Abstract
Nitric oxide (NO), a potent biological mediator, plays a key role in physiological as well as pathological processes, including inflammation and cancer. The role of NO in tumor biology remains incompletely understood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor cell survival and consequently their metastatic ability, a large body of clinical and experimental data suggest a promoting role of NO in tumor progression and metastasis. We suggest that tumor cells capable of very high levels of NO production die in vivo, and those producing or exposed to lower levels of NO, or capable of resisting NO-mediated injury undergo a clonal selection because of their survival advantage; they also utilize certain NO-mediated mechanisms for promotion of growth, invasion and metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor neovasculature, and (c) a suppression of host anti-tumor defense. In this review, we discuss these mechanisms on the basis of data derived from experimental models, in particular, a mouse mammary tumor model in which the expression of eNOS by tumor cells is positively correlated with invasive and metastatic abilities. Tumor-derived NO was shown to promote tumor cell invasiveness and angiogenesis. The invasion-stimulating effects of NO were due to an upregulation of matrix metalloproteases and a downregulation of their natural inhibitors. Treatment of tumor-bearing mice with NO-blocking agents reduced the growth and vascularity of primary tumors and their spontaneous metastases. We propose that selected NO-blocking drugs may be useful in treating certain human cancers either as single agents or as a part of combination therapies.
Similar content being viewed by others
References
Fidler IJ, Radinsky R: Editorial: Genetic control of cancer metastasis. J Nat Cancer Inst 82: 166-168, 1990
Nicolson GI: Cancer progression and growth: Relationship of paracrine and autocrine growth mechanisms to organ preference of metastasis. Exp Cell Res 204: 171-180, 1993
Folkman J: What is the evidence that tumors are angiogenesis dependent. J Nat Cancer Inst 82: 4-7, 1990
Stetler-Stevenson WG, Aznavoorian S, Liotta LA: Tumor cell interactions with the extracellular matrix during invasion and metastasis. Ann Rev Cell Biol 9: 541-573, 1993
Dedhar S: Integrin mediated signal transduction in oncogenesis: an overview. Cancer Met Rev 14: 165-172, 1995
MacDougall JR, Matrisian LM: Contribution of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Met Rev 14: 351-362, 1995
Akiyama SK, Olden K, Yamada KM: Fibronectin and integrins in invasion and metastasis. Cancer Met Rev 14: 173- 189, 1995
Turley EA: Hyaluronan anc cell locomotion. Cancer Met Rev 11: 21-30, 1992
Chambers AF, Macdonald IC, Schmidt EE, Koop S, Morris VL, Khokha R, Groom AC: Steps in tumor metastasis: New concepts in intravital videomicroscopy. Cancer Met Rev 14: 279-301, 1995
Palmer RMJ, Ferrige AS, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524-526, 1987
Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 377-386, 1980
Furchgot RF: Studies on endothelium-dependent vasodilation and the endothelium-derived relaxing factor. Acta Physiol Scand 139: 257-270, 1990
Moncada S, Palmer RMJ, Higgs EA: Byosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication. Biochem Pharmacol 38: 1709-1715, 1989
Malietta MA: Nitric oxide: biosynthesis and biological significance. Trends Biochem Sci 14: 488-492, 1989
Snyder SH, Bredt DS: Biological roles of nitric oxide. Sci Am 266: 68-71, 1992
Nathan CF, Hibbs JB Jr.: Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3: 65-70, 1991
Stuehr DJ, Nathan CF: Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 469: 1543-1555, 1989
Tamir S, Tannenbaum SR: The role of nitric oxide (NO) in the carcinogenetic process. BBA 1288: f31-f36, 1996
Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002-2012, 1993
Knowles RG, Moncada S: Nitric oxide synthases in mammals. Biochem J 298: 249-258, 1994
