作用，并揭示了一种缓解造血缺陷的潜在治疗方法。
