High-altitude hypoxia exacerbates chemotherapy-induced myelosuppression by lowering serum G-CSF/GM-CSF and regulating apoptosis and proliferation

Abstract

The unique hypoxic environment in high-altitude regions is increasingly drawing attention for its impact on the health of residents, particularly in patients post-chemotherapy. This study aimed to investigate the effects and potential mechanisms of high-altitude hypoxia on myelosuppression following chemotherapy, with the goal of providing a theoretical basis for clinical treatment. A retrospective clinical study of 80 patients with breast cancer revealed that patients in the plateau exhibited a significantly higher incidence of grade 3 or higher neutropenia and any level of neutropenia post-chemotherapy than those in the plain, with propensity score matching (PSM) confirming these associations. Animal experiments revealed that high-altitude hypoxia reduced the white blood cell (WBC) count, granulocyte count, lymphocyte count, and number of bone marrow nucleated cells (BMNCs) in cyclophosphamide (CTX)-treated mice. Additionally, high-altitude hypoxia induced a significant reduction in the proliferation index and an elevation in apoptosis rates in BMNCs. High-altitude hypoxia also significantly reduced serum levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Transcriptomic analysis of BMNCs demonstrated that high-altitude hypoxia might modulate the hematopoietic function in CTX-induced myelosuppression mice through pathways related to hematopoiesis, such as porphyrin metabolism, hematopoietic cell lineage, ECM-receptor interaction, and PI3K-Akt signaling pathway. Our results suggest that high-altitude hypoxia exacerbates chemotherapy-induced myelosuppression, possibly through reducing the serum level of G-CSF/GM-CSF and regulating apoptosis and proliferation by PI3K-Akt signaling pathway, highlighting that cancer patients undergoing chemotherapy in hypoxic environments may require enhanced supportive care to mitigate these adverse effects.

Keywords: Chemotherapy; Hematopoietic function; High-altitude hypoxia; Myelosuppression.

Fig. 1

Effect of high-altitude hypoxia on peripheral blood cell counts in CTX-induced myelosuppression mice. Mice were administered CTX at a dose of 100 mg/(kg d) via intraperitoneal injection for 3 consecutive days, while the control (ctrl) group was treated with the same volume of saline. A Experimental design. The levels of WBC (B), granulocyte (C), RBC (D), Hb (E), PLT (F), and lymphocyte (G) were assessed on days 2, 7, 14, and 21 post-chemotherapy. WBC white blood cell, Gran granulocyte, RBC red blood cell, Hb hemoglobin, PLT platelets, Lym lymphocyte. *P < 0.05, **P < 0.01, ***P < 0.001, compared to the ctrl group; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, compared to the model group. n = 15

Fig. 2

Effects of high-altitude hypoxia on hematopoietic function in CTX-induced myelosuppression mice. A Experimental design. Refer to the "Materials and Methods" section for specific administration protocols. B The number of bone marrow nucleated cells (BMNCs) was counted on day 2 post-CTX treatment (n = 6). Results are expressed as mean ± SD. ^###P < 0.0001 compared to the ctrl group; ***P < 0.0001 compared to the model group. C Representative H&E-stained sections of bone marrow are displayed for the indicated groups of mice. The scale bars in the upper and lower panels represent 100 µm and 20 µm, respectively

Fig. 3

Transcriptomic analysis. A Comparison of the number of upregulated and downregulated genes among three groups: model vs ctrl, HC vs model, and H vs ctrl. B–D Volcano plots of differentially expressed genes (DEGs) for the three comparisons: model vs ctrl, HC vs model, and H vs ctrl. E, F Pie charts illustrating the co-regulated DEGs. G, H Heatmap of hierarchical clustering

Fig. 4

Enrichment analysis. A GO analysis related to biological processes of DEGs. B KEGG enrichment analysis of DEGs. C Top 10 pathways enriched in Gene Set Enrichment Analysis (GSEA). D Apoptosis pathway enriched in GSEA

Fig. 5

Effect of hypoxia on the cell cycle and apoptosis of bone marrow nucleated cells (BMNCs) in CTX-induced myelosuppressed mice. A Propidium iodide (PI) staining was performed to assess the cell cycle of BMNCs using flow cytometric analysis. B Quantitative analysis of the durations of cell cycle phases (n = 6). C Flow cytometric analysis of apoptosis in BMNCs. D Quantitative analysis of apoptosis (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001, compared to the ctrl group; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, compared to the model group

Fig. 6

The levels of G-CSF (A), GM-CSF (B), EPO (C), and TPO (D) in serum were detected on day 2 after chemotherapy. *P < 0.05, **P < 0.01, ***P < 0.001, compared to the ctrl group; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, compared to the model group