Kobik L, Schmidt HHHW: Immunohistochemistry of nitric oxide synthase and nitric oxide related products. In: Feelisch M, Stamler J (eds) Methods in Nitric Oxide, John Wiley & Sons, New York 1996, pp 229-236
Morris SM, Billiar TR: New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266: E829-E839, 1994
Billiar TR: Nitric oxide: Novel biology with clinical relevance. Ann Surg 221: 339-349, 1995
Albina JE: On the expression of nitric oxide synthase by human macrophages. Why no NO? J Leukocyte Biol 58: 643-649, 1995
Tschugguel W, Knogler W, Czerwenka K, Mildner M, Weninger W, Zeillinger R, Huber JC: Presence of endothelial calcium-dependent nitric oxide synthase in breast apocrine metaplasia. Br J Cancer 74: 1423-1426, 1996
Goldstein S, Yang G-Y, Yang CS: Time dependent expression of inducible nitric oxide synthase (iNOS) in a rat model of Barrett’s esophagus and adenocarcinoma of the esophagus. Proc Amer Assoc Cancer Res 38: 353, 1997 (Abstract)
Miles D, Thomsen L, Balkwill F, Thavasu P, Moncada S: Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2. Eur J Clin Invest 24: 287-290, 1994
Thomsen LL, Lawton FG, Knowles RG, Beesley JE, Riveros-Moreno V, Moncada S: Nitric oxide synthase activity in human gynecological cancer. Cancer Res 54: 1352-1354, 1994
Cobbs CS, Brenman JE, Aldape KD, Bredt DS, Israel MA: Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res 55: 727-730, 1995
Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41-44, 1995
Chhatwal VJS, Ngoi SS, Chan STF, Chia YW, Moochhala SM: Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa an surrounding peritumoral normal mucosa. Carcinogenesis 15: 2081-2085, 1994
Moochhala S, Chhatwal VJS, Chan STF, Ngoi SS, Chia YW, Rauff A: Nitric oxide synthase activity and expression in human colorectal cancer. Carcinogenesis 17: 1171-1174, 1996
Jenkins DC, Charles IG, Baylis SA, Lelchuk R, Rodomski MW, Moncada S: Human colon cancer cell lines show a diverse pattern on nitric oxide synthase gene expression and nitric oxide generation. Brit J Cancer 70: 847-849, 1994
Buttery LDK, Springall DR, Andrade SP, Riveros-Moreno V, Hart I, Piper PJ, Polak JM: Induction of nitric oxide synthase in the neo-vasculature of experimental tumours in mice. J Path 171: 311-319, 1993
Kennovin GD, Hirst DG, Stratford MRL, Flitney FW: Inducible nitric oxide synthase is expressed in tumour-associated vasculature: inhibition retards tumor growth in vivo. In: Moncada S, Feelisch M, Busse R, Higgs EA (eds) Biology of Nitric Oxide, Part 4: Enzymology, Biochemistry and Immunology. Portland Press, London, 1994, pp 473-479
Orucevic A, Lala PK: Effects of NG-Methyl-L-Arginine, an inhibitor of nitric oxide synthesis, on IL-2 induced capillary leakage and anti-tumor responses in healthy and tumor bearing mice. Cancer Immunol Immunother 42: 38-46, 1996
Orucevic A, Lala PK: NG-Nitro-L-Arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin-2 induced capillary leakage and reduces tumor growth in adenocarcinoma bearing mice. Br J Cancer 72: 189-197, 1996
Edwards P, Cendan JC, Topping DB, Moldawer LL, Mackay S, Copeland EM, Lind DS: Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J Surg Res 63: 49-52, 1996
Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S: Roles of nitric oxide in tumor growth. Proc Natl Acad Sci USA 82: 4392-4396, 1995
Dong Z, Staroselsky AH, Qi X, Xie K, Fidler IJ: Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. Cancer Res 54: 789-793, 1994
Xie K, Huang S, Dong Z, Juang S-H, Gutman M, Xie Q-W, Nathan C, Fidler IJ: Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogated metastasis by K-1735 murine melanoma cells. J Exp Med 181: 1333-1343, 1995
Santer V, Mastramarino JH, Lala PK: Characterization of lymphocyte subsets in spontaneous mouse mammary tumors and host lymphoid organs. In J Cancer 25: 159-168, 1980
Gallahan D, Kozak C, Callahan R: A new common integration region (int 3) for mouse mammary tumor virus on chromosome 17. J Virol 61: 218-220, 1987
