MicroRNAs调节单核—巨噬细胞分化过程中非经典NF-κB通路的激活
|
摘要
单核细胞(Monocyte)是体内一类重要的无颗粒白细胞,单核细胞作为巨噬细胞(Macrophages)和树突状细胞(Dendritic cells)的前体,与巨噬细胞共同构成了机体先天免疫系统的重要部分。巨噬细胞分化和功能异常,通常与包括肿瘤在内的一系列疾病有关。然而,单核-巨噬细胞分化过程中诸多分子事件的发生以及其调控原理,我们仍然知之甚少。在这方面的进一步深入研究将无疑会帮助我们认识和解决诸如肿瘤、自身免疫疾病等一系列重大疾病。
MicroRNAs自1993年被初次发现以来,迅速成为了研究者们研究的热点,人们渐渐意识到MicroRNA在包括细胞分化等许多生物学过程中起着关键作用。特别是在免疫细胞分化和功能的调节中发挥了引人注目的作用。
本研究中,我们以人的原代单核细胞为模型,揭示了在单核-巨噬细胞分化过程中,MicroRNA——miR-223,miR-15a和miR-16通过调节非经典NF-κB信号通路的激活,进而在调控巨噬细胞的功能方面起到了至关重要的作用。我们发现,miR-223,miR-15a和miR-16在单核-巨噬细胞分化过程中显著下调。生物信息学分析发现NF-κB信号通路的重要激酶IKKα是这三个micoRNA的共同靶基因。进一步的研究证实了在巨噬细胞分化的过程中,这些microRNA表达水平的变化显著上调了IKKα蛋白水平。更重要的是,在巨噬细胞中高表达水平的IKKα,NIK以及信号分子TRAF2的降解介导了p100持续性地被剪切成p52。然而,由于在巨噬细胞中,NF-κB2转录因子的转录调节亚基RelB的蛋白表达水平极低,因此,高表达水平的p52对非经典NF-κB通路靶基因的表达起抑制作用。当巨噬细胞受到炎性因子刺激后,如LPS,随着细胞内RelB蛋白的快速补充,p52介导的这种抑制作用,迅速转为促进作用,促进非经典NF-κB通路靶基因的表达。综上所述,我们的结果揭示了在单核-巨噬细胞分化的过程中,特定microRNA的变化通过调控非经典NF-κB信号通路的激活使分化成熟的巨噬细胞处在一种抑制性的自我保护状态,并为机体应对后续的炎性刺激做好了准备。
Monocytes are a type of the nongranular leukocytes, which supply peripheral tissues with macrophages and dendritic cells (DC) precursors and constitute an important part of the innate immune system. It has been more and more uncovered by emerging publications that deregulation of macrophage functions and differentiation is often involved in many types of diseases including cancer. However, the molecular events happened during monocyte-macrophage differentiation are still largely unknown. Any further knowledge about this important process will definitely give more in sight to understand the differentiation of monocytes and will provide more therapeutic opportunity to treat cancer and other major related diseases.
MicroRNAs became the focus of many researchers since it has been discovered at 1993. Emerging evidence suggested that microRNAs are important component of immune cell differentiation and function.
In this study with human primary monocytes and macrophages, we show that during monocyte-macrophage differentiation, microRNAs, miR-223, miR-15a and miR-16 play a crucial role in regulating macrophage function by modulating non-canonical NF-κB signaling pathway. We found that during the differentiation of macrophage, these microRNAs are dramatically decreased. Bioinformatics analysis suggested that the IκB protein kinase, IKKαis the sharing target of these three microRNAs. We demonstrated that the levels of these microRNAs determine the expression amounts of IKKαin monocyte and macrophages respectively. Importantly, the high IKKαexpression in junction with NIK stabilization leads to an increased level of p52. Due to the absence of RelB expression in untreated macrophages, the high level of p52 represses target genes of the non-canonical NF-κB pathway. However, this inhibitory effect will be turned to promotional effect when the cells were further challenged by LPS. Thus, our data suggested during the differentiation of macrophage, the changes of certain microRNAs likely prevent macrophage hyperactive and yet prime the macrophage for a robust response to proinflammatory stimuli.
MicroRNAs自1993年被初次发现以来,迅速成为了研究者们研究的热点,人们渐渐意识到MicroRNA在包括细胞分化等许多生物学过程中起着关键作用。特别是在免疫细胞分化和功能的调节中发挥了引人注目的作用。
本研究中,我们以人的原代单核细胞为模型,揭示了在单核-巨噬细胞分化过程中,MicroRNA——miR-223,miR-15a和miR-16通过调节非经典NF-κB信号通路的激活,进而在调控巨噬细胞的功能方面起到了至关重要的作用。我们发现,miR-223,miR-15a和miR-16在单核-巨噬细胞分化过程中显著下调。生物信息学分析发现NF-κB信号通路的重要激酶IKKα是这三个micoRNA的共同靶基因。进一步的研究证实了在巨噬细胞分化的过程中,这些microRNA表达水平的变化显著上调了IKKα蛋白水平。更重要的是,在巨噬细胞中高表达水平的IKKα,NIK以及信号分子TRAF2的降解介导了p100持续性地被剪切成p52。然而,由于在巨噬细胞中,NF-κB2转录因子的转录调节亚基RelB的蛋白表达水平极低,因此,高表达水平的p52对非经典NF-κB通路靶基因的表达起抑制作用。当巨噬细胞受到炎性因子刺激后,如LPS,随着细胞内RelB蛋白的快速补充,p52介导的这种抑制作用,迅速转为促进作用,促进非经典NF-κB通路靶基因的表达。综上所述,我们的结果揭示了在单核-巨噬细胞分化的过程中,特定microRNA的变化通过调控非经典NF-κB信号通路的激活使分化成熟的巨噬细胞处在一种抑制性的自我保护状态,并为机体应对后续的炎性刺激做好了准备。
Monocytes are a type of the nongranular leukocytes, which supply peripheral tissues with macrophages and dendritic cells (DC) precursors and constitute an important part of the innate immune system. It has been more and more uncovered by emerging publications that deregulation of macrophage functions and differentiation is often involved in many types of diseases including cancer. However, the molecular events happened during monocyte-macrophage differentiation are still largely unknown. Any further knowledge about this important process will definitely give more in sight to understand the differentiation of monocytes and will provide more therapeutic opportunity to treat cancer and other major related diseases.
MicroRNAs became the focus of many researchers since it has been discovered at 1993. Emerging evidence suggested that microRNAs are important component of immune cell differentiation and function.
