NYMC Faculty Publications
CYP4a in Tumor-associated Macrophages Promotes Pre-metastatic Niche Formation and Metastasis
Author Type(s)
Faculty
DOI
10.1038/onc.2017.118
Journal Title
Oncogene
First Page
5045
Last Page
5057
Document Type
Article
Publication Date
8-1-2017
Department
Pharmacology
Keywords
cytochrome P-450 CYP4A genetics, breast neoplasms, enyzmology, genetics, pathology, tumor cell line, heterografts, female, humans, macrophages, experimental melanoma, mice, inbred C57BL mice, neoplasm metastasis, prognosis
Disciplines
Medicine and Health Sciences
Abstract
Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A+. TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1+.) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1+. myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1+. myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-beta, VEGF and SDF-1 abolished VEGFR1+. myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.Oncogene advance online publication, 8 May 2017; doi:10.1038/onc.2017.118.
Recommended Citation
Chen, X., Yu, T., Zhang, J., Li, Y., Chen, H., Guo, A., Yang, J., & Yang, J. (2017). CYP4a in Tumor-associated Macrophages Promotes Pre-metastatic Niche Formation and Metastasis. Oncogene, 36 (35), 5045-5057. https://doi.org/10.1038/onc.2017.118
Comments
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