Morris VL, Rao TR, Kozak CA, Gray DA, Leechan ECM, Connel TJ, Baylor CB, Jones RF, McGrath CM: Characterization of int-5, a locus associated with early events in mammary carcinogenesis. Oncogene Res 6: 53-63, 1991
Brodt P, Lala PK: Studies on clonal heterogeneity in two spontaneously metastasizing mammary carcinomas of recent origin. Int J Cancer 35: 265-273, 1985
Lala PK, Parhar RS, Singh P: Indomethacin therapy abrogates prostaglandin mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol 99: 108-118, 1986
Lala PK, Parhar RS: Eradication of spontaneous and experimental adenocarcinoma metastasis with chronic indomethacin and intermittant IL-2 therapy. Int J Cancer 54: 677-684, 1993
Forrester K, Ambs S, Lupold SE, Kapust RB, Spillare EA, Weinberg WC, Felly Bosco E, Wang XW, Geller DA, Tzeng E, Billiar TR, Harris C: Nitric oxide induced p53 accumulation of regulation of inducible nitric oxide synthase expression by wild type p53. Proc Natl Acad Sci USA 93: 2442-2447, 1996
Ambs S, Merriam WG, Bennett WP, Ogunfusika M, Hussain SP, Tzeng E, Geller DA, Billiar TR, Harris CC: Interaction of nitric oxide and p53 in tumor growth: a putative model for clonal selection of mutant p53 cells. Proc Amer Assoc Cancer Res 38: 273, 1997 (Abstract)
Sveinbjornsson B, Olsen R, Seternes OM, Seljelid R: Macrophage cytotoxicity against murine meth A sacroma involves nitric oxide mediated apoptosis. Biochem Biophys Res Commun 223: 643-649, 1996
Li L, Kilbourn RG, Adams J, Fidler IJ: Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells. Cancer Res 51: 245-254, 1991
Xie K, Huang S, Dong Z, Fidler IJ: Cytokine-induced apoptosis in transformed murine fibroblasts involves synthesis of endogenous nitric oxide. Intern J Oncol 3: 1043-1047, 1993
Brune B, Mohr S, Messmer UK: Protein thiol modification and apoptotic cell death as cGMP-independent nitric oxide (NO) signaling pathways. Rev Physiol Biochem Pharmacol 127: 1-30, 1996
Ho YS, Wang YJ, Lin JK: Induction of p53 and p21/WAF1/C1P1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinogen 16: 20-31, 1996
Albina JE, Martin BA, Henry WL Jr, Louis CA, Reichner JS: B cell lymphoma-2 transfected P815 cells resist reactive nitrogen intermediate-mediated macrophage-dependent cytotoxicity. J Immunol 157: 279-283, 1996
Xie K, Huang S, Wang Y, Bethran PJ, Juang SH, Dong Z, Reed JC, McDonnell TJ, McConkey DJ, Fidler IJ: Bcl-2 protects cells from cytokine-induced nitric oxide-dependent apoptosis. Cancer Immunol Immunother 43: 109-115, 1996
Orucevic A, Lala PK: Nitric oxide production by murine mammary adenocarcinoma cells promotes tumor cell invasiveness. Proc Amer Assoc Cancer Res 37: 77, 1996 (Abstract)
Murrell GAG, Jang D, Williams RJ: Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 206: 15-21, 1995
Tamura T, Takanishi Y, Kimura Y, Sasaki K, Norimatsu H, Takahashi K, Takigawa M: Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes. A possible mechanism of pathological neovascularization in arthritis. Endocrinology 137: 3729-3737, 1996
Ziche M, Morbidelli L, Donnini S, Presta M, Granger HG: Nitric oxide increases the expression of endogenous bFGF in post capillary venule endothelial cells. Proc Amer Assoc Cancer Res 38: 524, 1997 (Abstract)
Xie K, Fidler IJ: Decreased matrix metalloproteanase-2 (MMP-2) expression correlates with the suppression of tumorigenicity and metastasis of K-1735 murine melanoma cells transfected with the inducible nitric oxide synthase (iNOS). Proc Amer Assoc Cancer Res 38: 166, 1997 (Abstract)
Pipili-Synetos E, Sakkoula E, Haralabopoulos G, Andriopoulou P, Peristeris P, Maragoudakis ME: Evidence that nitric oxide is an endogenous antiangiogenic mediator. Br J Pharmacol 111: 894-902, 1994
Konturek SJ, Brzozowski T, Majka J, Pytko-Polonczyk J, Stachura J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharm 239: 215-217, 1993
Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, Geppetti P, Ledda F: Nitric oxide mediates angiogenesis in vivoand endothelial cell growth and migration in vitropromoted by substance P. J Clin Invest 94: 2036-2044, 1994