In this study with human primary monocytes and macrophages, we show that during monocyte-macrophage differentiation, microRNAs, miR-223, miR-15a and miR-16 play a crucial role in regulating macrophage function by modulating non-canonical NF-κB signaling pathway. We found that during the differentiation of macrophage, these microRNAs are dramatically decreased. Bioinformatics analysis suggested that the IκB protein kinase, IKKαis the sharing target of these three microRNAs. We demonstrated that the levels of these microRNAs determine the expression amounts of IKKαin monocyte and macrophages respectively. Importantly, the high IKKαexpression in junction with NIK stabilization leads to an increased level of p52. Due to the absence of RelB expression in untreated macrophages, the high level of p52 represses target genes of the non-canonical NF-κB pathway. However, this inhibitory effect will be turned to promotional effect when the cells were further challenged by LPS. Thus, our data suggested during the differentiation of macrophage, the changes of certain microRNAs likely prevent macrophage hyperactive and yet prime the macrophage for a robust response to proinflammatory stimuli.
引文
1. Volkman A. & Gowans JL. The origin of macrophages from human bone marrow in the rat. Br. J. Exp. Pathol. 1965,46: 62-68
2. Van Furth R. & Cohn ZA. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 1968,128: 415-435
3. Van Furth R., Diesselhoff-den Dulk MM. & Mattie H. Quantitative study on the production and kinetics of mononuclear phagocytes during an acute inflammatory reaction. J. Exp. Med. 1973, 138: 1314-1330
4. Fairweather, D. and Cihakova, D., Alternatively activated macrophages in infection and autoimmunity. J Autoimmun. 2009, 33 (3-4), 222-230
5. Mantovani, A., Allavena, P., Sica, A., and Balkwill, F., Cancer-related inflammation. Nature. 2008, 454 (7203), 436-444
6. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993 Dec 3; 75(5): 843-854.
7. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J., and Parker, R., Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006. 20 (5), 515-524
8. Petrocca, F. and Lieberman, J., Micromanagers of immune cell fate and function. Adv Immunol. 2009. 102, 227-244
9. Bartel, D. P., MicroRNAs: target recognition and regulatory functions. Cell. 2009. 136 (2), 215-233
10. Baltimore, D. et al., MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2009. 9 (8), 839-845
11. Kluiver, J., Kroesen, B. J., Poppema, S., and van den Berg, A., The role ofmicroRNAs in normal hematopoiesis and hematopoietic malignancies. Leukemia. 2006. 20 (11), 1931-1936
12. Johnnidis, J. B. et al., Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008. 451 (7182), 1125-1129
13. Hayden, M. S. and Ghosh, S., Shared principles in NFκB signaling. Cell. 2008. 132 (3), 344-362
14. Vallabhapurapu, S. and Karin, M., Regulation and function of NFκB transcription factors in the immune system. Annu Rev Immunol. 2009. 27, 693-733
15. Beinke, S. and Ley, S. C., Functions of NFκB1 and NFκB2 in immune cell biology. Biochem J. 2004. 382 (Pt 2), 393-409
16. Bonizzi, G. and Karin, M., The two NFκB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004. 25 (6), 280-288
17. Betel, D. et al., The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008. 36 (Database issue), D149-D153
18. Grimson, A. et al., MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007. 27 (1), 91-105
19. Saetrom, P. et al., Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res. 2007. 35 (7), 2333-2342
20. Alban Dupoux, Jessy Cartier, Séverine Cathelin, Rodolphe Filomenko, Eric Solary, and Laurence Dubrez-Daloz, cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand. Blood, 1 January 2009, Vol. 113, No. 1, 175-185.
21. Zarnegar, B. J. et al., Noncanonical NFκB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008 9 (12), 1371-1378
22. Vallabhapurapu, S. et al., Nonredundant and complementary functions of TRAF2and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NFκB signaling. Nat Immunol. 2008. 9 (12), 1364-1370
23. Dejardin, E. et al., The lymphotoxinβreceptor induces different patterns of gene expression via two NFκB pathways. Immunity. 2002. 17 (4), 525-535
24. Bonizzi, G. et al., Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J. 2004. 23 (21), 4202-4210
25. Bren, G. D. et al., Transcription of the RelB gene is regulated by NFκB. Oncogene. 2001. 20 (53), 7722-7733
26. Cimmino, A. et al., miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005. 102 (39), 13944-13949
27. Hashimoto, S. I., Komuro, I., Yamada, M., and Akagawa, K. S., IL-10 inhibits granulocyte-macrophage colony-stimulating factor-dependent human monocyte survival at the early stage of the culture and inhibits the generation of macrophages. J Immunol. 2001. 167 (7), 3619-3625
28. Komuro, I., Yasuda, T., Iwamoto, A., and Akagawa, K. S., Catalase plays a critical role in the CSF-independent survival of human macrophages via regulation of the expression of BCL-2 family. J Biol Chem. 2005. 280 (50), 41137-41145
29. McDonald, P. P., Bald, A., and Cassatella, M. A., Activation of the NFκB pathway by inflammatory stimuli in human neutrophils. Blood. 1997. 89 (9), 3421-3433
30. Grossmann, M. et al., The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci U S A. 1999. 96 (21), 11848-11853
31. Lawrence, T. et al., IKKalpha limits macrophage NFκB activation and contributes to the resolution of inflammation. Nature. 2005. 434 (7037), 1138-1143
32. Li, Q. et al., Enhanced NFκB activation and cellular function in macrophageslacking IkappaB kinase 1 (IKK1). Proc Natl Acad Sci U S A. 2005. 102 (35), 12425-12430
33. Bours, V. et al., The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell. 1993. 72 (5), 729-739
34. Yamamoto, M. et al., Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature. 2004. 430 (6996), 218-222
35. Bosisio, D. et al., A hyper-dynamic equilibrium between promoter-bound and nucleoplasmic dimers controls NFκB-dependent gene activity. EMBO J. 2006. 25 (4), 798-810
36. Basak, S., Shih, V. F., and Hoffmann, A., Generation and activation of multiple dimeric transcription factors within the NFκB signaling system. Mol Cell Biol. 2008. 28 (10), 3139-3150
1. K.E. de Visser, A. Eichten, L.M. Coussens, Nat. Rev. Cancer 6, 2006, 24–37.
2. Mantovani A. Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines. Biology of Disease 1. U.S.A, 1994, 5.
3. Mantovani A, Bottazi B, Sozzani S, Peri G, Allavena P, Dong QG, Vecchi A, colotta F. Cytokine Regulation of Monocyte Recruitment. Arch Immunol Ther Exp (Warsz). 1995; 43:149-52
4. Van-Ravenswaay-Claasen HH, Kluin PM, Fleuren GJ. Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Lab Invest 1992; 67: 166-74
5. Van-Furth R. In Galin JI, Goldestein IM, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. New York: Ravens Press, 1988; 281
6. Auger MJ, Ross JA. The biology of macrophage. In Lewis CE, McGee JO, eds. The Macrophage. Oxford: Oxford University Press, 1992; 2-74
7. Thorens B, Mermod JJ, Vassalli P. Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation. Cell 1987; 48: 671-9
8. Navarro S, Debili N, Bernaudin JF, Vainchenker W, Doly J. Regulation of the expression of IL-6 in human monocytes. J Immunol 1989; 142: 4339-45
9. Eierman DF, ohnson JCE, Haskill JS. Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates. J Immunol 1989; 142: 1970-6
10. C.D. Mills, K. Kincaid, J.M. Alt, M.J. Heilman, A.M. Hill, J. Immunol. 164 , 2000, 6166–6173.
11. A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Trends Immunol. 23 , 2002, 549–555.
12. A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, Trends Immunol. 25, 2004, 677–686.
13. N.A. Siciliano, J.A. Skinner, M.H. Yuk, J. Immunol. 177 , 2006, 7131–7138.
14. N.D. Savage, T. de Boer, K.V. Walburg, S.A. Joosten, K. van Meijgaarden, A. Geluk,T.H. Ottenhoff, J. Immunol. 181, 2008, 2220–2226.
