Search tips
Search criteria 


Logo of molmedLink to Publisher's site
Mol Med. 1998 November; 4(11): 707–714.
PMCID: PMC2230345

Involvement of macrophage migration inhibitory factor (MIF) in the mechanism of tumor cell growth.


BACKGROUND: Macrophage migration inhibitory factor (MIF) was recently rediscovered as a cytokine, pituitary hormone, and glucocorticoid-induced immunomodulator. MIF is constitutively expressed in various cells and enhances production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interferon gamma. Recently, it was reported that MIF mRNA was overexpressed in prostatic tumors, which suggests that MIF is a protein involved in tumor cell growth beyond inflammatory and immune responses. MATERIALS AND METHODS: We examined the expression of MIF in the murine colon carcinoma cell line colon 26 by Western and Northern blot analyses and immunohistochemistry. Next, we investigated the effects of transforming growth factor (TGF) beta, basic fibroblast growth factor (b-FGF), and platelet-derived growth factor (PDGF) on the expression of MIF mRNA. Furthermore, we examined whether MIF is involved in tumor cell proliferation, using an MIF anti-sense plasmid transfection technique. RESULTS: We demonstrated that MIF protein and its mRNA were highly expressed in colon 26 cells, using Western and Northern blot analyses, respectively. By immunohistochemical analysis, we found that MIF was localized largely in the cytoplasm of the tumor cells. In response to TGF-beta, b-FGF, and PDGF, MIF mRNA expression was significantly up-regulated. Following this, we transfected the cells with an anti-sense MIF plasmid, which revealed that this treatment induced significant suppression of cell proliferation. CONCLUSION: Although MIF plays multifunctional roles in a broad spectrum of pathophysiological states, little has been done to investigate the role of this protein in association with tumor growth. The current results suggest the possibility that MIF induces tumor cell growth in concert with other growth factors, which encouraged us to investigate a novel approach for tumor therapy using an anti-MIF antibody and an MIF anti-sense plasmid transfection technique.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Anzano MA, Rieman D, Prichett W, Bowen-Pope DF, Greig R. Growth factor production by human colon carcinoma cell lines. Cancer Res. 1989 Jun 1;49(11):2898–2904. [PubMed]
  • Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994 Jun 1;179(6):1895–1902. [PMC free article] [PubMed]
  • Sakai M, Nishihira J, Hibiya Y, Koyama Y, Nishi S. Glutathione binding rat liver 13k protein is the homologue of the macrophage migration inhibitory factor. Biochem Mol Biol Int. 1994 Jun;33(3):439–446. [PubMed]
  • Bacher M, Meinhardt A, Lan HY, Mu W, Metz CN, Chesney JA, Calandra T, Gemsa D, Donnelly T, Atkins RC, et al. Migration inhibitory factor expression in experimentally induced endotoxemia. Am J Pathol. 1997 Jan;150(1):235–246. [PubMed]
  • Bucala R. MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. FASEB J. 1996 Dec;10(14):1607–1613. [PubMed]
  • Wistow GJ, Shaughnessy MP, Lee DC, Hodin J, Zelenka PS. A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1272–1275. [PubMed]
  • Shimizu T, Ohkawara A, Nishihira J, Sakamoto W. Identification of macrophage migration inhibitory factor (MIF) in human skin and its immmunohistochemical localization. FEBS Lett. 1996 Mar 4;381(3):199–202. [PubMed]
  • Matsuda A, Tagawa Y, Matsuda H, Nishihira J. Identification and immunohistochemical localization of macrophage migration inhibitory factor in human cornea. FEBS Lett. 1996 May 6;385(3):225–228. [PubMed]
  • Lanahan A, Williams JB, Sanders LK, Nathans D. Growth factor-induced delayed early response genes. Mol Cell Biol. 1992 Sep;12(9):3919–3929. [PMC free article] [PubMed]
  • Matsuda A, Tagawa Y, Matsuda H, Nishihira J. Expression of macrophage migration inhibitory factor in corneal wound healing in rats. Invest Ophthalmol Vis Sci. 1997 Jul;38(8):1555–1562. [PubMed]
  • Meyer-Siegler K, Hudson PB. Enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. Urology. 1996 Sep;48(3):448–452. [PubMed]
  • Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. [PubMed]
  • Schägger H, von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. [PubMed]
  • Onodera S, Suzuki K, Matsuno T, Kaneda K, Takagi M, Nishihira J. Macrophage migration inhibitory factor induces phagocytosis of foreign particles by macrophages in autocrine and paracrine fashion. Immunology. 1997 Sep;92(1):131–137. [PubMed]
  • Mitchell R, Bacher M, Bernhagen J, Pushkarskaya T, Seldin MF, Bucala R. Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF). J Immunol. 1995 Apr 15;154(8):3863–3870. [PubMed]
  • Ohnishi Y, Sakamoto T, Fujii H, Kimura F, Murata J, Tazawa K, Fujimaki M, Sato Y, Kondo M, Une Y, et al. Characterization of a liver metastatic variant of murine colon 26 carcinoma cells. Tumour Biol. 1997;18(2):113–122. [PubMed]
  • Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 1966 Jul 1;153(3731):80–82. [PubMed]
  • David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A. 1966 Jul;56(1):72–77. [PubMed]
  • Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR. Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7522–7526. [PubMed]
  • Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993 Oct 21;365(6448):756–759. [PubMed]
  • Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7849–7854. [PubMed]
  • Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R. MIF as a glucocorticoid-induced modulator of cytokine production. Nature. 1995 Sep 7;377(6544):68–71. [PubMed]
  • Huang F, Newman E, Theodorescu D, Kerbel RS, Friedman E. Transforming growth factor beta 1 (TGF beta 1) is an autocrine positive regulator of colon carcinoma U9 cells in vivo as shown by transfection of a TGF beta 1 antisense expression plasmid. Cell Growth Differ. 1995 Dec;6(12):1635–1642. [PubMed]
  • Hsu S, Huang F, Friedman E. Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect. J Cell Physiol. 1995 Nov;165(2):239–245. [PubMed]
  • Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M, Kobrin MS, Korc M. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 1993 Nov 1;53(21):5289–5296. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