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Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.

ABSTRACT: In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is a chitinase-like protein found in human and absent in rodents, and its expression in TAMs and role in breast cancer progression was not studied to date. Here for the first time we demonstrate that YKL-39 is expressed on TAMs, predominantly positive for stabilin-1, but not by malignant cells or other stromal cells in human breast cancer. TGF-beta in combination with IL-4, but not IL-4 alone was responsible of the stimulation of the production of YKL-39 in human primary macrophages. Mechanistically, stabilin-1 directly interacted with YKL-39 and acted as sorting receptor for targeting YKL-39 into the secretory pathway. Functionally, purified YKL-39 acted as a strong chemotactic factor for primary human monocytes, and induced angiogenesis in vitro. Elevated levels of YKL-39 expression in tumors after neoadjuvant chemotherapy (NAC) were predictive for increased risk of distant metastasis and for poor response to NAC in patients with nonspecific invasive breast carcinoma. Our findings suggest YKL-39 as a novel therapeutic target, and blocking of its activity can be combined with NAC in order to reduce the risk of metastasis in breast cancer patients.

SUBMITTER: Liu T

PROVIDER: S-EPMC5980380 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.

Liu Tengfei T Larionova Irina I Litviakov Nikolay N Riabov Vladimir V Zavyalova Marina M Tsyganov Matvey M Buldakov Mikhail M Song Bin B Moganti Kondaiah K Kazantseva Polina P Slonimskaya Elena E Kremmer Elisabeth E Flatley Andrew A Klüter Harald H Cherdyntseva Nadezhda N Kzhyshkowska Julia J

Oncoimmunology 20180313 6

In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is a chitinase-like protein found in human and absent in rodents, and its expression in ...[more]

PMID: 29872578

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Project description:Macrophages constitute a heterogeneous cell population with pro- (M?1) and anti-inflammatory (M?2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by M?1 and M?2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients.Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for M?1 and M?2, respectively) and stimulated for 24 h with LPS, TNF?, or oncostatin M (OSM). M?1 and M?2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA.Pro-inflammatory M?1 cells secreted significantly more YKL-40 than M?2, which was independent of stimulation with LPS, TNF? or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in M?1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment.YKL-40 secretion from M?1 cells is higher than from M?2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in M?1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for M?1 macrophages in vitro, but not for monitoring the effect of ICS in COPD.ClinicalTrials.gov, registration number: NCT00158847.

Dataset Information

Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.

Publications

Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.

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