15. D.J. Cua, S.A. Stohlman, J. Immunol. 159, 1997, 5834–5840
16. Evans R. Macrophages in syngeneic animal tumours. Transplantation 1972; 14: 468-73
17. O’Sullivan C, Lewis CE. Tumour-associated leucocytes: friends or foes in breast carcinoma. Journal of Pathology 1994; 172: 229-35
18. Toomey D, Harmey J, Condron C, Kay E, Bouchier-Hayes D. Phenotyping of immune cell infiltrates in breast and colorectal tumours. Immunol Invest 1999; 28: 29-41
19. Mantovan, A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992;13:265-70
20. Brunda MJ, Sulich V, Wright RB, Palleroni AV. Tumoricidal activity and cytokine secretion by tumor-infiltrating macrophages. Int J Cancer 1991; 48: 704-8
21. C. D. Bucana, A. Fabra, R. Sanchez, and I. J. Fidler. Different patterns of macrophage infiltration into allogeneic-murine and xenogeneic-human neoplasms growing in nude mice. Am J Pathol. 1992 November; 141(5): 1225–1236.
22. Walter S, Bottazzi B, Govoni D, Colotta F, Mantovani A. Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JE. Int J Cancer 1991; 49: 431-5
23. Pupa SM, Bufalino R, Invernizzi AM, Andreola S, Rilke F, Lombardi L, Colnaghi MI, Menard S. Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas [see comments]. Comment in: J Clin Oncol 1996 Aug;14 (8):2406-7. Journal of Clinical Oncology 1996; 14: 85-94
24. Seljelid R. Tumour immunology: alternative perspectives. Scan J Immunol1997; 46: 437-44.
25. Hakansson L, Adell G, Boeryd B, Sjogren F, Sjodahl R. Infiltration of mononuclear inflammatorycells into primary colorectal carcinomas: an immunohistological analysis. British Journal of Cancer 1997; 75: 374-80
26. F. Balkwill, K.A. Charles, A. Mantovani, Cancer Cell 7, 2005, 211–217
27. L.M. Coussens, Z. Werb, Nature 420, 2002, 860–867.
28. C. Murdoch, A. Giannoudis, C.E. Lewis, Blood 104, 2004, 2224–2234.
29. Y. Wu, Y.Y. Li, K. Matsushima, T. Baba, N. Mukaida, J. Immunol. 181, 2008, 6384–6393.
30. E.Y. Lin, A.V. Nguyen, R.G. Russell, J.W. Pollard, J. Exp. Med. 193, 2001, 727–740.
31. M. Kerber, Y. Reiss, A. Wickersheim, M. Jugold, F. Kiessling, M. Heil, V. Tchaikovski, J. Waltenberger, M. Shibuya, K.H. Plate, M.R. Machein, Cancer Res. 68, 2008, 7342–7351.
32. C. Fischer, B. Jonckx, M. Mazzone, S. Zacchigna, S. Loges, L. Pattarini, E. Chorianopoulos, L. Liesenborghs, M. Koch, M. De Mol, M. Autiero, S. Wyns, S. Plaisance, L. Moons, N. van Rooijen, M. Giacca, J.M. Stassen, M. Dewerchin, D. Collen, P. Carmeliet, Cell 131, 2007, 463–475.
33. R. Du, K.V. Lu, C. Petritsch, P. Liu, R. Ganss, E. Passegue, H. Song, S. Vandenberg, R.S. Johnson, Z. Werb, G. Bergers, Cancer Cell 13, 2008, 206–220.
34. F. Balkwill, Nat. Rev. Cancer 4 , 2004, 540–550.
35. J.W. Pollard, Nat. Rev. Cancer 4 , 2004, 71–78.
36. Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A. Regulation of the macrophage content of neoplasms by chemoattractants. Science 1983; 220: 210
37. Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K. Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF). Biochem Biophys Res Commun 1989; 159: 249-55
38. Zachariae CO, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, Matsushima K. Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med 1990; 171: 2177-82
39. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 1992; 148: 1280-5
40. Valkovic T, Lucin K, Krstulja M, Dobi-Babic R, Jonjic N. Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer. Pathology, Research & Practice 1998, 194, 335-40.
41. Opdenakker G, Van-Damme J. Cytokines and proteases in invasive processes: molecular similarities between inflammation and cancer. Cytokine 1992; 4: 251-8
42. Hildenbrand R, Wolf G, Bohme B, Bleyl U, Steinborn A. Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue. J Leukoc Biol 1999; 66: 40-9
43. Jiang Y, Beller DI, Frendl G, Graves DT. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 1992; 148: 2423-8
44. Rojas A, Delgado R, Glaria L, Palacios M. Monocyte chemotactic protein-1 inhibits the induction of nitric oxide synthase in J774 cells. Biochem Biophys Res Commun 1993; 196: 274-9
45. Graves DT, Jiang Y. Chemokines, a family of chemotactic cytokines. Critical Reviews in Oral Biology & Medicine 1995, 6, 109-18.
46. Fioretti F, Fradelizi D, Stoppacciaro A, Ramponi S, Ruco L, Minty A, Sozzani S, Garlanda C, Vecchi A, Mantovani A. Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor. J Immunol 1998; 161: 342-6
47. Bottazzi B, Erba E, Nobili N, Fazioli F, Rambaldi A, Mantovani A. A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas. J Immunol 1990; 144: 2409-12
48. Fu YX, Cai JP, Chin YH, Watson GA, Lopez DM. Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF. Int J Cancer 1992; 50: 585-8
49. Dougherty ST, Eaves CJ, McBride WH, Dougherty GJ. Role of macrophage-colony-stimulating factor in regulating the accumulation and phenotype of tumor-associated macrophages. Cancer Immunology, Immunotherapy 1997, 44, 165-72
50. Dvorak HF, Nagy JA, Dvorak AM. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 1991; 3: 77-85
51. Ha SJ, Lee CH, Lee SB, Kim CM, Jang KL, Shin HS, Sung YC. A novel function of IL-12p40 as a chemotactic molecule for macrophages. J Immunol 1999; 163: 2902-8
52. G. Martin-Manso, S. Galli, L.A. Ridnour, M. Tsokos, D.A. Wink, D.D. Roberts, Cancer Res. 68 2008, 7090–7099.
53. L. Apetoh, F. Ghiringhelli, A. Tesniere, M. Obeid, C. Ortiz, A. Criollo, G. Mignot, M.C. Maiuri, E. Ullrich, P. Saulnier, H. Yang, S. Amigorena, B. Ryffel, F.J. Barrat, P. Saftig, F. Levi, R. Lidereau, C. Nogues, J.P. Mira, A. Chompret, V. Joulin, F. Clavel-Chapelon, J. Bourhis, F. Andre, S. Delaloge, T. Tursz, G. Kroemer, L. Zitvogel, Nat. Med. 13, 2007, 1050–1059.
54. P. Scaffidi, T. Misteli, M.E. Bianchi, Nature 418, 2002, 191–195.
55. C. Schlueter, H.Weber, B. Meyer, P. Rogalla, K. Roser, S. Hauke, J. Bullerdiek, Am. J. Pathol. 166, 2005, 1259–1263.
56. M.C. Bosco, G. Reffo, M. Puppo, L. Varesio, Cell Immunol. 228, 2004, 1–7.
57. A. Sica, A. Saccani, B. Bottazzi, S. Bernasconi, P. Allavena, B. Gaetano, F. Fei, G. LaRosa, C. Scotton, F. Balkwill, A. Mantovani, J. Immunol. 164, 2000, 733–738.
58. S. Gordon, P.R. Taylor, Nat. Rev. Immunol. 5, 2005, 953–964
59. B. Passlick, D. Flieger, H.W. Ziegler-Heitbrock, Blood 74, 1989, 2527–2534.
60. F. Geissmann, S. Jung, D.R. Littman, Immunity 19, 2003, 71–82.
61. C. Auffray, D. Fogg, M. Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, A. Cumano, G.Lauvau, F. Geissmann, Science 317, 2007, 666–670.
62. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002, 23, 549–555.
63. Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., Harris, A. L. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996, 56, 4625–4629.
64. Bingle, L., Lewis, C. E., Corke, K. P., Reed, M. W., Brown, N. J. Macrophages promote angiogenesis in human breast tumor spheroids in vivo. Br. J. Cancer, 2006, 94, 101–107.
65. Nishie, A., Ono, M., Shono, T., Fukushi, J., Otsubo, M., Onoue, H., Ito, Y., Inamura, T., Ikezaki, K., Fukui, M., Iwaki, T., Kuwano, M. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res. 1999, 5, 1107–1113.
66. Hanada, T., Nakagawa, M., Emoto, A., Nomura, T., Nasu, N., Nomura, Y. Prognostic value of tumor-associated macrophage count in human bladder cancer. Int. J. Urol, 2000, 7, 263–269.
67. Lissbrant, I. F., Stattin, P., Wikstrom, P., Damber, J. E., Egevad, L., Bergh, A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int. J. Oncol. 2000, 17, 445–451.
68. Koide, N., Nishio, A., Sato, T., Sugiyama, A., Miyagawa, S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am. J. Gastroenterol. 2004, 99, 1667–1674.
69. Hotchkiss, K. A., Ashton, A. W., Klein, R. S., Lenzi, M. L., Zhu, G. H., Schwartz, E. L. Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration. Cancer Res. 2003, 63, 527–533.
70. Pollard, J. W. Tumor-educated macrophages promote tumor progression and metastasis. Nat. Rev. Cancer 2004, 4, 71–78.
71. DeNardo, D. G., Johansson, M., Coussens, L. M. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 2008, 27, 11–18.
72. Mantovani, A., Allavena, P., Sica, A., Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444.
73. Giraudo, E., Inoue, M., Hanahan, D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 2004, 114, 623–633.
74. Winkler, F., Kozin, S. V., Tong, R. T., Chae, S. S., Booth, M. F., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., di Tomaso, E., Munn, L. L., Jain, R. K. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004, 6, 553–563.
75. Shojaei, F., Ferrara, N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 2008, 68, 5501–5504.
76. Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., Lewis, C. E. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 2000, 192, 150–158.
77. Schioppa, T., Uranchimeg, B., Saccani, A., Biswas, S. K., Doni, A., Rapisarda, A., Bernasconi, S., Saccani, S., Nebuloni, M., Vago, L., Mantovani, A., Melillo, G., Sica, A. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 2003, 198, 1391–1402.
78. Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 2004, 4, 540–550.
79. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25, 677–686.
80. Luster, A. D. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 1998, 338, 436–445.
81. Strieter, R. M., Belperio, J. A., Phillips, R. J., Keane, M. P. CXC chemokines in angiogenesis ofcancer. Semin. Cancer Biol. 2004, 14, 195–200.
82. S. Gordon, Nat. Rev. Immunol. 3, 2003, 23–35.
83. A. Sica, A. Saccani, B. Bottazzi, N. Polentarutti, A. Vecchi, J. van Damme, A. Mantovani, J. Immunol. 164, 2000, 762–767.
84. P. Allavena, L. Piemonti, D. Longoni, S. Bernasconi, A. Stoppacciaro, L. Ruco, A. Mantovani, Eur. J. Immunol. 28, 1998, 359–369.
85. S. Kusmartsev, D.I. Gabrilovich, J. Immunol. 174, 2005, 4880–4891.
86. S.P. Bak, A. Alonso, M.J. Turk, B. Berwin, Mol. Immunol. 2008.
87. P.C. Rodriguez, A.H. Zea, J. DeSalvo, K.S. Culotta, J. Zabaleta, D.G. Quiceno, J.B. Ochoa, A.C. Ochoa, J. Immunol. 171, 2003, 1232–1239.
88. P. Sinha, V.K. Clements, S. Ostrand-Rosenberg, Cancer Res. 65, 2005, 11743–11751.
89. P.C. Rodriguez, D.G. Quiceno, A.C. Ochoa, Blood 109, 2007, 1568–1573.
90. A.H. Zea, P.C. Rodriguez, K.S. Culotta, C.P. Hernandez, J. DeSalvo, J.B. Ochoa, H.J. Park, J. Zabaleta, A.C. Ochoa, Cell Immunol. 232, 2004, 21–31.
91. G. Gallina, L. Dolcetti, P. Serafini, C. De Santo, I. Marigo, M.P. Colombo, G. Basso, F. Brombacher, I. Borrello, P. Zanovello, S. Bicciato, V. Bronte, J. Clin. Invest. 116, 2006, 2777–2790.
92. I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S.Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers, A. Lackner, X. Alvarez, A. Ochoa, L. Chen,W. Zou, J. Exp. Med. 203, 2006, 871–881.
