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G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

ABSTRACT: Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DR^lo macrophages that promoted migration of breast cancer cells via secretion of TGF-?. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p < 0.001) and associated with CD163⁺ macrophages (p < 0.0001), poorer overall survival (OS) (p = 0.021) and significantly increased numbers of TGF-?⁺ cells. While G-CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCII^hi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCII^loF4/80^hiMR^hi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called "gate-keeper" subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression.

SUBMITTER: Hollmen M

PROVIDER: S-EPMC4839343 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

Hollmén Maija M Karaman Sinem S Schwager Simon S Lisibach Angela A Christiansen Ailsa J AJ Maksimow Mikael M Varga Zsuzsanna Z Jalkanen Sirpa S Detmar Michael M

Oncoimmunology 20151124 3

Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-s ...[more]

PMID: 27141367

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Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

Project description:Several lines of evidence suggest that altered adenosine deaminase (ADA) activity, especially its ADA2 iso-enzyme, is associated with malignant breast cancer (BC) development. Triple-negative breast cancer (TNBC) is currently the most challenging BC subtype due to its metastatic potential and recurrence. Herein, we analyzed the sources of ADA iso-enzymes in TNBC by investigating the effects of cell-to-cell interactions between TNBC cells, macrophages, lymphocytes, and endothelial cells. We also examined the potential relationship between ADA activity and cancer progression in TNBC patients. In vitro analyses demonstrated that the interactions of immune and endothelial cells with MDA-MB-231 triple negative BC cells modulated their extracellular adenosine metabolism pattern. However, they caused an increase in the ADA1 activity, and did not alter ADA2 activity in cancer cells. In turn, the co-culture of MDA-MB-231 cells with THP-1 monocyte/macrophages, Jurkat cells, and human lung microvascular endothelial cells (HULEC) caused the increase in ADA2 activity on THP-1 cells and ADA1 activity on Jurkat cells and HULEC. Clinical sample analysis revealed that TNBC patients had higher plasma ADA2 activities and lower ADA1/ADA2 ratio at advanced stages of cancer development than in the initial stages, while patients with hormone receptor positive, HER2 negative (HR+HER2-), and triple positive (HR+HER2+) breast cancers at the same stages showed opposite trends. TNBC patients also demonstrated positive associations between plasma ADA2 activity and pro-tumor M2 macrophage markers, as well as between ADA1 activity and endothelial dysfunction or inflammatory parameters. The analysis of TNBC patients, at 6 and 12 months following cancer treatment, did not showed significant changes in plasma ADA activities and macrophage polarization markers, which may be the cause of their therapeutic failure. We conclude that alterations in both ADA iso-enzymes can play a role in breast cancer development and progression by the modulation of extracellular adenosine-dependent pathways. Additionally, the changes in ADA2 activity that may contribute to the differentiation of macrophages into unfavorable pro-tumor M2 phenotype deserve special attention in TNBC.

Project description:Background:Recently, researchers have classified highly heterogeneous triple negative breast cancer (TNBC) into different subtypes from different perspectives and investigated the characteristics of different subtypes to pursue individualized treatment. With the increase of immunotherapy and its preliminary application in TNBC treatment, the value of immune-related strategies in the treatment of TNBC has been initially reflected. Based thereon, this study plans to classify and further explore TNBC from the perspective of immune cell infiltration. Method:The fractions of immune cells of TNBC patients were assessed by six immune component analysis methods in The Cancer Genome Atlas (TCGA) database. Hub genes significantly related to poor prognosis were verified by weighted gene co-expression network analysis (WGCNA) analysis, Lasso analysis, and univariate KM analysis. Two cohorts of TNBC patients with complete prognosis information were collected for validation analysis. Finally, the Genomics of Drug Sensitivity in Cancer (GDSC) database was adopted to ascertain the sensitivity differences of different populations based on hub-gene grouping to different chemotherapy drugs. Results:Five hub genes (CD79A, CXCL13, IGLL5, LHFPL2, and PLEKHF1) of the key co-expression gene module could divide TNBC patients into two groups (Cluster A and Cluster B) based on consistency cluster analysis. The patients with Cluster A were responsible for significantly worse prognosis than the patients with Cluster B (P = 0.023). In addition, another classification method, PCoA, and two other datasets (GSE103091 and GSE76124), were used to obtain consistent results with previous findings, which verified the stability of the classification method and dataset in this study. The grouping criteria based on the previous results were developed and the accuracy of the cut-off values was validated. A prognosis model of TNBC patients was then constructed based on the grouping results of five hub genes and N staging as prognostic factors. The results of ROC and decision curve analyses showed that this model had high prediction accuracy and patients could benefit therefrom. Finally, GDSC database analysis proved that patients in Cluster A were more sensitive to Vinorelbine. Separate analysis of the sensitivity of patients in Cluster A to Gemcitabine and Vinorelbine showed that the patients in Cluster A exhibited higher sensitivity to Vinorelbine. We hypothesized that these five genes were related to gemcitabine resistance and they could serve as biomarkers for clinical drug decision-making after anthracene resistance and taxane resistance in patients with advanced TNBC. Conclusion:This study found five hub prognostic genes associated with macrophages, and a prognostic model was established to predict the survival of TNBC patients. Finally, these five genes were related to gemcitabine resistance in TNBC patients.

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G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

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G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

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