Cancer Research Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wang, H. H.
Right arrow Articles by Orr, F. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, H. H.
Right arrow Articles by Orr, F. W.
[Cancer Research 60, 5862-5869, October 15, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

B16 Melanoma Cell Arrest in the Mouse Liver Induces Nitric Oxide Release and Sinusoidal Cytotoxicity: A Natural Hepatic Defense against Metastasis1

Hui Helen Wang, Alan R. McIntosh, Brian B. Hasinoff, Edward S. Rector, Naeem Ahmed, Dwight M. Nance and F. William Orr2

Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3E OW3 [H. H. W., E. S. R., N. A., D. M. N., F. W. O.], and Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 [A. R. M., B. B. H.]

The formation of liver metastases involves interactions between intravascular cancer cells and the hepatic microvasculature. Here we provide evidence that the arrest of intravascular B16F1 melanoma cells in the liver induces a rapid local release of nitric oxide (NO) that causes apoptosis of the melanoma cells and inhibits their subsequent development into hepatic metastases. B16F1 melanoma cells (5 x 105) labeled with fluorescent microspheres were injected into the portal circulation of C57BL/6 mice. The production of NO in vivo was detected by electron paramagnetic resonance spectroscopy ex vivo using an exogenous NO-trapping agent. A burst of NO was observed in liver samples examined immediately after tumor cell injection. The relative electron paramagnetic resonance signal intensity was 667 ± 143 units in mice injected with tumor cells versus 28 ± 5 units after saline injection (P < 0.001). Two-thirds of cells arrested in the sinusoids compared with the terminal portal venules (TPVs). By double labeling of B16F1 cells with fluorescent microspheres and a TdT-mediated UTP end labeling assay, we determined that the melanoma cells underwent apoptosis from 4–24 h after arrest. The mean rate of apoptosis was 2-fold greater in the sinusoids than in the TPVs at 4, 8, and 24 h after injection (P < 0.05–0.01). Apoptotic cells accounted for 15.9 ± 0.8% of tumor cells located in the sinusoids and 7.1 ± 0.9% of tumor cells in the TPVs. The NO synthase inhibitor NG-nitro-L-arginine methyl ester completely blocked the NO burst (P < 0.001) and inhibited the apoptosis of B16F1 cells in the sinusoids by 77%. However, the rate of tumor cell apoptosis in the TPVs was not changed. There were 5-fold more metastatic nodules in the livers of NG-nitro-L-arginine methyl ester-treated mice (P < 0.05). The inactive enantiomer NG-nitro-D-arginine methyl ester had no effect on the initial NO burst or on apoptosis of tumor cells in vivo. Both annexin V phosphatidylserine plasma membrane labeling and DNA end labeling of apoptotic cells were demonstrated after a 5-min exposure (a time equivalent to the initial transient NO induction in vivo) of B16F1 cells to a NO donor in vitro. These results identify the existence of a natural defense mechanism against cancer metastasis whereby the arrest of tumor cells in the liver induces endogenous NO release, leading to sinusoidal tumor cell killing and reduced hepatic metastasis formation.




This article has been cited by other articles:


Home page
 J. Immunol.Home page
L. Burdelya, M. Kujawski, G. Niu, B. Zhong, T. Wang, S. Zhang, M. Kortylewski, K. Shain, H. Kay, J. Djeu, et al.
Stat3 Activity in Melanoma Cells Affects Migration of Immune Effector Cells and Nitric Oxide-Mediated Antitumor Effects
J. Immunol., April 1, 2005; 174(7): 3925 - 3931.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. M. Laguinge, S. Lin, R. N. Samara, A. N. Salesiotis, and J. M. Jessup
Nitrosative Stress in Rotated Three-Dimensional Colorectal Carcinoma Cell Cultures Induces Microtubule Depolymerization and Apoptosis
Cancer Res., April 15, 2004; 64(8): 2643 - 2648.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. L. Ortega, J. Carretero, E. Obrador, J. Gambini, M. Asensi, V. Rodilla, and J. M. Estrela
Tumor Cytotoxicity by Endothelial Cells. IMPAIRMENT OF THE MITOCHONDRIAL SYSTEM FOR GLUTATHIONE UPTAKE IN MOUSE B16 MELANOMA CELLS THAT SURVIVE AFTER IN VITRO INTERACTION WITH THE HEPATIC SINUSOIDAL ENDOTHELIUM
J. Biol. Chem., April 11, 2003; 278(16): 13888 - 13897.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
H. Qiu, F.W. Orr, D. Jensen, H. H. Wang, A. R. McIntosh, B. B. Hasinoff, D. M. Nance, S. Pylypas, K. Qi, C. Song, et al.
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
Am. J. Pathol., February 1, 2003; 162(2): 403 - 412.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. M. Medeiros, A. Morais, A. Vasconcelos, S. Costa, D. Pinto, J. Oliveira, P. Ferreira, and C. Lopes
Outcome in Prostate Cancer: Association with Endothelial Nitric Oxide Synthase Glu-Asp298 Polymorphism at Exon 7
Clin. Cancer Res., November 1, 2002; 8(11): 3433 - 3437.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
C. W. Wong, C. Song, M. M. Grimes, W. Fu, M. W. Dewhirst, R. J. Muschel, and A.-B. Al-Mehdi
Intravascular Location of Breast Cancer Cells after Spontaneous Metastasis to the Lung
Am. J. Pathol., September 1, 2002; 161(3): 749 - 753.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
R. Edwards, T. Colombo, and P. Greaves
"Have You Seen This?" Peliosis Hepatis
Toxicol Pathol, June 1, 2002; 30(4): 521 - 523.
[Abstract] [PDF]

Home page
 Am. J. Pathol.Home page
Y. K. Song, T. R. Billiar, and Y. J. Lee
Role of Galectin-3 in Breast Cancer Metastasis : Involvement of Nitric Oxide
Am. J. Pathol., March 1, 2002; 160(3): 1069 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
B.-K. Moon, Y. J. Lee, P. Battle, J. M. Jessup, A. Raz, and H.-R. C. Kim
Galectin-3 Protects Human Breast Carcinoma Cells against Nitric Oxide-Induced Apoptosis : Implication of Galectin-3 Function during Metastasis
Am. J. Pathol., September 1, 2001; 159(3): 1055 - 1060.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Carretero, E. Obrador, J. M. Esteve, A. Ortega, J. A. Pellicer, F. V. Sempere, and J. M. Estrela
Tumoricidal Activity of Endothelial Cells. INHIBITION OF ENDOTHELIAL NITRIC OXIDE PRODUCTION ABROGATES TUMOR CYTOTOXICITY INDUCED BY HEPATIC SINUSOIDAL ENDOTHELIUM IN RESPONSE TO B16 MELANOMA ADHESION IN VITRO
J. Biol. Chem., July 6, 2001; 276(28): 25775 - 25782.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2000 by the American Association for Cancer Research.