Differentiation and gene expression profile of tumor-associated macrophages

Schmieder, Astrid; Michel, Julia; Schönhaar, Kathrin; Goerdt, Sergij; Schledzewski, Kai

doi:10.1016/j.semcancer.2012.02.002

Cited by 202 publications

(149 citation statements)

References 115 publications

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“…34,35 In agreement, mRNA for IFNg, a cytokine produced by Th1 and CD8 C T cells, was strongly upregulated by NGR-mTNF treatment, supporting the idea of an increased infiltration and/or activation of proinflammatory lymphocytes. The expression level of several genes involved in proangiogenesis and vessel abnormalization 28,36 was not altered (Fig. 5A).…”

Section: Ngr-mtnf Treatment Upregulates Mrna Levels Of Ifng Proinflamentioning

confidence: 95%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-a (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG ¡/¡ ) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGRmTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8 C T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGRmTNF-treated tumors from immunocompetent mice.These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment.

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Section: Ngr-mtnf Treatment Upregulates Mrna Levels Of Ifng Proinflamentioning

confidence: 95%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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“…M2 macrophages are typically induced by type II cytokines (IL-4, IL-10 and IL-13) and have reduced antigen presentation capacity, promote angiogenesis through secretion of VEGF, facilitate tissue remodeling and ultimately tumor progression [76]. Evaluation of immune cell infiltrates in 21 MCC tumors, found that nearly all of the macrophages present within MCC stained positive for CD163, a marker often used to identify M2 macrophages.…”

Section: Infiltration Of M2 Macrophagesmentioning

confidence: 99%

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

Vandeven

Nghiem

2016

Immunotherapy

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Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (∼80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virusnegative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immunebased approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

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“…3 TAMs develop a phenotype similar to M2-polarized macrophages and respond to recruitment to the tumor microenvironment. 4 Previous studies have commonly associated elevated numbers of TAMs with tumor progression and poor patient outcome. 5 This association is likely linked to the typical presence of M2-polarized TAMs during cancer invasion, 6 however, the exact mechanisms by which these cells influence the progression of pancreatic cancer are not clear.…”

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confidence: 99%

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

Liu

Shi

et al. 2013

Laboratory Investigation

383

290

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M2-polarized tumor-associated macrophages (TAMs) are key regulators of the link between inflammation and cancer. A negative correlation between infiltration intensity of M2-polarized TAMs and prognosis of pancreatic cancer has been reported. Epithelial-mesenchymal transition (EMT) is an important biological process in the progression of primary tumors toward metastasis. Inflammation-induced EMT has been previously shown, therefore, we hypothesized M2-polarized TAMs could induce EMT in pancreatic cancer. Toll-like receptor 4 (TLR4) signaling has an active role in tumor progression during chronic inflammation and the receptor is primarily expressed on macrophages. Activation of TLR4 on M2-polarized TAMs stimulates an increase in the cytokine interleukin-10 (IL-10); consequently, another aim was to investigate the potential role of TLR4/IL-10 signaling in the EMT of pancreatic cancer. Treatment with IL-4 (20 ng/ml) for 24 h successfully induced the polarization of macrophage cell line RAW 264.7 to M2 phenotype, IL-10 high , IL-12 low , and IL-23 low , and high expression of CD204 and CD206. A coculture system allowed investigation of the roles of M2-polarized TAMs and TLR4/IL-10 signaling in the EMT of Panc-1 and BxPC-3 pancreatic cancer cell lines. Our results showed that coculture with M2-polarized TAMs increased fibroblastic morphology, upregulated mesenchymal markers vimentin and snail at the mRNA and protein levels, and increased proliferation, migration, and metalloproteinase (MMP)2 and MMP9 proteolytic activity in pancreatic cancer cells. Simultaneously, coculture with M2-polarized TAMs decreased the expression of the epithelial marker E-cadherin. Coculture with pancreatic cancer cells increased TLR4 mRNA and protein expression in M2-polarized TAMs. Application of TLR4 siRNA and neutralizing antibodies against TLR4 and IL-10 markedly inhibited E-cadherin reduction and the upregulation of snail and vimentin. Furthermore, activation of TLR4 signaling by lipopolysaccharide profoundly increased the EMT of pancreatic cancer cells. In conclusion, M2-polarized TAMs promoted EMT in pancreatic cancer cells partially through TLR4/IL-10 signaling, suggesting novel therapeutic strategies and enhancing our understanding of M2-polarized TAMs. Pancreatic ductal adenocarcinoma is highly malignant and is resistant to chemo-and radiotherapeutics. 1 Recent evidence suggests the inflammatory environment of the tumor is critical for its progression. 2 Tumor-associated macrophages (TAMs) are derived from circulating monocytes, which are highly abundant within the tumor and provide a key link between inflammation and cancer. 3 TAMs develop a phenotype similar to M2-polarized macrophages and respond to recruitment to the tumor microenvironment. 4 Previous studies have commonly associated elevated numbers of TAMs with tumor progression and poor patient outcome. 5 This association is likely linked to the typical presence of M2-polarized TAMs during cancer invasion, 6 however, the exact mechanisms by which these cells influence the pr...

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Differentiation and gene expression profile of tumor-associated macrophages

Cited by 202 publications

References 115 publications

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

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