Interleukin-6 gene ablation in a transgenic mouse model of malignant skin melanoma.
Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Taken together, these results indicate that IL-6 enhances both the development of melanoma precursor lesions and the subsequent growth of the resulting tumors in the MT-ret model of melanoma development.
von Felbert
Verena
V
Department of Dermatology, University of Bern, Bern, Switzerland.
Córdoba
Francisco
F
Weissenberger
Jakob
J
Vallan
Claudio
C
Kato
Masashi
M
Nakashima
Izumi
I
Braathen
Lasse Roger
LR
Weis
Joachim
J
D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005838:Genotype; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D037102:Lectins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011230:Precancerous Conditions; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D037102:Lectins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D019869:Phosphatidylinositol 3-Kinases
Eur J Neurosci. 1999 Sep;11(9):2995-3004
10510164
J Neurooncol. 1997 Jan;31(1-2):115-22
9049837
Surg Today. 1997;27(6):534-41
9306547
Melanoma Res. 1998 Feb;8(1):24-30
9508373
Eur Cytokine Netw. 1998 Jun;9(2):187-92
9681395
Oncogene. 1998 Oct 8;17(14):1885-8
9778055
Clin Cancer Res. 1996 Aug;2(8):1405-9
9816314
Br J Dermatol. 1998 Sep;139(3):415-21
9767285
J Exp Med. 1999 Jan 4;189(1):63-73
9874564
J Biol Chem. 1999 Jan 15;274(3):1257-66
9880494
Oncogene. 1999 Jan 28;18(4):1023-32
10023678
J Invest Dermatol. 2000 Feb;114(2):343-8
10651996
J Neurosci Res. 1999 Feb 15;55(4):411-22
10723052
Crit Rev Biochem Mol Biol. 2000;35(1):35-70
10755665
Exp Hematol. 2000 Nov;28(11):1239-49
11063872
Breast Cancer Res. 2000;2(2):86-90
11250696
Oncogene. 2001 Feb 8;20(6):677-85
11314001
J Invest Dermatol. 2001 Jul;117(1):132-40
11442760
Oncogene. 2001 Sep 20;20(42):5991-6000
11593406
Oncogene. 2001 Nov 8;20(51):7536-41
11709725
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1509-14
11805288
Oncogene. 2002 Mar 27;21(13):2000-8
11960372
Science. 2002 Jul 5;297(5578):63-4
12098689
Oncogene. 2002 Oct 10;21(46):7001-10
12370822
Biochim Biophys Acta. 2002 Nov 11;1592(3):323-43
12421676
Oncogene. 2002 Dec 5;21(55):8404-13
12466961
Am J Pathol. 2003 Feb;162(2):655-63
12547723
Anticancer Res. 2002 Nov-Dec;22(6C):4093-100
12553038
J Neurosci. 2003 Mar 1;23(5):1730-41
12629177
Oncogene. 2003 Mar 13;22(10):1517-27
12629515
J Neuropathol Exp Neurol. 2003 Mar;62(3):315-28
12638735
Oncogene. 2003 Jun 26;22(26):4092-101
12821943
Biochem J. 2003 Aug 15;374(Pt 1):1-20
12773095
Oncogene. 2003 Oct 30;22(49):7809-18
14586407
Immunity. 1999 Jan;10(1):105-15
10023775
Int J Cancer. 2005 Jun 10;115(2):202-13
15688401
Rev Physiol Biochem Pharmacol. 2003;149:1-38
12687404
Mol Cell Biol. 2004 May;24(9):3607-22
15082758
Oncogene. 2004 Apr 22;23(19):3308-16
15064729
Cancer Res. 2004 Aug 1;64(15):5270-82
15289333
Nature. 1977 Mar 3;266(5597):63-4
758007
J Invest Dermatol. 1991 Feb;96(2):180-5
1899443
J Invest Dermatol. 1991 Jul;97(1):97-100
2056197
EMBO J. 1991 Nov;10(11):3167-75
1915289
Immunology. 1992 Jan;75(1):92-8
1371497
Exp Hematol. 1992 May;20(4):395-400
1568457
Lymphokine Cytokine Res. 1992 Jun;11(3):161-6
1391235
Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9215-9
1409627
J Cell Biol. 1993 Mar;120(5):1281-8
8436594
J Immunother Emphasis Tumor Immunol. 1993 Feb;13(2):98-109
8318501
Int J Cancer. 1994 Mar 15;56(6):853-7
7509778
Nature. 1994 Mar 24;368(6469):339-42
8127368
Arch Dermatol Res. 1994;286(1):62-8
8141614
Br J Cancer. 1994 May;69(5):911-3
8180022
Melanoma Res. 1995 Feb;5(1):41-7
7734955
Cancer Res. 1995 May 15;55(10):2200-5
7743524
Cytokine. 1995 Feb;7(2):142-9
7780033
J Neurosci Res. 1995 Apr 15;40(6):826-35
7629895
Hum Gene Ther. 1995 Jun;6(6):805-11
7548280
Int J Immunopharmacol. 1996 Feb;18(2):167-72
8799367
Melanoma Res. 1996 Jun;6(3):191-201
8819122
Int J Cancer. 1999 Apr 20;84(2):160-8
10096249
Melanoma Res. 1999 Apr;9(2):181-8
10380941
Oncogene. 1999 Jun 24;18(25):3742-53
10391682
Cell. 1999 Aug 6;98(3):295-303
10458605