This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qiu, H. Articles by Al-Mehdi, A.-B. Search for Related Content PubMed PubMed Citation Articles by Qiu, H. Articles by Al-Mehdi, A.-B.

(American Journal of Pathology. 2003;162:403-412.)
© 2003 American Society for Investigative Pathology

Regular Articles

Arrest of B16 Melanoma Cells in the Mouse Pulmonary Microcirculation Induces Endothelial Nitric Oxide Synthase-Dependent Nitric Oxide Release that Is Cytotoxic to the Tumor Cells

Hongming Qiu^*, F.William Orr^*, Derrek Jensen^*, Hui Helen Wang^*, Alan R. McIntosh, Brian B. Hasinoff, Dwight M. Nance^*, Susan Pylypas^*, Ke Qi^*, Chun Song, Ruth J. Muschel^¶ and Abu-Bakr Al-Mehdi^||

From the Department of Pathology,^* Faculty of Medicine, and the Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada; the Department of General Surgery, Nanshan Hospital, Shenzhen, China; the Institute of Environmental Medicine, and the Department of Pathology and Laboratory Medicine,^¶ University of Pennsylvania, Philadelphia Pennsylvania; and the Department of Pharmacology,^|| University of South Alabama, Mobile, Alabama

Metastatic cancer cells seed the lung via blood vessels. Because endothelial cells generate nitric oxide (NO) in response to shear stress, we postulated that the arrest of cancer cells in the pulmonary microcirculation causes the release of NO in the lung. After intravenous injection of B16F1 melanoma cells, pulmonary NO increased sevenfold throughout 20 minutes and approached basal levels by 4 hours. NO induction was blocked by N^G-nitro-L-arginine methyl ester (L-NAME) and was not observed in endothelial nitric oxide synthase (eNOS)-deficient mice. NO production, visualized ex vivo with the fluorescent NO probe diaminofluorescein diacetate, increased rapidly at the site of tumor cell arrest, and continued to increase throughout 20 minutes. Arrested tumor cells underwent apoptosis with apoptotic counts more than threefold over baseline at 8 and 48 hours. Neither the NO signals nor increased apoptosis were seen in eNOS knockout mice or mice pretreated with L-NAME. At 48 hours, 83% of the arrested cells had cleared from the lungs of wild-type mice but only 55% of the cells cleared from eNOS-deficient or L-NAME pretreated mice. eNOS knockout and L-NAME-treated mice had twofold to fivefold more metastases than wild-type mice, measured by the number of surface nodules or by histomorphometry. We conclude that tumor cell arrest in the pulmonary microcirculation induces eNOS-dependent NO release by the endothelium adjacent to the arrested tumor cells and that NO is one factor that causes tumor cell apoptosis, clearance from the lung, and inhibition of metastasis.

This article has been cited by other articles:

				L. Ying and L. J. Hofseth An Emerging Role for Endothelial Nitric Oxide Synthase in Chronic Inflammation and Cancer Cancer Res., February 15, 2007; 67(4): 1407 - 1410. [Abstract] [Full Text] [PDF]