Boyan Wang1,2, Yi Wang1,2, Hainan Chen1,2, Senyu Yao1,2, Xiaofan Lai2,3, Yuan Qiu1,2, Jianye Cai2,4, Yinong Huang2,5, Xiaoyue Wei1,2, Yuanjun Guan6, Tao Wang1,2, Jiancheng Wang7,8, Andy Peng Xiang9,10,11. 1. Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 628# Zhenyuan Road, Shenzhen, Guangdong, China. 2. 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. 3. Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. 4. Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-Sen University, Guangzhou, China. 5. Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. 6. Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. 7. Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 628# Zhenyuan Road, Shenzhen, Guangdong, China. wangjch38@mail.sysu.edu.cn. 8. 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. wangjch38@mail.sysu.edu.cn. 9. Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 628# Zhenyuan Road, Shenzhen, Guangdong, China. xiangp@mail.sysu.edu.cn. 10. 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. xiangp@mail.sysu.edu.cn. 11. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND:Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancerpatients. 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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