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

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 7

Stat3 is critical for myeloid cell–induced tumor angiogenesis by in vivo.

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Stat3 is critical for myeloid cell–induced tumor angiogenesis by in vivo...
(A) Matrigel plugs containing a mixture of B16 melanoma cells and CD11b+CD11c– myeloid cells isolated from spleens of tumor-bearing mice were implanted into mice with Stat3–/– hematopoietic system. Both Stat3+/+ and Stat3–/– myeloid cells were used for the Matrigel assays. Plugs were harvested for hemoglobin content measurement 6 d after implanting in vivo. Data are mean ± SEM of 3 independent experiments combined. *P < 0.05 (see Methods, Table 1, and Table 2 for detailed statistical analysis). (B) Representative microphotographs of Matrigel plug frozen sections stained with CD31 (red) and pY705-Stat3 (green) antibodies. Arrows indicate newly formed vessels. Original magnification, ×100. (C) Stat3 activity allows multidirectional crosstalk in the tumor stroma. Stat3 activity in tumor cells propagates, through Stat3-regulated factors (circles), to myeloid cells and ECs, and Stat3 activity in myeloid cells can further impact Stat3 activity in ECs, contributing to tumor angiogenesis.