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Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice
Maciej Kujawski, … , Heidi Kay, Hua Yu
Maciej Kujawski, … , Heidi Kay, Hua Yu
Published September 5, 2008
Citation Information: J Clin Invest. 2008;118(10):3367-3377. https://doi.org/10.1172/JCI35213.
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Research Article Oncology

Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice

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Abstract

The underlying molecular mechanisms that cause immune cells, mediators of our defense system, to promote tumor invasion and angiogenesis remain incompletely understood. Constitutively activated Stat3 in tumor cells has been shown to promote tumor invasion and angiogenesis. Therefore, we sought to determine whether Stat3 activation in tumor-associated inflammatory cells has a similar function. We found that Stat3 signaling mediates multidirectional crosstalk among tumor cells, myeloid cells in the tumor stroma, and ECs that contributes to tumor angiogenesis in mice. Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. Stat3-regulated factors produced by both tumor cells and tumor-derived myeloid cells also induced constitutive activation of Stat3 in tumor endothelium, and inhibiting Stat3 in ECs substantially reduced in vitro tumor factor–induced endothelial migration and tube formation. In vivo assays demonstrated the requirement for Stat3 signaling in tumor-associated myeloid cells for tumor angiogenesis. Our results indicate that, by virtue of the ability of Stat3 in tumor cells and tumor-derived myeloid cells to upregulate expression of factors that activate Stat3 in ECs, Stat3 mediates multidirectional crosstalk among tumor cells, tumor-associated myeloid cells, and ECs that contributes to tumor angiogenesis.

Authors

Maciej Kujawski, Marcin Kortylewski, Heehyoung Lee, Andreas Herrmann, Heidi Kay, Hua Yu

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Figure 1

Role of Stat3 in the contribution of tumor-associated MDSCs to tumor angiogenesis.

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Role of Stat3 in the contribution of tumor-associated MDSCs to tumor ang...
(A) Flow cytometric analysis of cells isolated from spleens and B16 tumors shows accumulation of Gr1+CD11b+ cells in the tumors and spleens of tumor-bearing mice. Cells were labeled with antibodies for CD11b, CD11c, and Gr1, as indicated. (B) Top: Western blot analysis of VEGF protein levels in Gr1+CD11b+ cells isolated from B16 melanoma. Gr1+CD11b+ cells were purified by flow cytometric cell sorting, using spleens and/or tumors from mice with Stat3+/+ and Stat3–/– hematopoietic systems. Bottom: Flow cytometric analysis of CD11b+ cells isolated from B16 tumors indicates increased Stat3 activation in Stat3+/+ but not in Stat3–/– cells. (C) ECs form tube structures when coincubated with Stat3+/+ but not Stat3–/– MDSCs (Gr1+CD11b+CD11c–) isolated directly from B16 melanoma (tumor-associated MDSCs; TM-MDSC). Tumor supernatant (spnt) was also added to the EC culture as a positive control. Graph shows mean ± SEM of 2 independent experiments (n = 3). *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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