K-ras activation generates an inflammatory response in lung tumors

Ji, Hongbin; Houghton, A. McGarry; Mariani, Thomas J.; Perera, Samanthi A.; Kim, C. B.; Padera, Robert F.; Tonon, Giovanni; McNamara, Kate; Marconcini, Luiz A; Hezel, Aram F.; El-Bardeesy, Nabeel; Bronson, Roderick T.; Sugarbaker, David J.; Maser, Richard S.; Shapiro, Steven D.; Wong, Kwok-Kin

doi:10.1038/sj.onc.1209237

Cited by 245 publications

(222 citation statements)

References 34 publications

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“…6H show a lung tumor with positive staining for SP-C, despite its originating in the bronchioalveolar epithelium, and weak CCSP staining. The progressive loss of CCSP as lung tumors gain an aggressive phenotype has been reported previously (Linnoila et al 2000;Ji et al 2006).…”

Section: Amplification Of the Basc Pool In P27 Ck − Micementioning

confidence: 94%

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Besson¹,

Hwang²,

Cicero³

et al. 2007

Genes Dev.

197

182

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The cell cycle inhibitor p27 Kip1 also has cyclin-cyclin-dependent kinase (CDK)-independent functions. To investigate the significance of these functions in vivo, we generated a knock-in mouse in which four amino acid substitutions in the cdkn1b gene product prevent its interaction with cyclins and CDKs (p27 CK − ). In striking contrast to complete deletion of the cdkn1b gene, which causes spontaneous tumorigenesis only in the pituitary, the p27 CK − protein dominantly caused hyperplastic lesions and tumors in multiple organs, including the lung, retina, pituitary, ovary, adrenals, spleen, and lymphomas. Moreover, the high incidence of spontaneous tumors in the lung and retina was associated with amplification of stem/progenitor cell populations. Therefore, independently of its role as a CDK inhibitor, p27 Kip1 promoted stem cell expansion and functioned as a dominant oncogene in vivo. Thus, the p27 CK − mouse unveils a dual role for p27 during tumorigenesis: It is a tumor suppressor by virtue of its cyclin-CDK regulatory function, and also an oncogene through a cyclin-CDK-independent function. This may explain why the cdkn1b gene is rarely inactivated in human tumors, and the p27 CK − mouse in which the tumor suppressor function is lost but the cyclin-CDK-independent-oncogenic-function is maintained may represent a more faithful model for the widespread role of p27 misregulation in human cancers than the p27 null.[Keywords: p27 Kip1 ; lung tumor; oncogene; retina; bronchioalveolar stem cell; desquamative interstitial pneumonitis] Supplemental material is available at http://www.genesdev.org.

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Section: Amplification Of the Basc Pool In P27 Ck − Micementioning

confidence: 94%

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Besson¹,

Hwang²,

Cicero³

et al. 2007

Genes Dev.

197

182

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“…Tumors in various mouse models of KRAS-driven lung cancer -such as Cc10-Cre;Kras G12D (also known as Ccsp-Cre;Kras G12D ), Adeno-Cre;Kras G12D and Kras LA1 modelsupregulate neutrophil-related chemokines and display expansion of neutrophils 90,[106][107][108][109] ( Figure 2). These phenotypes may be a result of direct upregulation of neutrophil-related cytokines like GM-CSF and CXCL8 by KRAS signaling 29,30,110 .…”

Section: Neutrophils and Tumor Initiationmentioning

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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“…Because most of the SCLC lesions are found in bronchioles and terminal bronchioles, which are composed in majority of Clara cells, we crossed Rb lox/lox ;p53 loxlox mice to Scgb1a1-Cre mice. [19][20][21] Scgb1a1 codes for the Clara cell-specific protein (CCSP, also known as CCA or CC10), which marks Clara cells throughout the distal bronchiolar epithelium as well as BASCs at the BADJ 15,22 and Cre expression in the Scgb1a1-Cre strain, has been shown to be limited to the bronchiolar epithelium. [19][20][21] To confirm these previous reports, we crossed Scgb1a1-Cre mice to Rosa26 lox-stop-lox-LacZ (Rosa26R) reporter mice, where lacZ expression is induced after Cre-mediated recombination, 23 and detected lacZ activity by X-gal staining in the bronchiolar epithelium but not in neuroendocrine cells, as expected (Fig.…”

Section: Characterization Of the Cell Of Origin For Small Cell Lung Cmentioning

confidence: 99%

Characterization of the cell of origin for small cell lung cancer

et al. 2011

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K-ras activation generates an inflammatory response in lung tumors

Cited by 245 publications

References 34 publications

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Neutrophils in cancer: neutral no more

Characterization of the cell of origin for small cell lung cancer

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K-ras activation generates an inflammatory response in lung tumors

Cited by 245 publications

References 34 publications

Discovery of an oncogenic activity in p27Kip1that causes stem cell expansion and a multiple tumor phenotype

Discovery of an oncogenic activity in p27Kip1that causes stem cell expansion and a multiple tumor phenotype

Neutrophils in cancer: neutral no more

Characterization of the cell of origin for small cell lung cancer

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Product

Resources

About

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype