Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

Abstract

The specific functions of plasminogen, stromal plasminogen activator, stromal plasminogen activator receptor, and stromal plasminogen activator inhibitor in the progression of the murine soft tissue sarcoma, T241 were investigated. Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma in syngeneic mice. The reduced tumor growth was associated with a dramatic increase in tumor-infiltrating F4/80-positive macrophages and a diminution of vessel density, but not with obvious differences in fibrin and collagen deposition, or invasiveness of the tumor. Ablation of plasminogen activation by the tumor stroma only modestly impaired the prolonged growth of the sarcoma, suggesting that tumor cell-produced plasminogen activator is sufficient to mediate productive plasminogen activation. Plasminogen facilitated sarcoma progression, angiogenesis, and suppression of macrophage infiltration in the absence of either stromal urokinase plasminogen activator receptor or stromal plasminogen activator inhibitor. These data demonstrate that tumor cell-produced plasminogen activator and host plasminogen cooperate to facilitate soft tissue sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.

Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth

“…These observations are consistent with the bellshape effect of PAI-1 observed in vitro in the aortic ring assay and in vivo, in a model of laserinduced choroidal neoangiogenesis . By demonstrating that in vivo PAI-1 effects on tumor development and vascularization are dependent on its concentration, our findings resolve apparently conflicting data indicating that PAI-1 can inhibit as well as promote angiogenesis (Soff et al, 1995;Bajou et al, 1998;Gutierrez et al, 2000;McMahon et al, 2001;Stefansson et al, 2001;Curino et al, 2002).…”

Laser capture microdissection-based in vivo genomic profiling of wound keratinocytes identifies similarities and differences to squamous cell carcinoma

“…The analysis, by its inherent design, is limited to studying changes in steady-state levels of mRNA, and changes in wound healing gene expression that manifest at the level of mRNA translation or post-translational protein modification will go unnoticed. However, the method can be easily extended to also address changes in protein expression levels and post-translational modifications (Knezevic et al, 2001;Curino et al, 2002; T Pedersen and A Curino, unpublished data). The LCM and cDNA array analysis successfully identified multiple genes whose mRNA levels have previously been shown to be altered during skin wound healing.…”

“…The isolation of keratinocytes from histological sections by LCM was performed essentially as described (Bonner et al, 1997;Simone et al, 1998;Leethanakul et al, 2000;Curino et al, 2002). Cryostat sections (6 mm) were prepared perpendicular to the longitudinal direction of the wound, and the sections were kept on dry ice, or at À801C, until they were subjected to LCM.…”

Species-specific urokinase receptor ligands reduce glioma growth and increase survival primarily by an antiangiogenesis mechanism

“…Other studies showed modest effects of uPA deficiency on tumor growth and angiogenesis. 40,41 Another approach taken was to use a defective adenovirus to express a murine ATF systemically, which prolongs mouse survival and prevents liver metastasis in a colon carcinoma model. 32 In this study, a significant reduction in tumor angiogenesis and increase in apoptotic index was observed, in contrast to that seen in the uPA À / À mice.…”