Adhesion of circulating tumor cells to microvascular endothelium plays an important role in tumor metastasis to distant organs. The purpose of this study was to determine whether nitric oxide (NO) would attenuate tumor cell adhesion (TCA) to naive or lipopolysaccharide (LPS)-treated postcapillary venules. A melanoma cell line, RPMI 1846, was shown to be much more adhesive to postcapillary venules isolated from rat mesentery than to corresponding precapillary arterioles. Although venules exposed to LPS for 4 h demonstrated an increased adhesivity for the melanoma cells, TCA to LPS-treated arterioles was not altered. Isolated venules exposed to DETA/NO (1 mm), an NO donor, for 30 min prior to tumor cell perfusion prevented the increment in adhesion induced by LPS and attenuated TCA to naive postcapillary venules. While L-arginine (100 μm), an NO precursor, failed to decrease TCA to naive postcapillary venules, this treatment abolished LPS-stimulated TCA to postcapillary venules. The effect of l-arginine was reversed by administration of N ω-nitro-l-arginine methyl ester (l-NAME, 100 μm), an NO synthase (NOS) inhibitor. These observations indicate that both exogenous and endogenous NO modulate TCA to postcapillary venules. To assess the role of NO-induced activation of cGMP in the reduction in TCA produced by DETA/NO, two additional series of experiments were conducted. In the first series, LY-83583 (10 μm), a guanylyl cyclase inhibitor, was shown to completely reverse the effect of DETA/NO on TCA to both naive and LPS-activated postcapillary venules. On the other hand, administration of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-B-cGMP) (1 mm), a cell permeant cGMP analog, mimicked the effect of DETA/NO and reduced TCA to LPS-stimulated postcapillary venules. These data suggest that (a) tumor cells are more likely to adhere to postcapillary venules than to corresponding precapillary arterioles, (b) LPS enhances TCA to postcapillary venules, (c) both exogenously applied (DETAINO) and endogenously generated (l-arginine) NO attenuate the enhanced adhesion induced by LPS, but only DETA/NO reduced TCA to naive postcapillary venules, and (d) the NO-induced reduction in TCA to LPS-activated postcapillary venules occurs by a cGMP-dependent mechanism.[/p]
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References
Fidler IJ, 1990, Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes Memorial Award Lecture. Cancer Res, 50, 6130–8.
Nicolson GL, 1988, Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta, 948, 175–224.
Nicolson GL, 1989, Metastatic tumor cell interactions with endothelium, basement membrane and tissue. Curr Opin Cell Biol, 1, 1009–19.
Tang DG, Digho CA and Horn KV, 1994, Activation of microvascular endothelium by eicosanoid 12(S)hydroxyeicosatetraenoic acid leads to enhanced tumor cell adhesion via up-regulation of surface expression of 'αv[beta]3 integrin: a posttranscriptional, protein kinase C- and cytoskeleton-dependent process. Cancer Res, 54, 1119–1129.
Chen YQ, Duniec ZM, Liu B et al. 1994, Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. Cancer Res, 54, 1574–9.
Nierodzik MLR, Kajumo F and Karpatkin S, 1992, Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res, 52, 3267–72.
Scher RL, Koch WM and Richtsmeier WJ, 1993, Induction of the intercellular adhesion molecule (ICAM-1) on squamous cell carcinoma by interferon gamma. Arch Otolaryngol-Head Neck Surg, 119, 432–8.
Bereta M, Bereta J, Cohen S, Zaifert K and Cohen MC, 1991, Effect of inflammatory cytokines on the adherence of tumor cells to endothelium in a murine model. Cellular Immunology, 136, 263–77.
Dejana E, Bertocchi F, Bortolami MC et al. 1988, Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest, 82, 1466–70.
Rice GE, Gimbrone MA Jr and Bevilacqua MP, 1988, Tumor cell-endothelial interactions: increased adhesion of human melanoma cells to activated vascular endothelium. Am J Pathol, 133, 204–10.
