PT  - JOURNAL ARTICLE
AU  - Sabrina de Souza Ferreira
AU  - Tatjana Wallmann
AU  - Thomas Kerzel
AU  - Majken Wallerius
AU  - Margarita Bartish
AU  - Laura-Sophie Landwehr
AU  - Yangxun Pan
AU  - Dennis Alexander Agardy
AU  - Jonas Bergh
AU  - Johan Hartman
AU  - Mario Leonardo Squadrito
AU  - Charlotte Rolny
TI  - Macrophage-derived VEGF-C decreases hematogenous metastatic dissemination by normalizing the tumor vasculature
AID  - 10.1101/2022.01.26.468593
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.26.468593
4099  - http://biorxiv.org/content/early/2022/03/22/2022.01.26.468593.short
4100  - http://biorxiv.org/content/early/2022/03/22/2022.01.26.468593.full
AB  - Expression levels of the pro-lymphangiogenic vascular endothelial growth factor (VEGF)-C in the primary tumor correlates to the occurrence of proximal lymph node metastasis for most solid cancers including those of the breast. However, the role of VEGF-C in regulating tumor cell dissemination to distant organs such as the lungs, is currently unclear. By using an experimental tumor model of breast cancer (BC), we show that perivascular tumor-associated macrophages (TAMs), key regulators of hematogenous spreading, expressing VEGF-C, decrease tumor cell dissemination to the lungs. The mechanism whereby TAM-derived VEGF-C hampered pulmonary mechanism was ascribed to a phenotypic change of TAMs that augmented VEGFR3 expression on tumor vessels facilitating tumor vessel normalization and functionality. In contrast, tumor cell-derived VEGF-C increases vessel abnormalization and pulmonary metastases corresponding to lack of VEGFR3 expression on tumor vessels. Further evidence that TAM-derived VEGF-C may play a role in hematogenous spreading was obtained from human breast cancer specimens. In line with our experimental data, perivascular TAM-derived VEGF-C is inversely correlated with malignant grade and the occurrence of three-cell complexes composed of a perivascular macrophage, a tumor cell and an endothelial cell (collectively defined as tumor microenvironment of metastasis, or TMEM), which are sites of breast cancer intravasation and dissemination. Instead, cancer cell-derived VEGF-C correlated with malignant grade and TMEM complexes. Thus, our study reveals novel and apparent paradoxical roles of TAM-derived VEGF-C in regulating hematogenous tumor spreading in both experimental models and clinical samples.Competing Interest StatementThe authors have declared no competing interest.