Identification of a G-CSF-Granulocytic MDSC axis that promotes tumor progression

Abrams, Scott I.; Waight, Jeremy D.

doi:10.4161/onci.19334

Cited by 46 publications

(40 citation statements)

References 10 publications

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“…Moreover, when CAIX levels are diminished within the primary tumor, circulating G-CSF levels are near those observed in na€ ve mice, resulting in a concomitant reduction in G-MDSC detected in the lung. On the basis of our observations identifying reduced plasma G-CSF in mice with CAIX-depleted tumors, it is likely that the observed CAIX-G-CSF axis is one mode by which CAIX activity promotes the metastasis of hypoxic breast cancers, by influencing the G-CSF-granulocytic MDSC axis (44). These important findings are our contribution to this field.…”

Section: Discussionmentioning

confidence: 57%

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Chafe¹,

Lou²,

Sceneay

et al. 2015

Cancer Research

117

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The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-kB in hypoxic breast cancer cells and constitutive activation of the NF-kB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-kB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche. Cancer Res; 75(6); 996-1008.Ó2015 AACR.

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Section: Discussionmentioning

confidence: 57%

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Chafe¹,

Lou²,

Sceneay

et al. 2015

Cancer Research

117

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“…Similarly, tumor-secreted G-CSF that contributes to neutrophil mobilization, activation and stimulation of oxidative metabolism [188][189][190][191], is also involved in the polarization towards immunosuppressive MDSCs [192,193]. The presence of G-MDSCs was shown to be important for promoting tumor growth [193].…”

Section: Regulation Of Neutrophil Mobilization Recruitment and Activmentioning

confidence: 99%

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Sionov

Fridlender

Granot

2014

Cancer Microenvironment

342

261

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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

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“…It was revealed that tumor-induced granulocyte colony-stimulating factor (G-CSF) is one of those factors (Waight et al 2011;Abrams and Waight 2012;Luyckx et al 2012;Kawano et al 2015). Our recent study also showed that the serum G-CSF level is associated with the inhibition of expansion and differentiation of G-MDSCs in tumor-bearing adiponectin knockout mice (Han et al 2013).…”

Section: The Subsets Of Mdscsmentioning

confidence: 86%

“…Recently, fibrocytic MDSCs (F-MDSCs) are characterized as a novel MDSC subset in human (Abrams and Waight 2012;Zhang et al 2013;Mazza et al 2014;Zoso et al 2014;Gunaydin et al 2015). F-MDSCs show tumorassociated circulating fibrocyte phenotypes and have T cell-mediated immunosuppressive functions.…”

Section: The Subsets Of Mdscsmentioning

confidence: 99%

Phenotypic and functional dissection of myeloid-derived suppressor cells

Han

Yang

2016

Appl Biol Chem

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Myeloid-derived suppressor cells (MDSCs) are originated and differentiated population from common hematopoietic progenitor cells. Generally, in the late stage of inflammation, MDSCs differentiation and expansion are promoted to suppress the over-activated immune system so that the immune system can maintain the homeostasis. Recently, it has been revealed that MDSCs accumulate in cancer patients and tumor-bearing experimental animals, and these tumor-derived MDSCs suppress anti-tumor immunity by secreting immunosuppressive cytokines including reactive oxygen species and inducible nitric oxide synthase. This fact prompts scientists to shed light on MDSCs as significant targets for anti-cancer immunotherapy. However, due to morphological, phenotypic, and functional heterogeneities of MDSCs, it is not easy to develop therapeutic strategies targeting MDSCs. In this review, we will summarize recent progress on defined subsets of MDSCs and their strategies to suppress T cellmediated anti-tumor immunity.

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Identification of a G-CSF-Granulocytic MDSC axis that promotes tumor progression

Cited by 46 publications

References 10 publications

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Phenotypic and functional dissection of myeloid-derived suppressor cells

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