93. I. Kryczek, S. Wei, G. Zhu, L. Myers, P. Mottram, P. Cheng, L. Chen, G. Coukos, W. Zou, Cancer Res. 67, 2007, 8900–8905.
94. T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, W. Zou, Nat. Med. 10 , 2004, 942–949.
95. M. Kortylewski, M. Kujawski, T.Wang, S.Wei, S. Zhang, S. Pilon-Thomas, G. Niu, H. Kay, J. Mule, W.G. Kerr, R. Jove, D. Pardoll, H. Yu, Nat. Med. 11, 2005, 1314–1321.
96. D.S. Dace, R.S. Apte, Rejuvenation Res. 11, 2008, 177–185.
97. P. Sinha, V.K. Clements, S. Ostrand-Rosenberg, J. Immunol. 174 , 2005, 636–645.
98. A. Saccani, T. Schioppa, C. Porta, S.K. Biswas, M. Nebuloni, L. Vago, B. Bottazzi, M.P. Colombo, A. Mantovani, A. Sica, Cancer Res. 66, 2006, 11432–11440.
99. J. Rius, M. Guma, C. Schachtrup, K. Akassoglou, A.S. Zinkernagel, V. Nizet, R.S. Johnson, G.G. Haddad, M. Karin, Nature 453, 2008, 807–811.
100. Condeelis, J., Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell, 2006, 124, 263–266.
101. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315, 1650–1659.
102. Joyce, J. A., Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer, 2009, 9, 239–252.
103. Hagemann, T., Robinson, S. C., Schulz, M., Trumper, L., Balkwill, F. R., Binder, C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF- dependent upregulation of matrix metalloproteases. Carcinogenesis, 2004, 25, 1543–1549.
104. Mytar, B., Woloszyn, M., Szatanek, R., Baj-Krzyworzeka, M., Siedlar, M., Ruggiero, I., Wieckiewicz, J., Zembala, M. Tumor cell-induced deactivation of human monocytes. J. Leukoc. Biol. 2003, 74, 1094–1101.
105. Giavazzi, R., Garofalo, A., Bani, M. R., Abbate, M., Ghezzi, P., Boraschi, D., Mantovani, A., Dejana, E. Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res. 1990, 50, 4771–4775.
106. Pollard, J. W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 2008, 84, 623–630.
107. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., Shibuya, M. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2002, 2, 289–300.
108. Hagemann, T., Wilson, J., Kulbe, H., Li, N. F., Leinster, D. A., Charles, K., Klemm, F., Pukrop, T., Binder, C., Balkwill, F. R. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK. J. Immunol. 2005, 175, 1197–1205.
109. Pukrop, T., Klemm, F., Hagemann, T., Gradl, D., Schulz, M., Siemes, S., Trumper, L., Binder, C. Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc. Natl. Acad. Sci. 2006, USA 103, 5454–5459.
110. Egeblad, M., Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer, 2002, 2, 161–174.
111. Lynch, C. C., Matrisian, L. M. Matrix metalloproteinases in tumor-host cell communication. Differentiation, 2002, 70, 561–573.
112. Mohamed, M. M., Sloane, B. F. Cysteine cathepsins: multifunctional enzymes in cancer. Nat. Rev. Cancer, 2006, 6, 764–775.
113. Gocheva, V., Joyce, J. A. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle, 2007, 6, 60–64.
114. Sangaletti, S., Di Carlo, E., Gariboldi, S., Miotti, S., Cappetti, B., Parenza, M., Rumio, C., Brekken, R. A., Chiodoni, C., Colombo, M. P. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 2008, 68, 9050–9059.
115. Wyckoff, J. B., Wang, Y., Lin, E. Y., Li, J. F., Goswami, S., Stanley, E. R., Segall, J. E., Pollard, J. W., Condeelis, J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007, 67, 2649–2656.
116. Pawelek, J. M., Chakraborty, A. K. (2008) Fusion of tumor cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat. Rev. Cancer, 2008, 8, 377–386.
2. Van Furth R. & Cohn ZA. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 1968,128: 415-435
3. Van Furth R., Diesselhoff-den Dulk MM. & Mattie H. Quantitative study on the production and kinetics of mononuclear phagocytes during an acute inflammatory reaction. J. Exp. Med. 1973, 138: 1314-1330
4. Fairweather, D. and Cihakova, D., Alternatively activated macrophages in infection and autoimmunity. J Autoimmun. 2009, 33 (3-4), 222-230
5. Mantovani, A., Allavena, P., Sica, A., and Balkwill, F., Cancer-related inflammation. Nature. 2008, 454 (7203), 436-444
6. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993 Dec 3; 75(5): 843-854.
7. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J., and Parker, R., Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006. 20 (5), 515-524
8. Petrocca, F. and Lieberman, J., Micromanagers of immune cell fate and function. Adv Immunol. 2009. 102, 227-244
9. Bartel, D. P., MicroRNAs: target recognition and regulatory functions. Cell. 2009. 136 (2), 215-233
10. Baltimore, D. et al., MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2009. 9 (8), 839-845
11. Kluiver, J., Kroesen, B. J., Poppema, S., and van den Berg, A., The role ofmicroRNAs in normal hematopoiesis and hematopoietic malignancies. Leukemia. 2006. 20 (11), 1931-1936
12. Johnnidis, J. B. et al., Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008. 451 (7182), 1125-1129
13. Hayden, M. S. and Ghosh, S., Shared principles in NFκB signaling. Cell. 2008. 132 (3), 344-362
14. Vallabhapurapu, S. and Karin, M., Regulation and function of NFκB transcription factors in the immune system. Annu Rev Immunol. 2009. 27, 693-733
15. Beinke, S. and Ley, S. C., Functions of NFκB1 and NFκB2 in immune cell biology. Biochem J. 2004. 382 (Pt 2), 393-409
16. Bonizzi, G. and Karin, M., The two NFκB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004. 25 (6), 280-288
17. Betel, D. et al., The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008. 36 (Database issue), D149-D153
18. Grimson, A. et al., MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007. 27 (1), 91-105
19. Saetrom, P. et al., Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res. 2007. 35 (7), 2333-2342
20. Alban Dupoux, Jessy Cartier, Séverine Cathelin, Rodolphe Filomenko, Eric Solary, and Laurence Dubrez-Daloz, cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand. Blood, 1 January 2009, Vol. 113, No. 1, 175-185.
