Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts

Yao, Min; Smart, Curtis; Hu, Qingting; Cheng, Nikki

doi:10.1016/j.tranon.2017.06.009

Cited by 16 publications

(15 citation statements)

References 39 publications

(83 reference statements)

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“…PI3Ki in SKBr3 upon treatment with EGF/HRG induced a reduction in CCL2 expression at both the mRNA and protein level (Figure 5A and 5B, respectively). Conversely, MEKi induced up-modulation of CCL2, likely owing to the described activation of Akt upon continuous blockage of MEK signals, 17 as we also observed in our models (data not shown). Downstream of the PI3K-AKT pathway, BAY 11–7082, a NF-kB inhibitor, significantly reduced the CCL2 improvement mediated by EGF/HRG in SKBr3 cells (Figure 5A-B).…”

Section: Resultssupporting

confidence: 82%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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Section: Resultssupporting

confidence: 82%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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“…Ceasing treatment with CCL2 inhibitors resulted in regrowth of breast tumor xenografts in animal models (66). However, this rebound may be due to neutralizing antibodies themselves, rather than CCL2 as a target (20). These present studies indicate that targeting CCL2 or CCR2 expression inhibits tumor growth and could provide a therapeutic benefit when combined with other therapies.…”

Section: Discussionmentioning

confidence: 69%

“…Tissues were fixed in 10% neutral formalin buffer (NBF), paraffin embedded, and hematoxylin and eosin (H&E) stained as described (20). For immunostaining, 5-mm sections were dewaxed and heated in 10 mmol/L sodium citrate (pH 6.0) at low pressure for 2 minutes using a pressure cooker.…”

Section: Histology/immunohistochemistrymentioning

confidence: 99%

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Yao

Fang

Smart

et al. 2019

Molecular Cancer Research

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Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation.Implications: This report sheds novel light on CCL2/ CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.

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“…CCL2 regulates the monocyte and macrophage migration and infiltration into inflamed, but also tumor tissues. Therefore, a variety of cancers, e.g., glioma [ 110 ], breast tumors [ 111 ], or prostate cancer [ 112 ] are associated with increased serum concentrations of CCL2. Physiological anti-tumor responses can be inhibited by tumor-associated macrophages (TAMs) or myeloid-derived suppressor cells (MDSCs), which promote tumor growth [ 110 ].…”

Section: C-c Motif Chemokine Ligandmentioning

confidence: 99%

“…There, tumor growth, macrophage recruitment, and tumor angiogenesis were not affected by CCL2 blockade. Surprisingly, human CCL2 levels were significantly increased in both circulating blood and tumor interstitial fluid, whereas murine CCL2 levels were not affected [ 111 ].…”

Section: C-c Motif Chemokine Ligandmentioning

confidence: 99%

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

Dommel¹,

Blüher

2021

IJMS

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The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases.

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Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts

Cited by 16 publications

References 39 publications

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

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