Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential.
Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis.
Plasmin, a serine protease, is involved in many physiologically relevant processes, including haemostasis, cellular recruitment during immune response, tumour growth, and also neuronal migration and synaptic remodelling.
A panel of eight molecular markers of metastatic potential was chosen for immunohistochemical analysis of the tumor: p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, urokinase plasminogen activator (UPA), UPA receptor, and plasminogen activator inhibitor.
Accruing evidence suggests an association between increased activity of plasminogen activators and transformed cells, and urokinase activity with tumour aggressiveness.
Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas.
Angiostatin, an internal peptide fragment of plasminogen, has recently been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo.
As MMP7 and MMP9 have been shown to generate angiostatin from circulating plasminogen, and angiostatin acts as a potent inhibitor of endothelial cell proliferation, we determined whether tumor vascularization was altered in the alpha1-null mice.
Assuming that the elastase 1 secreted from the transduced cells is likely to be exempt from rapid inhibition by its physiological inhibitor, alpha1-protease inhibitor, as shown in the inflammatory tissues, the elastase 1 secreted from the tumor cells may effectively digest the plasminogen that is abundantly present in the extravascular spaces and generate the kringle 1-3 segment in the vicinity of implanted tumor cell clusters.
But herein, we demonstrate a nanosized vascular disruptive agent (VDA) PLG-CA4 has supper advantages over small molecular combretastatin-A4 phosphate (CA4P) because the PLG-CA4 was mainly distributed around the tumor vessels due to its low tissue penetration in solid tumor.
Cell adhesion and motility assays demonstrated that ALV, owing to its ATF moiety, could interact with uPAR on the tumor cell surface with high affinity and specificity, and thereby might competitively inhibit the plasmin activation by localized urokinase and contribute to the suppression of tumor invasion.
Compared to the monotherapy of PLG-CA4, inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) attenuates the immunosuppressive effect of PLG-CA4 treatment by decreasing the number of M2-like TAMs (2.0 × 10<sup>4</sup> to 1.5 × 10<sup>4</sup> per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 × 10<sup>4</sup> to 5.7 × 10<sup>4</sup> per tumor).
Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis.
Downregulation of matrix metalloprotease-9 and urokinase plasminogen activator by TX-1877 results in decreased tumor growth and metastasis on xenograft model of rectal cancer.
Examination of resected tumors for urokinase revealed (a) localization of the antigen to the tumor cells and (b) higher levels of the plasminogen activator in tumor tissue than in adjacent non-malignant tissue.
Expression of the urokinase-type plasminogen activation system including urokinase (uPA) and its receptor (uPAR) has been associated with the complex process of cell migration, a tumour's invasive potential as well as a reduced overall and disease-free survival of patients with solid cancers and haematological disorders.