Moser R, Schleiffenbaum B, Groscurth P and Fehr J, 1989, Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophil passage. J Clin Invest, 83, 444–55.
Chirivi RGS, Garofalo A, Padura IM, Mantovani A and Giavazzi R, 1993, Interleukin 1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin 1 or lipopolysaccharide in a human melanoma/nude mouse system. Cancer Res, 53, 5051–4.
Radomski MW, Palmer RMJ and Moncada S, 1987, Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol, 92, 181–7.
Furlong B, Henderson AH, Lewis MJ and Smith JA, 1987, Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol, 90, 687–92.
Radomski MW, Palmer RMJ and Moncada S, 1987, Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. The Lancet, 2, 1057–8.
De Graaf JC, Banga JD, Moncada S, Palmer RMJ, De Groot PG and Sixma JJ, 1992, Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation, 85, 2284–90.
Kubes P, Suzuki M and Granger DN, 1991, Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc the Natl Acad Sci USA, 88, 4651–5.
Provost P, Lam JYT, Lacoste L, Merhi Y and Waters D, 1994, Endothelium-derived nitric oxide attenuates neutrophil adhesion to endothelium under arterial flow conditions. Arteriosclerosis and Thrombosis, 14, 331–5.
Dong Z, Staroselsky AH, Qi X, Xie K and Fidler IJ, 1994, Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. Cancer Res, 54, 789–93.
Mehta P, Lawson D, Ward MB, Kimura A and Gee A, 1987, Effect of human tumor cells on platelet aggregation: potential relevance to pattern of metastasis. Cancer Res, 47, 3115–17.
Vidal MJ, Zocchi MR, Poggi A, Pellegatta F and Chierchia SL, 1992, Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. J Cardiovascular Pharmacol, 20(supp1.12), S155-S159.
Giavazzi R, Foppolo M, Dossi R and Remuzzi A, 1993, Rolling and adhesion of human tumor cells on vascular endothelium under physiological flow conditions. J Clin Invest, 92, 3038–44.
Mooradian DL, Hutsell TC and Keefer LK, 1995, Nitric oxide (NO) donor molecules: effect of NO release rate on vascular smooth muscle cell proliferation in vitro. J Cardiovascular Pharmacol, 25, 674–8.
Yuan Y, Granger HJ, Zawieja DC, DeFily DV and Chilian WM, 1993, Histamine increases venular permeability via a phospholipase C-NO synthaseguanylate cyclase cascade. Am J Physiol, 264, H1734-H1739.
Zaifert K and Cohen MC, 1993, COLO 205 utilizes E-selectin to adhere to human endothelium. Clin Immunol Immunopathol, 68, 51–6.
Menter DG, Patton JT, Updyke TV et al. 1991, Transglutaminase stabilizes melanoma adhesion under laminar flow. Cell Biophys, 18, 123–43.
Richardson PDI, Granger DN and Taylor AE, 1979, Capillary filtration coefficient: the technique and its application to the small intestine. Cardiovascular Res, 13, 547–61.
Ignarro LJ, 1990, Biosynthesis and metabolism of endothelium-derived nitric oxide. Ann Rev Pharmacol and Toxicol, 30, 535–60.
Moncada S, Palmer RMJ and Higgs EA, 1991, Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev, 43, 109–42.
Gruetter CA, Barry BK, McNamara DB, Gruetter DY, Kadowitz PJ and Ignarro LJ, 1979, Relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine. J Cyclic Nucleotide Res, 5, 211–24.
Palmer RMJ, Ferrige AG and Moncada S, 1987, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 327, 524–6.
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Kong, L., Dunn, G.D., Keefert, L.K. et al. Nitric oxide reduces tumor cell adhesion to isolated rat postcapillary venules. Clin Exp Metast 14, 335–343 (1996). https://doi.org/10.1007/BF00123392
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DOI: https://doi.org/10.1007/BF00123392