Leibovich SJ, Polverini PJ, Fong TW, Harlow LA, Koch AE: Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase dependent effector mechanism. Proc Nat Acad Sci USA 91: 4190-4194, 1994
Morbidelli L, Chang C-H, Douglas JG, Granger JH, Ledda F, Ziche M: Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 39: H411-H415, 1996
Doi K, Akaike T, Horie H, Noguchi Y, Fujii S, Beppu T, Ogawa M, Maeda H: Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth. Cancer 77: 1598-1604, 1996
Kibbey MC, Grant DS, Kleinman HK: Role of SIKVAV site of laminin in promotion of angiogenesis and tumor growth: an in vivomatrigel model. J Natl Cancer Inst 84: 1633-1638, 1992
Stuehr DJ, Marletta MA: Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia colilipopolysaccharide. Proc Nat Acad Sci USA 82: 7738-7742, 1985
Keller R, Geiges M, Keist R: L-arginine-dependent reactive nitrogen intermediates as mediators of tumor cell killing by activated macrophages. Cancer Res 50: 1421-1425, 1990
Liew FY, Millot S, Parkinson C, Palmer RMJ, Moncada S: Macrophage killing of Leishmariaparasite in vivois mediated by nitric oxide from L-arginine. J Immunol 144: 4794-4797, 1990
Mills CD, Shearer J, Evans R, Caldwell MD: Macrophage arginine metabolism and inhibition or stimulation of cancer. J Immunol 149: 2709-2714, 1992
Cifone MG, Festiccia C, Cironi L, Cavallo G, Chessa MA, Pensa V, Tubaro E, Santoni A: Induction of the nitric oxidesynthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells. Cell Immunol 157: 181-194, 1994
Xiao L, Eneroth PH, Qureshi GA: Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity. Scand J Immunol 42: 505-511, 1995
Filep JG, Baron C, Lachance S, Perreault C, Chan JS: Involvement of nitric oxide in target cell lysis and DNA fragmentation induced by murine natural killer cells. Blood 87: 5136-5143, 1996
Hoffman RA, Langrehr JM, Billiar TR, Curran RD, Simmons RL: Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol 145: 2220-2226, 1990
Albina JE, Abate JA, Henry WL Jr.: Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation: role of IFN-??in the induction of nitric oxide-synthesizing pathway. J Immunol 147: 144-148, 1991
Lejeune P, Lagadec P, Onier N, Pinard D, Ohshima H, Jeannin J-F: Nitric oxide involvement in tumor-induced immunosuppression. J Immunol 152: 5077-5083, 1994
Orucevic A, Lala PK: Effects of NG-Nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, on IL-2 induced LAK cell generation in vivoand in vitroin healthy and tumor-bearing mice. Cell Immunol 169: 126-132, 1996
Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-364, 1996
McLillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L: A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 182: 1683-1693, 1995
Ambs S, Hussain SP, Harris CC: Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J 11: 443-448, 1997
Hollstein M, Sidransky D, Vogelstein B, Harris CC: P53 mutations in human cancer. Science 253: 49-53, 1991
Kim Y-M, Bergonia H, Lancaster JR Jr.: Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett 374: 228-232, 1995
Brüne B, Gölkel C, vonKnethen A: Cytokine and low-level nitric oxide prestimulation block p53 accumulation and apoptosis of raw 264.7 macrophages. Biochem Biophys Res Commun 229: 396-401, 1996
Lala PK, Al-Mutter N, Orucevic A: Effects of chronic indomethacin therapy on the development and progression of spontaneous mammary tumors in C3H/HCJ mice. Int J Cancer 73: 371-380, 1997
Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R: Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not fibroblast growth factor-induced angiogenesis. J Clin Invest 99: 2625-2634, 1997
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lala, P.K., Orucevic, A. Role of nitric oxide in tumor progression: Lessons from experimental tumors. Cancer Metastasis Rev 17, 91–106 (1998). https://doi.org/10.1023/A:1005960822365
Issue Date:
DOI: https://doi.org/10.1023/A:1005960822365