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Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1

Oncogene volume 41, pages 1634–1646 (2022)Cite this article

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Abstract

Diabetes mellitus (DM) characterized by hyperglycemia is a chronic metabolic disorder that leads to many symptoms and vascular complications. Despite the close association between DM and cancer progression, the response and role of endothelial cells (ECs) under diabetic conditions in tumor metastasis remain to be elucidated. In this study, we sought to determine whether and how ECs under diabetic conditions contribute to tumor metastasis. We have taken advantage of syngeneic mouse tumor models of Lewis lung carcinoma (LLC) and melanoma (B16F10) cells and a streptozotocin (STZ)-induced hyperglycemia model. We demonstrated that hyperglycemia increased the metastasis of LLC and B16F10 cells in an experimental metastasis model with an intravenous injection of the tumor cells. We also found that hyperglycemia promoted lung metastasis of tumor cells by increasing the adhesiveness of ECs to facilitate the adhesion of tumor cells to ECs rather than affecting the metastatic behavior of tumor cells themselves. From the analysis of gene expression in primary lung ECs from STZ-treated mice, we identified that vWF promoted the adhesion of tumor cells to ECs and the transendothelial migration of tumor cells. Mechanistically, hyperglycemia-induced oxidative stress in ECs, and increased oxidative stress enhanced vWF expression in ECs through an increase in the transcription factor GATA1. These results provide evidence for the role of vWF in ECs in promoting hyperglycemia-induced tumor metastasis and potential therapeutic targets for the regulation of vWF expression in ECs and hyperglycemia-induced tumor metastasis.

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Fig. 1: Hyperglycemia increases tumor metastasis but not primary tumor growth.
Fig. 2: High glucose conditions do not affect the proliferation and migration of tumor cells.
Fig. 3: vWF in ECs mediates the adhesion and transendothelial migration of tumor cells.
Fig. 4: Oxidative stress increases vWF expression in diabetic lung ECs.
Fig. 5: Oxidative stress increases vWF expression in ECs via the transcription factor GATA1.
Fig. 6: The antioxidant NAC inhibit H2O2-induced increase in adhesion of tumor cells to ECs and transendothelial migration of tumor cells.
Fig. 7: vWF in ECs mediates H2O2-induced increase in adhesion of tumor cells to ECs and transendothelial migration of tumor cells.
Fig. 8: Insulin supplementation attenuates hyperglycemia-induced oxidative stress and vWF expression in ECs and tumor metastasis in diabetic mice.

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Acknowledgements

We appreciate Dr. Kyong Soo Park for technical assistance in insulin supplementation experiments. This work is supported by funding from the National Research Foundation of Korea grant funded by the Korea government (2020R1A2C1008008 to CHC) and the SNUH Research Fund (0420210290 to CHC).

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Authors and Affiliations

  1. Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

    Han-Seok Jeong, Da-Hye Lee, Seung-Hoon Kim, Chang-Han Lee, Hyun Mu Shin, Hang-Rae Kim & Chung-Hyun Cho

  2. Department of Pharmacology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

    Han-Seok Jeong, Da-Hye Lee, Seung-Hoon Kim, Chang-Han Lee & Chung-Hyun Cho

  3. Wide River Institute of Immunology, College of Medicine, Seoul National University, Hongcheon, 25159, Republic of Korea

    Hyun Mu Shin

  4. Department of Anatomy and Cell Biology, Seoul National University, Seoul, 03080, Republic of Korea

    Hang-Rae Kim

  5. Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

    Chung-Hyun Cho

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Contributions

HSJ performed majority of the experiments, analyzed the results, and wrote the manuscript. CHC (corresponding author) supervised the project and wrote the manuscript. DHL and SHK assisted with all experiments and reviewed the manuscript. HMS and HRK performed RNA sequencing, pathway analysis, and reviewed the manuscript. CHL helped in project design, data analysis, and reviewed the manuscript.

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Correspondence to Chung-Hyun Cho.

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Jeong, HS., Lee, DH., Kim, SH. et al. Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1. Oncogene 41, 1634–1646 (2022). https://doi.org/10.1038/s41388-022-02207-y

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