Abstract
BackgroundCancer 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.MethodsC57BL/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.ResultsThe 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.ConclusionThis 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.
Highlights
Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients
This study investigated the role of transforming growth factor β (TGFβ) released by bone remodeling in the progression of cancerrelated anemia and revealed a potential therapeutic approach for relieving defects in hematopoiesis
Erythropoiesis is defective in cancer cachexia To detect the features of cancer-related anemia (CRA), we constructed a tumorbearing model through subcutaneous injection of the Lewis lung carcinoma (LLC) cell line into the flanks of mice (n = 6/group) (Fig. S1a-b)
Summary
Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer cachexia is an irreversible but common wasting syndrome in terminal stage cancer patients that is characterized by weight loss, anorexia, asthenia, and anemia [1,2,3]. A portion of cancer-related anemia (CRA) is secondary to antineoplastic treatment, primary CRA is developed in more than 30% of patients [4, 5]. BFU-E is largely dormant but capable of differentiating into erythroid colony-forming units (CFU-E) [9]. The stromal niche forms parts of the bone marrow microenvironment and influences the steady-state and stress-induced proliferation and differentiation of erythroid progenitor cells [13,14,15]
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