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

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.

Comments

Please see the work itself for the complete list of authors.

Link to Full Text

Share

COinS