21. Zarnegar, B. J. et al., Noncanonical NFκB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008 9 (12), 1371-1378
22. Vallabhapurapu, S. et al., Nonredundant and complementary functions of TRAF2and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NFκB signaling. Nat Immunol. 2008. 9 (12), 1364-1370
23. Dejardin, E. et al., The lymphotoxinβreceptor induces different patterns of gene expression via two NFκB pathways. Immunity. 2002. 17 (4), 525-535
24. Bonizzi, G. et al., Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J. 2004. 23 (21), 4202-4210
25. Bren, G. D. et al., Transcription of the RelB gene is regulated by NFκB. Oncogene. 2001. 20 (53), 7722-7733
26. Cimmino, A. et al., miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005. 102 (39), 13944-13949
27. Hashimoto, S. I., Komuro, I., Yamada, M., and Akagawa, K. S., IL-10 inhibits granulocyte-macrophage colony-stimulating factor-dependent human monocyte survival at the early stage of the culture and inhibits the generation of macrophages. J Immunol. 2001. 167 (7), 3619-3625
28. Komuro, I., Yasuda, T., Iwamoto, A., and Akagawa, K. S., Catalase plays a critical role in the CSF-independent survival of human macrophages via regulation of the expression of BCL-2 family. J Biol Chem. 2005. 280 (50), 41137-41145
29. McDonald, P. P., Bald, A., and Cassatella, M. A., Activation of the NFκB pathway by inflammatory stimuli in human neutrophils. Blood. 1997. 89 (9), 3421-3433
30. Grossmann, M. et al., The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci U S A. 1999. 96 (21), 11848-11853
31. Lawrence, T. et al., IKKalpha limits macrophage NFκB activation and contributes to the resolution of inflammation. Nature. 2005. 434 (7037), 1138-1143
32. Li, Q. et al., Enhanced NFκB activation and cellular function in macrophageslacking IkappaB kinase 1 (IKK1). Proc Natl Acad Sci U S A. 2005. 102 (35), 12425-12430
33. Bours, V. et al., The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell. 1993. 72 (5), 729-739
34. Yamamoto, M. et al., Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature. 2004. 430 (6996), 218-222
35. Bosisio, D. et al., A hyper-dynamic equilibrium between promoter-bound and nucleoplasmic dimers controls NFκB-dependent gene activity. EMBO J. 2006. 25 (4), 798-810
36. Basak, S., Shih, V. F., and Hoffmann, A., Generation and activation of multiple dimeric transcription factors within the NFκB signaling system. Mol Cell Biol. 2008. 28 (10), 3139-3150
1. K.E. de Visser, A. Eichten, L.M. Coussens, Nat. Rev. Cancer 6, 2006, 24–37.
2. Mantovani A. Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines. Biology of Disease 1. U.S.A, 1994, 5.
3. Mantovani A, Bottazi B, Sozzani S, Peri G, Allavena P, Dong QG, Vecchi A, colotta F. Cytokine Regulation of Monocyte Recruitment. Arch Immunol Ther Exp (Warsz). 1995; 43:149-52
4. Van-Ravenswaay-Claasen HH, Kluin PM, Fleuren GJ. Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Lab Invest 1992; 67: 166-74
5. Van-Furth R. In Galin JI, Goldestein IM, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. New York: Ravens Press, 1988; 281
6. Auger MJ, Ross JA. The biology of macrophage. In Lewis CE, McGee JO, eds. The Macrophage. Oxford: Oxford University Press, 1992; 2-74
7. Thorens B, Mermod JJ, Vassalli P. Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation. Cell 1987; 48: 671-9
8. Navarro S, Debili N, Bernaudin JF, Vainchenker W, Doly J. Regulation of the expression of IL-6 in human monocytes. J Immunol 1989; 142: 4339-45
9. Eierman DF, ohnson JCE, Haskill JS. Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates. J Immunol 1989; 142: 1970-6
10. C.D. Mills, K. Kincaid, J.M. Alt, M.J. Heilman, A.M. Hill, J. Immunol. 164 , 2000, 6166–6173.
11. A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Trends Immunol. 23 , 2002, 549–555.
12. A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, Trends Immunol. 25, 2004, 677–686.
13. N.A. Siciliano, J.A. Skinner, M.H. Yuk, J. Immunol. 177 , 2006, 7131–7138.
14. N.D. Savage, T. de Boer, K.V. Walburg, S.A. Joosten, K. van Meijgaarden, A. Geluk,T.H. Ottenhoff, J. Immunol. 181, 2008, 2220–2226.
15. D.J. Cua, S.A. Stohlman, J. Immunol. 159, 1997, 5834–5840
16. Evans R. Macrophages in syngeneic animal tumours. Transplantation 1972; 14: 468-73
17. O’Sullivan C, Lewis CE. Tumour-associated leucocytes: friends or foes in breast carcinoma. Journal of Pathology 1994; 172: 229-35
18. Toomey D, Harmey J, Condron C, Kay E, Bouchier-Hayes D. Phenotyping of immune cell infiltrates in breast and colorectal tumours. Immunol Invest 1999; 28: 29-41
19. Mantovan, A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992;13:265-70
20. Brunda MJ, Sulich V, Wright RB, Palleroni AV. Tumoricidal activity and cytokine secretion by tumor-infiltrating macrophages. Int J Cancer 1991; 48: 704-8
21. C. D. Bucana, A. Fabra, R. Sanchez, and I. J. Fidler. Different patterns of macrophage infiltration into allogeneic-murine and xenogeneic-human neoplasms growing in nude mice. Am J Pathol. 1992 November; 141(5): 1225–1236.
22. Walter S, Bottazzi B, Govoni D, Colotta F, Mantovani A. Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JE. Int J Cancer 1991; 49: 431-5
23. Pupa SM, Bufalino R, Invernizzi AM, Andreola S, Rilke F, Lombardi L, Colnaghi MI, Menard S. Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas [see comments]. Comment in: J Clin Oncol 1996 Aug;14 (8):2406-7. Journal of Clinical Oncology 1996; 14: 85-94
24. Seljelid R. Tumour immunology: alternative perspectives. Scan J Immunol1997; 46: 437-44.
25. Hakansson L, Adell G, Boeryd B, Sjogren F, Sjodahl R. Infiltration of mononuclear inflammatorycells into primary colorectal carcinomas: an immunohistological analysis. British Journal of Cancer 1997; 75: 374-80
26. F. Balkwill, K.A. Charles, A. Mantovani, Cancer Cell 7, 2005, 211–217
27. L.M. Coussens, Z. Werb, Nature 420, 2002, 860–867.
28. C. Murdoch, A. Giannoudis, C.E. Lewis, Blood 104, 2004, 2224–2234.
29. Y. Wu, Y.Y. Li, K. Matsushima, T. Baba, N. Mukaida, J. Immunol. 181, 2008, 6384–6393.
30. E.Y. Lin, A.V. Nguyen, R.G. Russell, J.W. Pollard, J. Exp. Med. 193, 2001, 727–740.
31. M. Kerber, Y. Reiss, A. Wickersheim, M. Jugold, F. Kiessling, M. Heil, V. Tchaikovski, J. Waltenberger, M. Shibuya, K.H. Plate, M.R. Machein, Cancer Res. 68, 2008, 7342–7351.
