TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

Pang, Yanli; Gara, Sudheer Kumar; Achyut, Bhagelu R.; Li, Zhaoyang; Yan, Hannah H.; Day, Chi-Ping; Weiss, Jonathan M.; Trinchieri, Giorgio; Morris, John C.; Yang, Li

doi:10.1158/2159-8290.cd-12-0527

Cited by 133 publications

(148 citation statements)

References 58 publications

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“…Transforming growth factor β (TGFβ), G-CSF and interferon β (IFNβ) are the most well-studied molecules in this process. TGFβ and G-CSF activate a tumor-and metastasispromoting program 25,27,65,[85][86][87][88] , by regulating the transcription factors inhibitor of DNA 1 (ID1), retinoblastoma 1 (RB1) and interferon regulatory factor 8 (IRF8) that control the immunosuppressive functions of neutrophils 25,87,89,90 . IFNβ acts as a negative regulator of the pro-tumorigenic phenotype of neutrophils 91,92 .…”

Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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“…TGF-β signaling and crosstalk with other signaling networks can induce cancer cell survival and help them to become more aggressive. 28 Thus, inhibition of TGF-β signaling could be an alternative therapy for cancer patients. 29 Many investigations have recently shown that loss of TGF-β inhibitors and increased TGF-β gene expression are associated with the tumor aggressiveness and would promotes breast, colon, endometrial, ovarian, cervical, and melanoma tumor progression.…”

mentioning

confidence: 99%

Increased P-35, EBI3 Transcripts and Other Treg Markers in Peripheral Blood Mononuclear Cells of Breast Cancer Patients with Different clinical Stages

Hamidinia¹,

Boroujerdnia²,

Talaiezadeh³

et al. 2015

Adv Pharm Bull

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“…Recent studies have showed that host immune cells play a critical role in switching the activity of TGFβ [20,21]. Genetic abrogation of TGFβ signaling specifically in myeloid cells resulted in reduction of bone and lung metastasis in an in vivo mouse model system [20,21]. These two studies have unequivocally suggested that specific targeting of TGFβ signaling in myeloid cells reduces tumor metastasis.…”

Section: Editorialmentioning

confidence: 99%

“…However, the precise molecular mechanisms determining when the TGFβ switches from a tumor suppressor to promoter poses a great challenge in the field. Recent studies have showed that host immune cells play a critical role in switching the activity of TGFβ [20,21]. Genetic abrogation of TGFβ signaling specifically in myeloid cells resulted in reduction of bone and lung metastasis in an in vivo mouse model system [20,21].…”

Section: Editorialmentioning

confidence: 99%