Unimpeded skin carcinogenesis in K14-HPV16 transgenic mice deficient for plasminogen activator inhibitor.
Angiogenesis, extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least, the plasminogen activating system and its main physiological inhibitor, the plasminogen activator inhibitor-1 (PAI-1). Considering the recognized importance of PAI-1 in the regulation of tumor angiogenesis and invasion in murine models of skin tumor transplantation, we explored the functional significance of PAI-1 during early stages of neoplastic progression in the transgenic mouse model of multistage epithelial carcinogenesis (K14-HPV16 mice). We have studied the effect of genetic deletion of PAI-1 on inflammation, angiogenesis, lymphangiogenesis and tumor progression. In this model, PAI-1 deficiency neither impaired keratinocyte hyperproliferation or tumor development nor affected the infiltration of inflammatory cells and development of angiogenic or lymphangiogenic vasculature. We are reporting evidence for concomitant lymphangiogenic and angiogenic switches independent to PAI-1 status. Taken together, these data indicate that PAI-1 is not rate limiting for neoplastic progression and vascularization during premalignant progression, or that there is a functional redundancy between PAI-1 and other tumor regulators, masking the effect of PAI-1 deficiency in this long-term model of multistage epithelial carcinogenesis.
Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliqué-GIGA Cancer, Tour de Pathologie (B23), Sart-Tilman, Liège, University of Liège, Liège, Belgium.
Anne
A
Masset
Catherine
C
Maillard
Nor Eddine
NE
Sounni
Nathalie
N
Jacobs
Françoise
F
Bruyére
Philippe
P
Delvenne
Marlene
M
Tacke
Thomas
T
Reinheckel
Jean-Michel
JM
Foidart
Lisa M
LM
Coussens
Agnès
A
Noël
D000818:Animals; D052162:Human papillomavirus 16 / Q000235:genetics*; D053547:Keratin-14 / Q000235:genetics*; D042583:Lymphangiogenesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000502:physiology*; D011230:Precancerous Conditions / Q000209:etiology; D012878:Skin Neoplasms / Q000098:blood supply / Q000209:etiology*
D053547:Keratin-14; C507446:Krt14 protein, mouse; D017395:Plasminogen Activator Inhibitor 1