Abstract
In the present study we investigated whether synthesis of nitric oxide (NO) by macrophages is affected by contact with tumor cells. Although it is well known that NO generated by macrophages influences different activities related to tumor progression, there is limited information on the modulatory role of tumor cells on NO release by macrophages. The experimental protocol used in our study consisted in the determination of NO secreted by macrophages, either resident or inflammatory, co-cultivated with tumor cells (B16 melanoma and L929 fibrosarcoma cells) at different cell densities and macrophage:tumor cell ratios. This experimental in vitro protocol simulates the different interactions between macrophages and tumor cells that occur during the development of a tumor mass. We found that the co-cultivation with tumor cells induced an increased secretion of NO in macrophages provided that they express an inflammatory phenotype, and they were challenged with LPS or IFNγ/LPS. Two more variables were found to be critical in the increase of NO generation in inflammatory macrophages cultivated with tumor cells: a high cell density and a prevalence of tumor cells over macrophages. The enhancement of NO secreted in inflammatory macrophages stimulated by tumor cells was not observed in normal murine fibroblasts co-cultivated with tumor cells.
Similar content being viewed by others
References
V Schirrmacher (1980) ArticleTitleShifts in tumor cell phenotypes induced by signals from the microenvironment: relevance for the immunobiology of cancer metastasis Immunobiol 157 89–98
GL Nicolson (1987) ArticleTitleTumor cell instability, diversification, and progression to the metastatic phenotype: from oncogene to oncofetal expression Cancer Res 47 1473–87 Occurrence Handle3545445
GJ Gasic (1986) ArticleTitleRole of plasma, platelets, and endothelial cells in tumor metastasis Cancer Metastasis Rev 3 99–116
DR Welch DJ Schissel RP Howrey et al. (1989) ArticleTitleTumor-elicited polymorphonuclear cells, in contrast to “normal” circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells Proc Natl Acad Sci USA 86 5859–63 Occurrence Handle2762301
KEP Roozendaal Particlevan JGM Klijn B Ooijen Particlevan (1996) ArticleTitleDifferential regulation of breast tumor cell proliferation by stromal fibroblasts of various breast tissue sources Int J Cancer 65 120–5 Occurrence Handle10.1002/(SICI)1097-0215(19960103)65:1<120::AID-IJC20>3.0.CO;2-J Occurrence Handle8543388
KD Elgert DG Alleva DW Mullins (1998) ArticleTitleTumor-induced immune dysfunction: the macrophage connection J Leukoc Biol 64 275–90 Occurrence Handle9738653
SA Kadhim RC Rees (1984) ArticleTitleEnhancement of tumor growth in mice: evidence for the involvement of host macrophages Cell Immunol 87 259–69 Occurrence Handle10.1016/0008-8749(84)90150-3 Occurrence Handle6611212
P Baetselier ParticleDe A Kapon S Katzav et al. (1985) ArticleTitleSelecting, accelerating and suppressing interactions between macrophages and tumor cells Invasion Metastasis 5 106–24 Occurrence Handle3884534
E Gorelik RH Wiltrout M Brunda et al. (1982) ArticleTitleAugmentation of metastasis formation by thioglycollate-elicited macrophages Int J Cancer 29 575–81 Occurrence Handle7095902
H Mashiba K Matsunaga (1986) ArticleTitleInhibition and augmentation of lymphoma metastasis by adoptively transferred peritoneal macrophages in hamster Cancer Lett 33 11–8 Occurrence Handle10.1016/0304-3835(86)90096-0 Occurrence Handle3768859
M Mukai K Shinkai R Tateishi et al. (1987) ArticleTitleMacrophage potentiation of invasive capacity of rat ascites hepatoma cells Cancer Res 47 2167–71 Occurrence Handle3030545
H Akedo K Shinkai M Mukai et al. (1989) ArticleTitlePotentiation and inhibition of tumor cell invasion by host cells and mediators Invasion Metastasis 9 134–48 Occurrence Handle2708005
O Cecconi L Calorini A Mannini et al. (1997) ArticleTitleEnhancement of lung-colonizing potential of murine tumor cell lines co-cultivated with activated macrophages Clin Exp Metastasis 15 94–101 Occurrence Handle10.1023/A:1018440508189 Occurrence Handle9062385
IJ Fidler AJ Schroit (1998) ArticleTitleRecognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self Biochim Biophys Acta 948 151–73
PW Whitworth CC Pak J Esgro et al. (1989/1990) ArticleTitleMacrophages and cancer Cancer Metastasis Rev 8 319–51
DG Alleva CG Burger KD Elgert (1993) ArticleTitleTumor growth increases Ia- macrophage synthesis of tumor necrosis factor-α and prostaglandin E2: changes in macrophage suppressor activity J Leukoc Biol 53 550–8 Occurrence Handle8388910
KH Leung DG Fisher HS Koren (1983) ArticleTitleErythromyeloid tumor cells (K562) induce PGE synthesis in human peripheral blood monocytes J Immunol 131 445–9 Occurrence Handle6575096
AP Malick KD Elgert R Garner et al. (1987) ArticleTitleProstaglandin E2 production by Mac-2+ macrophages: tumor-induced population shift J Leukoc Biol 42 673–81 Occurrence Handle2960767
MRI. Young (1994) ArticleTitleEicosanoids and the immunology of cancer Cancer Metastasis Rev 13 337–48 Occurrence Handle10.1007/BF00666103 Occurrence Handle7712595
JD Hasday EM Shah AP Lieberman (1990) ArticleTitleMacrophage tumor necrosis factor-alpha release is induced by contact with tumor cells J Immunol 145 371–9 Occurrence Handle2358679
