Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

Tsai, Chien-Sheng; Chen, Fang-Hsin; Wang, Chun‐Chieh; Huang, Hsin‐Chun; Jung, Shih‐Ming; Wu, Chi‐Jung; Lee, Chung-Chi; McBride, William H.; Chiang, Chi-Shiun; Hong, Ji-Hong

doi:10.1016/j.ijrobp.2007.01.041

Cited by 206 publications

(157 citation statements)

References 35 publications

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“…For instance, radiation activates latent transforming growth factor β (87,88). There is also some evidence that radiation enhances the immunosuppressive and protumorigenic phenotype of macrophages (89,90). Recent data indicate that Treg cells are intrinsically more radio resistant than other T cells and are proportionally increased after radiotherapy (91,92).…”

Section: Why Are Abscopal Effects Uncommon?mentioning

confidence: 99%

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Formenti

Demaria²

2013

JNCI: Journal of the National Cancer Institute

852

660

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The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.

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Section: Why Are Abscopal Effects Uncommon?mentioning

confidence: 99%

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Formenti

Demaria²

2013

JNCI: Journal of the National Cancer Institute

852

660

View full text Add to dashboard Cite

show abstract

“…While the M1 phenotype has anti-tumor effects, M2 may promote tumor growth, 27 immune suppression, 54,55 or tumor re-growth after RT. 56 The functional phenotypes of TAMs can change in response to different microenvironments. 57,58 This has brought caution to defining TAM subtypes.…”

Section: Sdf-1 Promotes Glioma Invasion and Tam Tropism S-c Wang Et Almentioning

confidence: 99%

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

Wang

Hong

Hsueh

et al. 2012

Laboratory Investigation

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A distinguishing feature of high-grade gliomas is the infiltration of neoplastic cells into adjacent brain tissues that mark most of these tumors surgically incurable. To study the factors associated with tumor invasion, we established a new murine brain tumor model, ALTS1C1 derived from SV40 large T antigen-transfected astrocytes. This new brain tumor model recapitulates several histopathological features of human high-grade glioma including increased cellularity, prominent cellular pleomorphism, geographic necrosis, active mitosis, and extensive invasion of tumor cells into adjacent brain tissues. More importantly, ALTS1C1 expressed a relatively high level of stromal-derived factor-1 (SDF-1/CXCL12) in vitro and in vivo and higher microvascular density (MVD) in vivo. To define the roles of SDF-1 in this tumor model, the expression of SDF-1 in ALTS1C1 cells was inhibited by specific siRNA. SDF-knockdown ALTS1C1 (SDF kd ) cells took longer than parental ALTS1C1 cells to form tumors and in contrast to the wild-type tumors they had well-defined regular borders and lacked infiltration tracts. The SDF kd tumors were also associated with a lower MVD and more hypoxic areas. In contrast to parental tumors, the density of F4/80-positive tumor-associated macrophages (TAMs) in SDF kd tumor was higher in non-hypoxic than in hypoxic regions. SDF-1 production by tumor cells therefore seems critical for the aggregation of TAMs into areas of hypoxia and tumor invasiveness. This study not only provides new insight into the role of SDF-1 in brain tumor invasion and the relationship between TAMs and hypoxia, but also provides a new preclinical brain tumor model for designing new treatment options for invasive cases.

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“…Classically, proinflammatory (M1) macrophages express inducible NO synthase (iNOS) and metabolize arginine by releasing NO (or RNI) and citrulline, whereas immunosuppressive (M2) macrophages up-regulate arginase (I and II) to metabolize arginine into urea and L-ornithine (29). Interestingly, in some mouse tumor models TAM express high levels of both iNOS and arginase-1 simultaneously (30,31). TAM from murine fibrosarcoma, which otherwise show a M2 phenotype, also express proinflammatory Th1 chemokines like CCL5, CXCL9, and CXCL10 (9).…”

Section: Plasticity and Divergent Macrophage Phenotypes In Tumorsmentioning

confidence: 99%

Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms

Biswas

Sica

Lewis

2008

The Journal of Immunology

377

318

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Recent studies have shown that macrophages play an important part in both tumor initiation and various key steps in growth and metastasis. These cells show a remarkable degree of plasticity during tumor development with a “switch” in macrophage phenotypes occurring during the course of tumor progression. During chronic inflammation they appear to predispose a given tissue to tumor initiation by the release of factors that promote neoplastic transformation. Following this, their phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis. In this review, we discuss the evidence for this plasticity of macrophage functions, the specific signaling mechanisms that may be regulating it, and the new targets for anticancer therapies highlighted by these findings.

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Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

Cited by 206 publications

References 35 publications

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms

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