Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by host-derived urokinase-type plasminogen activator.
Bottom Line: Indeed, in livers of uPA-ablated mice elevated TIMP-1 levels did not trigger HGF signalling and did not promote metastasis of a murine T-lymphoma cell line.Furthermore, host uPA was necessary for the recruitment of neutrophilic granulocytes and the associated increase of HGF in livers with elevated TIMP-1 levels.This newly identified co-operation between TIMP-1 and host uPA suggests that therapies, simultaneously interfering with pro- and anti-proteolytic pathways may be beneficial for patients with metastatic disease.
Affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar der Technischen Universität, Munich, Germany.Show MeSH
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Mentions: We investigated also whether uPA derived from the tumour cells might play an analogue role in TIMP-1-induced scattered metastasis. For this purpose, we first inoculated AdTIMP-1 or Addl70–3 adenoviruses, respectively, in wild-type mice. Three days later the animals were challenged with tumour cells showing a highly efficient shRNAi-based knockdown of uPA (L-CI.5sshuPA) (Fig. 5A). As control, L-CI.5s cells transduced with a scrambled vector were used (L-CI.5sshscr). Lack of uPA expression by tumour cells did not significantly reduce TIMP-1-associated increase of overall metastatic burden (Fig. 5B, C) and did not inhibit TIMP-1-induced tumour cell scattering throughout the liver parenchyma (Fig. 6A). Immunofluorescence analysis of liver sections revealed that TIMP-1-induced c-Met phoshorylation was not impaired by lack of tumour cell-derived uPA (Fig. 6B). Quantification of multicellular foci on X-Gal-stained liver surfaces showed decreased numbers of macrometastases, independent of elevated TIMP-1 levels (Fig. 5D).
Affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar der Technischen Universität, Munich, Germany.