R. DeMarco JE Ensor JD Hasady (1992) ArticleTitleTumor-stimulated release of tumor necrosis factor-alpha by human monocyte-derived macrophages Cell Immunol 140 304–18 Occurrence Handle10.1016/0008-8749(92)90198-X Occurrence Handle1544164
A Siegert C Denkert A Leclere et al. (1999) ArticleTitleSuppression of the reactive oxygen intermediate production of human macrophages by colorectal adenocarcinoma cell lines Immunology 98 551–6 Occurrence Handle10.1046/j.1365-2567.1999.00915.x Occurrence Handle10594687
K Isobe I Nakashima (1993) ArticleTitleAbundant production of nitric oxide from murine macrophages by direct stimulation of tumor cells Biochem Biophys Res Commun 192 499–504 Occurrence Handle10.1006/bbrc.1993.1443 Occurrence Handle8484761
H Jiang CA Stewart DJ Fast et al. (1996) ArticleTitleTumor-derived recognition factor (TDRF) induces production of TNF-alpha by murine macrophages, but requires synegy with IFN-gamma alone or in combination with IL-2 to induce nitric oxide synthase Int J Immunopharmacol 18 479–90 Occurrence Handle10.1016/S0192-0561(96)00053-7 Occurrence Handle9023587
H Jiang CA Stewart RW Leu (1995) ArticleTitleTumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity Immunobiology 192 321–42 Occurrence Handle7544321
H Maekawa K Iwabuchi I Nagaoka et al. (2000) ArticleTitleActivated peritoneal macrophages inhibit the proliferation of rat ascites hepatoma AH-130 cells via the production of tumor necrosis factor-alpha and nitric oxide Inflamm Res 49 541–7 Occurrence Handle10.1007/s000110050629 Occurrence Handle11089907
M Tonetti E Millo L Sturla et al. (1997) ArticleTitleEffects of the murine L929 and L1210 cell lines on nitric oxide and TNFα production by RAW 264.7 murine macrophages Biochem Biophys Res Commun 230 636–40 Occurrence Handle10.1006/bbrc.1996.6022 Occurrence Handle9015376
M Zembala M Siedlar J Marcinkiewicz et al. (1994) ArticleTitleHuman monocytes are stimulated for nitric oxide release in vitro by some tumor cells but not by cytokines and lipopolysaccharide Eur J Immunol 24 435–9 Occurrence Handle8299693
M Siedlar B Mytar A Krzeszowiak et al. (1999) ArticleTitleDemonstration of iNOS-mRNA and iNOS in human monocytes stimulated with cancer cells in vitro J Leukoc Biol 65 597–604 Occurrence Handle10331487
LL Thomsen DW Miles L Happerfield et al. (1995) ArticleTitleNitric oxide synthase activity in human breast cancer Br J Cancer 72 41–4 Occurrence Handle7541238
MR Dinapoli CL Calderon DM. Lopez (1996) ArticleTitleThe altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene J Exp Med 183 1323–9 Occurrence Handle10.1084/jem.183.4.1323 Occurrence Handle8666890
HA Naama MD McCarter VE Mack et al. (2001) ArticleTitleSuppression of macrophage nitric oxide production by melanoma: mediation by a melanoma-derived product Melanoma Res 11 229–38 Occurrence Handle10.1097/00008390-200106000-00004 Occurrence Handle11468511
PJ Bugelski RL Kirsh JM Sowinski et al. (1985) ArticleTitleChanges in the macrophage content of lung metastases at different stages in tumor growth Am J Pathol 118 419–24 Occurrence Handle3976845
PJ Bugelski SP Corvin SM North et al. (1987) ArticleTitleMacrophage content of spontaneous metastases at different stages of growth Cancer Res 47 4141–5 Occurrence Handle3300960
Adams DO, Hamilton TA. Molecular basis of macrophage activation: diversity and its origins. In CE Lewis, JO’D Mc Gee (ed) The Natural Immune System: The Macrophages. Oxford University Press, 1992
S. Gordon (2003) ArticleTitleAlternative activation of macrophages Nat Rev 3 23–35
S Gattoni-Celli L Calorini MM Simile et al. (1993) ArticleTitleModulation by MHC class I antigens of the biology of melanoma cells. Non immunological mechanism Melanoma Res 3 285–9 Occurrence Handle8219762
TR Chen (1977) ArticleTitleIn situ detection of Mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain Exp Cell Res 104 255–2 Occurrence Handle10.1016/0014-4827(77)90089-1 Occurrence Handle65285
BB Aggarwal K Mehta (1996) ArticleTitleThe determination and regulation of nitric oxide production from macrophages by lipopolysaccharides, cytokines, and retinoids Method Enzymol 269 166–71
DJ Stuher MA. Marletta (1985) ArticleTitleMammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide Proc Natl Acad Sci USA 82 7738–42 Occurrence Handle3906650
D Fukumura RK Jain (1998) ArticleTitleRole of nitric oxide in angiogenesis and microcirculation in tumors Cancer Metastasis Rev 17 77–89 Occurrence Handle10.1023/A:1005908805527 Occurrence Handle9544424
M Saio S Radoja M Marino et al. (2001) ArticleTitleTumor-infiltrating macrophages induce apoptosis in activated CD8+ T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide J Immunol 167 5583–93 Occurrence Handle11698429
SC Sicher MA Vazquez CY Lu (1994) ArticleTitleInhibition of macrophage Ia expression by nitric oxide J Immunol 153 1293–300 Occurrence Handle8027556
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Calorini, L., Bianchini, F., Mannini, A. et al. Enhancement of Nitric Oxide Release in Mouse Inflammatory Macrophages Co-cultivated with Tumor Cells of a Different Origin. Clin Exp Metastasis 22, 413–419 (2005). https://doi.org/10.1007/s10585-005-1263-x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10585-005-1263-x