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Allergic Pulmonary Inflammation Promotes the Recruitment of Circulating Tumor Cells to the Lung

Divisions of ¹ Pulmonary Medicine and ² Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona; ³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, ⁴ Mayo Clinic Comprehensive Cancer Center, Genetic Epidemiology and Risk Assessment, and ⁵ Mayo Clinic Comprehensive Cancer Center, Division of Surgical Oncology, Mayo Clinic Rochester, Rochester, Minnesota; ⁶ Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and ⁷ National Institute of Environmental Health Sciences, Laboratory of Signal Transduction, Research Triangle Park, North Carolina

Requests for reprints: James J. Lee, Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, SCJMRB-Research, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259. Phone: 480-301-7183; Fax: 480-301-7017; E-mail: jjlee{at}mayo.edu.

Key Words: Metastasis • Asthma • Endothelial Cell • Diapedesis • Breast Cancer

Allergen-induced respiratory inflammation facilitates and/or elicits the extravasation of proinflammatory leukocytes by well-understood mechanisms that mediate the movement of multiple cell types. The nonspecific character of these pathways led us to hypothesize that circulating cancer cells use similar mechanisms, promoting secondary tumor formation at distal sites. To test this hypothesis, the frequency of metastasis to the lung as a function of allergic pulmonary inflammation was assessed following the i.v. injection of B16-F10 melanoma cells in mice. These studies showed that allergen-induced pulmonary inflammation resulted in a >3-fold increase in lung metastases. This increase was dependent on CD4⁺ T-cell activities; however, it occurred independent of the induced eosinophilia associated with allergen provocation. Interventional strategies showed that existing therapeutic modalities for asthma, such as inhaled corticosteroids, were sufficient to block the enhanced pulmonary recruitment of cancer cells from circulation. Additional mechanistic studies further suggested that the ability of circulating cancer cells to extravasate to surrounding lung tissues was linked to the activation of the vascular endothelium via one or more G_i-coupled receptors. Interestingly, a survey of a clinical breast cancer surgical database showed that the incidence of asthma was higher among patients with lung metastases. Thus, our data show that allergic respiratory inflammation may represent a risk factor for the development of lung metastases and suggest that amelioration of the pulmonary inflammation associated with asthma will have a direct and immediate benefit to the 7% to 8% of breast cancer patients with this lung disease. [Cancer Res 2008;68(20):8582–9]

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