Altered tumor angiogenesis and metastasis of B16 melanoma in transgenic mice overexpressing tissue inhibitor of metalloproteinases-1.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) has emerged as a multifunctional protein that plays contrasting roles during angiogenesis and cancer spread. We have investigated the growth, vascularization and metastasis of B16 melanoma cells in a transgenic mouse model with elevated TIMP-1 levels in the systemic circulation. Transgenic C57BL/6j-CBA mice overexpressing human TIMP-1 in the liver under the control of the mouse albumin promoter/enhancer were employed. An early subcutaneous growth advantage and an increased tumor angiogenic response were observed in transgenic animals with respect to wild-type hybrid mice. On the contrary, there was a dramatic decrease in the lung colonizing ability of B16 melanoma cells in TIMP-1 transgenic mice. No significant effect on metastasis formation was observed in another transgenic mouse model with increased TIMP-1 expression in lungs but low plasma levels, where the transgene was placed under the control of the murine mammary tumor virus promoter. These results support the notion that TIMP-1 displays paradoxical effects on tumor progression and suggest that circulating TIMP-1 is efficient in suppressing lung colonization of melanoma cells.
de Lorenzo
Mariana S
MS
Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, R. Saenz Pena 180, Bernal B1876BXD, Buenos Aires, Argentina.
Ripoll
Giselle V
GV
Yoshiji
Hitoshi
H
Yamazaki
Masaharu
M
Thorgeirsson
Unnur P
UP
Alonso
Daniel F
DF
Gomez
Daniel E
DE
D000418:Albumins / Q000235:genetics; D000818:Animals; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000502:physiology*; D008175:Lung Neoplasms / Q000503:physiopathology / Q000556:secondary*; D008545:Melanoma / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000503:physiopathology; D012878:Skin Neoplasms / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D019076:Transgenes
D000418:Albumins; D019715:Tissue Inhibitor of Metalloproteinase-1