32. C. Fischer, B. Jonckx, M. Mazzone, S. Zacchigna, S. Loges, L. Pattarini, E. Chorianopoulos, L. Liesenborghs, M. Koch, M. De Mol, M. Autiero, S. Wyns, S. Plaisance, L. Moons, N. van Rooijen, M. Giacca, J.M. Stassen, M. Dewerchin, D. Collen, P. Carmeliet, Cell 131, 2007, 463–475.
33. R. Du, K.V. Lu, C. Petritsch, P. Liu, R. Ganss, E. Passegue, H. Song, S. Vandenberg, R.S. Johnson, Z. Werb, G. Bergers, Cancer Cell 13, 2008, 206–220.
34. F. Balkwill, Nat. Rev. Cancer 4 , 2004, 540–550.
35. J.W. Pollard, Nat. Rev. Cancer 4 , 2004, 71–78.
36. Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A. Regulation of the macrophage content of neoplasms by chemoattractants. Science 1983; 220: 210
37. Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K. Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF). Biochem Biophys Res Commun 1989; 159: 249-55
38. Zachariae CO, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, Matsushima K. Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med 1990; 171: 2177-82
39. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 1992; 148: 1280-5
40. Valkovic T, Lucin K, Krstulja M, Dobi-Babic R, Jonjic N. Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer. Pathology, Research & Practice 1998, 194, 335-40.
41. Opdenakker G, Van-Damme J. Cytokines and proteases in invasive processes: molecular similarities between inflammation and cancer. Cytokine 1992; 4: 251-8
42. Hildenbrand R, Wolf G, Bohme B, Bleyl U, Steinborn A. Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue. J Leukoc Biol 1999; 66: 40-9
43. Jiang Y, Beller DI, Frendl G, Graves DT. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 1992; 148: 2423-8
44. Rojas A, Delgado R, Glaria L, Palacios M. Monocyte chemotactic protein-1 inhibits the induction of nitric oxide synthase in J774 cells. Biochem Biophys Res Commun 1993; 196: 274-9
45. Graves DT, Jiang Y. Chemokines, a family of chemotactic cytokines. Critical Reviews in Oral Biology & Medicine 1995, 6, 109-18.
46. Fioretti F, Fradelizi D, Stoppacciaro A, Ramponi S, Ruco L, Minty A, Sozzani S, Garlanda C, Vecchi A, Mantovani A. Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor. J Immunol 1998; 161: 342-6
47. Bottazzi B, Erba E, Nobili N, Fazioli F, Rambaldi A, Mantovani A. A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas. J Immunol 1990; 144: 2409-12
48. Fu YX, Cai JP, Chin YH, Watson GA, Lopez DM. Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF. Int J Cancer 1992; 50: 585-8
49. Dougherty ST, Eaves CJ, McBride WH, Dougherty GJ. Role of macrophage-colony-stimulating factor in regulating the accumulation and phenotype of tumor-associated macrophages. Cancer Immunology, Immunotherapy 1997, 44, 165-72
50. Dvorak HF, Nagy JA, Dvorak AM. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 1991; 3: 77-85
51. Ha SJ, Lee CH, Lee SB, Kim CM, Jang KL, Shin HS, Sung YC. A novel function of IL-12p40 as a chemotactic molecule for macrophages. J Immunol 1999; 163: 2902-8
52. G. Martin-Manso, S. Galli, L.A. Ridnour, M. Tsokos, D.A. Wink, D.D. Roberts, Cancer Res. 68 2008, 7090–7099.
53. L. Apetoh, F. Ghiringhelli, A. Tesniere, M. Obeid, C. Ortiz, A. Criollo, G. Mignot, M.C. Maiuri, E. Ullrich, P. Saulnier, H. Yang, S. Amigorena, B. Ryffel, F.J. Barrat, P. Saftig, F. Levi, R. Lidereau, C. Nogues, J.P. Mira, A. Chompret, V. Joulin, F. Clavel-Chapelon, J. Bourhis, F. Andre, S. Delaloge, T. Tursz, G. Kroemer, L. Zitvogel, Nat. Med. 13, 2007, 1050–1059.
54. P. Scaffidi, T. Misteli, M.E. Bianchi, Nature 418, 2002, 191–195.
55. C. Schlueter, H.Weber, B. Meyer, P. Rogalla, K. Roser, S. Hauke, J. Bullerdiek, Am. J. Pathol. 166, 2005, 1259–1263.
56. M.C. Bosco, G. Reffo, M. Puppo, L. Varesio, Cell Immunol. 228, 2004, 1–7.
57. A. Sica, A. Saccani, B. Bottazzi, S. Bernasconi, P. Allavena, B. Gaetano, F. Fei, G. LaRosa, C. Scotton, F. Balkwill, A. Mantovani, J. Immunol. 164, 2000, 733–738.
58. S. Gordon, P.R. Taylor, Nat. Rev. Immunol. 5, 2005, 953–964
59. B. Passlick, D. Flieger, H.W. Ziegler-Heitbrock, Blood 74, 1989, 2527–2534.
60. F. Geissmann, S. Jung, D.R. Littman, Immunity 19, 2003, 71–82.
61. C. Auffray, D. Fogg, M. Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, A. Cumano, G.Lauvau, F. Geissmann, Science 317, 2007, 666–670.
62. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002, 23, 549–555.
63. Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., Harris, A. L. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996, 56, 4625–4629.
64. Bingle, L., Lewis, C. E., Corke, K. P., Reed, M. W., Brown, N. J. Macrophages promote angiogenesis in human breast tumor spheroids in vivo. Br. J. Cancer, 2006, 94, 101–107.
65. Nishie, A., Ono, M., Shono, T., Fukushi, J., Otsubo, M., Onoue, H., Ito, Y., Inamura, T., Ikezaki, K., Fukui, M., Iwaki, T., Kuwano, M. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res. 1999, 5, 1107–1113.
66. Hanada, T., Nakagawa, M., Emoto, A., Nomura, T., Nasu, N., Nomura, Y. Prognostic value of tumor-associated macrophage count in human bladder cancer. Int. J. Urol, 2000, 7, 263–269.
67. Lissbrant, I. F., Stattin, P., Wikstrom, P., Damber, J. E., Egevad, L., Bergh, A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int. J. Oncol. 2000, 17, 445–451.
68. Koide, N., Nishio, A., Sato, T., Sugiyama, A., Miyagawa, S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am. J. Gastroenterol. 2004, 99, 1667–1674.
69. Hotchkiss, K. A., Ashton, A. W., Klein, R. S., Lenzi, M. L., Zhu, G. H., Schwartz, E. L. Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration. Cancer Res. 2003, 63, 527–533.
70. Pollard, J. W. Tumor-educated macrophages promote tumor progression and metastasis. Nat. Rev. Cancer 2004, 4, 71–78.
71. DeNardo, D. G., Johansson, M., Coussens, L. M. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 2008, 27, 11–18.
72. Mantovani, A., Allavena, P., Sica, A., Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444.
73. Giraudo, E., Inoue, M., Hanahan, D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 2004, 114, 623–633.
74. Winkler, F., Kozin, S. V., Tong, R. T., Chae, S. S., Booth, M. F., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., di Tomaso, E., Munn, L. L., Jain, R. K. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004, 6, 553–563.
