Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF–induced neutrophil recruitment

Phan, Vernon T.; Wu, Xiumin; Cheng, Jason H.; Sheng, Rebecca X.; Chung, Alicia S.; Zhuang, Guanglei; Tran, Christopher; Song, Qinghua; Kowanetz, Marcin; Sambrone, Amy; Tan, Martha; Meng, Y. Gloria; Jackson, Erica; Peale, Franklin; Junttila, Melissa R.; Ferrara, Napoleone

doi:10.1073/pnas.1303302110

Cited by 106 publications

(84 citation statements)

References 47 publications

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“…These data suggest that simultaneous inhibition of neutrophils and anti-angiogenic therapy might be an effective anticancer strategy. Indeed, therapeutic synergy is observed when anti-VEGFA therapy is combined with depletion of neutrophils via anti-Gr1 or anti-G-CSF antibodies 179,181 .…”

Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

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: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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“…PLR can occur in 10% to 15% of cancer patients and are strongly predictive of poor clinical outcomes (33,34). We have previously reported that activation of the oncogenic RAS/MEK/ERK pathway induces expression of G-CSF from tumor cells through the Ets transcription factor (37). Blockade of G-CSF release through MEK inhibition, antibody-mediated G-CSF neutralization, or targeted inactivation of the G-CSF receptor in mice, resulted in suppression of aberrant neutrophil accumulation and inhibition of tumor angiogenesis and metastasis (35,(37)(38)(39).…”

Section: Deregulation Of Neutrophils By the Tumor Microenvironmentmentioning

confidence: 99%

“…We have previously reported that activation of the oncogenic RAS/MEK/ERK pathway induces expression of G-CSF from tumor cells through the Ets transcription factor (37). Blockade of G-CSF release through MEK inhibition, antibody-mediated G-CSF neutralization, or targeted inactivation of the G-CSF receptor in mice, resulted in suppression of aberrant neutrophil accumulation and inhibition of tumor angiogenesis and metastasis (35,(37)(38)(39). The significance of tumor-derived GM-CSF or IL6 on neutrophil homeostasis in malignancies has been less extensively characterized.…”

Section: Deregulation Of Neutrophils By the Tumor Microenvironmentmentioning

confidence: 99%

The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis

Liang

Ferrara

2016

Cancer Immunology Research

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Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumorassociated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis.

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“…Oncogenic pathways also influence the recruitment of inflammatory cells, which themselves may exhibit pro-angiogenic and pro-coagulant phenotypes [51,52]. For example, myeloid cells and monocytes could release TF-containing EVs (microparticles/MPs) [53], while neutrophils may deploy extracellular chromatin traps (NET-osis) [54], or participate in other events that could add to cancer-related coagulation perturbations.…”

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confidence: 99%