Inhibition of TGFβ Improves Hematopoietic Stem Cell Niche and Ameliorates Cancer-related Anemia

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2021 Jan 19

PMID 33461597

Citations 9

Authors

Boyan Wang

Yi Wang

Hainan Chen

Senyu Yao

Xiaofan Lai

Yuan Qiu

Jianye Cai

Yinong Huang

Xiaoyue Wei

Yuanjun Guan

Tao Wang

Jiancheng Wang

Andy Peng Xiang

Affiliations

Soon will be listed here.

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.

Citing Articles

TGFβ family signaling in human stem cell self-renewal and differentiation.

Liu S, Ren J, Hu Y, Zhou F, Zhang L Cell Regen. 2024; 13(1):26.

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The crosstalk between lung cancer and the bone marrow niche fuels emergency myelopoiesis.

Calderon-Espinosa E, De Ridder K, Benoot T, Jansen Y, Vanhonacker D, Heestermans R Front Immunol. 2024; 15:1397469.

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The mean reticulocyte volume is a valuable index in early diagnosis of cancer-related anemia.

Lin H, Zhan B, Shi X, Feng D, Tao S, Wo M PeerJ. 2024; 12:e17063.

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Comparison of osteoclast differentiation protocols from human induced pluripotent stem cells of different tissue origins.

Blumke A, Ijeoma E, Simon J, Wellington R, Purwaningrum M, Doulatov S Stem Cell Res Ther. 2023; 14(1):319.

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Role of growth differentiation factor 15 in cancer cachexia (Review).

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