75. Shojaei, F., Ferrara, N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 2008, 68, 5501–5504.
76. Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., Lewis, C. E. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 2000, 192, 150–158.
77. Schioppa, T., Uranchimeg, B., Saccani, A., Biswas, S. K., Doni, A., Rapisarda, A., Bernasconi, S., Saccani, S., Nebuloni, M., Vago, L., Mantovani, A., Melillo, G., Sica, A. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 2003, 198, 1391–1402.
78. Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 2004, 4, 540–550.
79. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25, 677–686.
80. Luster, A. D. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 1998, 338, 436–445.
81. Strieter, R. M., Belperio, J. A., Phillips, R. J., Keane, M. P. CXC chemokines in angiogenesis ofcancer. Semin. Cancer Biol. 2004, 14, 195–200.
82. S. Gordon, Nat. Rev. Immunol. 3, 2003, 23–35.
83. A. Sica, A. Saccani, B. Bottazzi, N. Polentarutti, A. Vecchi, J. van Damme, A. Mantovani, J. Immunol. 164, 2000, 762–767.
84. P. Allavena, L. Piemonti, D. Longoni, S. Bernasconi, A. Stoppacciaro, L. Ruco, A. Mantovani, Eur. J. Immunol. 28, 1998, 359–369.
85. S. Kusmartsev, D.I. Gabrilovich, J. Immunol. 174, 2005, 4880–4891.
86. S.P. Bak, A. Alonso, M.J. Turk, B. Berwin, Mol. Immunol. 2008.
87. P.C. Rodriguez, A.H. Zea, J. DeSalvo, K.S. Culotta, J. Zabaleta, D.G. Quiceno, J.B. Ochoa, A.C. Ochoa, J. Immunol. 171, 2003, 1232–1239.
88. P. Sinha, V.K. Clements, S. Ostrand-Rosenberg, Cancer Res. 65, 2005, 11743–11751.
89. P.C. Rodriguez, D.G. Quiceno, A.C. Ochoa, Blood 109, 2007, 1568–1573.
90. A.H. Zea, P.C. Rodriguez, K.S. Culotta, C.P. Hernandez, J. DeSalvo, J.B. Ochoa, H.J. Park, J. Zabaleta, A.C. Ochoa, Cell Immunol. 232, 2004, 21–31.
91. G. Gallina, L. Dolcetti, P. Serafini, C. De Santo, I. Marigo, M.P. Colombo, G. Basso, F. Brombacher, I. Borrello, P. Zanovello, S. Bicciato, V. Bronte, J. Clin. Invest. 116, 2006, 2777–2790.
92. I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S.Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers, A. Lackner, X. Alvarez, A. Ochoa, L. Chen,W. Zou, J. Exp. Med. 203, 2006, 871–881.
93. I. Kryczek, S. Wei, G. Zhu, L. Myers, P. Mottram, P. Cheng, L. Chen, G. Coukos, W. Zou, Cancer Res. 67, 2007, 8900–8905.
94. T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, W. Zou, Nat. Med. 10 , 2004, 942–949.
95. M. Kortylewski, M. Kujawski, T.Wang, S.Wei, S. Zhang, S. Pilon-Thomas, G. Niu, H. Kay, J. Mule, W.G. Kerr, R. Jove, D. Pardoll, H. Yu, Nat. Med. 11, 2005, 1314–1321.
96. D.S. Dace, R.S. Apte, Rejuvenation Res. 11, 2008, 177–185.
97. P. Sinha, V.K. Clements, S. Ostrand-Rosenberg, J. Immunol. 174 , 2005, 636–645.
98. A. Saccani, T. Schioppa, C. Porta, S.K. Biswas, M. Nebuloni, L. Vago, B. Bottazzi, M.P. Colombo, A. Mantovani, A. Sica, Cancer Res. 66, 2006, 11432–11440.
99. J. Rius, M. Guma, C. Schachtrup, K. Akassoglou, A.S. Zinkernagel, V. Nizet, R.S. Johnson, G.G. Haddad, M. Karin, Nature 453, 2008, 807–811.
100. Condeelis, J., Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell, 2006, 124, 263–266.
101. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315, 1650–1659.
102. Joyce, J. A., Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer, 2009, 9, 239–252.
103. Hagemann, T., Robinson, S. C., Schulz, M., Trumper, L., Balkwill, F. R., Binder, C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF- dependent upregulation of matrix metalloproteases. Carcinogenesis, 2004, 25, 1543–1549.
104. Mytar, B., Woloszyn, M., Szatanek, R., Baj-Krzyworzeka, M., Siedlar, M., Ruggiero, I., Wieckiewicz, J., Zembala, M. Tumor cell-induced deactivation of human monocytes. J. Leukoc. Biol. 2003, 74, 1094–1101.
105. Giavazzi, R., Garofalo, A., Bani, M. R., Abbate, M., Ghezzi, P., Boraschi, D., Mantovani, A., Dejana, E. Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res. 1990, 50, 4771–4775.
106. Pollard, J. W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 2008, 84, 623–630.
107. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., Shibuya, M. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2002, 2, 289–300.
108. Hagemann, T., Wilson, J., Kulbe, H., Li, N. F., Leinster, D. A., Charles, K., Klemm, F., Pukrop, T., Binder, C., Balkwill, F. R. Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK. J. Immunol. 2005, 175, 1197–1205.
109. Pukrop, T., Klemm, F., Hagemann, T., Gradl, D., Schulz, M., Siemes, S., Trumper, L., Binder, C. Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc. Natl. Acad. Sci. 2006, USA 103, 5454–5459.
110. Egeblad, M., Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer, 2002, 2, 161–174.
111. Lynch, C. C., Matrisian, L. M. Matrix metalloproteinases in tumor-host cell communication. Differentiation, 2002, 70, 561–573.
112. Mohamed, M. M., Sloane, B. F. Cysteine cathepsins: multifunctional enzymes in cancer. Nat. Rev. Cancer, 2006, 6, 764–775.
113. Gocheva, V., Joyce, J. A. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle, 2007, 6, 60–64.
114. Sangaletti, S., Di Carlo, E., Gariboldi, S., Miotti, S., Cappetti, B., Parenza, M., Rumio, C., Brekken, R. A., Chiodoni, C., Colombo, M. P. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 2008, 68, 9050–9059.
115. Wyckoff, J. B., Wang, Y., Lin, E. Y., Li, J. F., Goswami, S., Stanley, E. R., Segall, J. E., Pollard, J. W., Condeelis, J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007, 67, 2649–2656.
116. Pawelek, J. M., Chakraborty, A. K. (2008) Fusion of tumor cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat. Rev. Cancer, 2008, 8, 377–386.