Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner.
Angiogenesis and tumor expansion are associated with extracellular matrix remodeling and involve various proteases such as the plasminogen (Plg)/plasminogen activator (PA) system. Recently, several experimental data have implicated the plasminogen activator inhibitor-1 (PAI-1) in tumor angiogenesis in murine systems. However, little is known about PAI-1 functions in human skin carcinoma progression. By generating immunodeficient mice (in Rag-1-/- or nude background) deleted for PAI-1 gene (PAI-1-/-), we have evaluated the impact of host PAI-1 deficiency on the tumorigenicity of two malignant human skin keratinocyte cell lines HaCaT II-4 and HaCaT A5-RT3 forming low-grade and high-grade carcinomas, respectively. When using the surface transplantation model, angiogenesis and tumor invasion of these two cell lines are strongly reduced in PAI-1-deficient mice as compared to the wild-type control animals. After subcutaneous injection in PAI-1-/- mice, the tumor incidence is reduced for HaCaT II-4 cells, but not for those formed by HaCaT A5-RT3 cells. These data indicate that PAI-1 produced by host cells is an important contributor to earlier stages of human skin carcinoma progression. It exerts its tumor-promoting effect in a tumor stage-dependent manner, but PAI-1 deficiency is not sufficient to prevent neoplastic growth of aggressive tumors of the human skin.
Maillard
Catherine
C
Laboratory of Tumor and Development Biology, CRCE, CBIG, University of Liège, Tour de Pathologie (B23), Sart Tilman, Liège B-4000, Belgium.
Jost
Maud
M
Rømer
Maria Unni
MU
Brunner
Nils
N
Houard
Xavier
X
Lejeune
Annabelle
A
Munaut
Carine
C
Bajou
Khalid
K
Melen
Laurence
L
Dano
Keld
K
Carmeliet
Peter
P
Fusenig
Norbert E
NE
Foidart
Jean Michel
JM
Noel
Agnès
A
D000818:Animals; D018450:Disease Progression; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000098:blood supply / Q000209:etiology / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000637:transplantation
D018398:Homeodomain Proteins; D017395:Plasminogen Activator Inhibitor 1; C064658:RAG-1 protein
Cancer Res. 2000 Oct 15;60(20):5839-47
11059781
Differentiation. 1999 Jun;64(5):263-75
10374263
Cancer Res. 2001 Mar 1;61(5):2189-93
11280785
FASEB J. 2001 Apr;15(6):1021-7
11292663
J Biol Chem. 2001 Mar 16;276(11):8135-41
11083866
Surg Oncol Clin N Am. 2001 Apr;10(2):417-32, x-xi
11382595
J Biol Chem. 2001 Sep 7;276(36):33964-8
11441025
J Immunol. 2001 Sep 15;167(6):3406-13
11544332
J Cell Physiol. 2001 Oct;189(1):23-33
11573201
Am J Pathol. 2001 Oct;159(4):1567-79
11583982
Am J Pathol. 2001 Nov;159(5):1681-8
11696429
J Natl Cancer Inst. 2002 Jan 16;94(2):116-28
11792750
FASEB J. 2002 Feb;16(2):147-54
11818362
Oncogene. 2002 Dec 12;21(57):8830-42
12483535
Differentiation. 2002 Dec;70(9-10):486-97
12492491
J Cell Biol. 2003 Mar 3;160(5):781-91
12615913
Cell Mol Life Sci. 2003 Mar;60(3):463-73
12737307
Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2791-7
12766088
Oncogene. 2003 Jul 10;22(28):4389-97
12853975
FASEB J. 2003 Oct;17(13):1904-6
12897066
Cancer Res. 2003 Sep 15;63(18):5844-9
14522908
Curr Pharm Des. 2004;10(1):39-49
14754404
J Biol Chem. 2004 Feb 13;279(7):6143-51
14625301
J Clin Pathol. 2004 Jun;57(6):577-84
15166260
Oncogene. 2004 Sep 9;23(41):6986-90
15286708
Br J Dermatol. 1983 Feb;108(2):163-70
6337617
Cancer Res. 1990 May 1;50(9):2840-7
2183932
EMBO J. 1992 Dec;11(13):4825-33
1334458
Cancer Res. 1994 Sep 1;54(17):4671-5
8062262
J Clin Invest. 1996 Apr 15;97(8):1924-30
8621777
Blood. 1996 Jun 1;87(11):4718-22
8639841
Cell Mol Life Sci. 2000 Jan 20;57(1):25-40
10949579
Nat Med. 1997 Nov;3(11):1222-7
9359696
Nat Med. 1998 Aug;4(8):923-8
9701244
Am J Pathol. 1999 Mar;154(3):775-84
10079255
APMIS. 1999 Jan;107(1):120-7
10190288
J Cell Biol. 2001 Feb 19;152(4):777-84
11266468