Expression of a urokinase‐type plasminogen activator during tumor growth leads to angiogenesis via galanin activation in tumor‐bearing mice

Abstract

Small‐cell lung carcinoma releases progalanin. The released progalanin is activated via a nonclassical processing pathway, being processed into an active form of galanin (1–20) by plasmin in extracellular components. Plasmin is produced from plasminogen activators. To clarify the regulation of progalanin via plasminogen activation by urokinase and tissue‐plasminogen activator (t‐PA), we investigated the regulation mechanism for urokinase and t‐PA expression and their effect on galanin activation. Additionally, we studied the effect of activated galanin on angiogenesis. To determine the effect of cell density, we measured the expression levels of urokinase and t‐PA using real‐time PCR and plasminogen/gelatin zymography in a cell culture. The urokinase expression increased under both high cell density and presence of cell membrane fractions. However, urokinase increments induced by conditioned medium were low. These results indicate that expression of plasminogen activators is regulated by cell membrane factors. We used tumor‐bearing mice to clarify the expression of plasminogen activators and galanin activation. Real‐time PCR showed that urokinase was substantially higher in the central parts of tumors compared to the periphery, and this was confirmed by plasminogen/gelatin zymography. To evaluate the biological effect of plasminogen activators on tumor growth, we used tranexamic acid as a plasminogen inhibitor. Tranexamic acid decreased galanin (1–20) and the hemoglobin content of tumors and suppressed tumor growth. Additionally, galanin had no effect on the hemoglobin content of tumors derived from cells lacking GALR2. These results demonstrate the regulation of urokinase expression in tumors through progalanin activation in extracellular compartments, and confirm that galanin plays a role in angiogenesis.

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

“…Variants in PLAU , MASP1 , and C2 , as well as risk alleles in PLG and PLAU [6, 20], suggests a disruption in the fibrinolysis and complement cascade in response to microbial threads or cellular debris as a trigger for MS. In addition, PLAU activation increases angiogenesis, which has been associated with MS severity, and sustains the inflammatory response by providing oxygen and nutrients to the sites of inflammation [147, 148]. Complement genes are necessary for the generation of anaphylatoxins C3a and C5a, opsonisation of pathogens, and formation of the membrane attack complex [39].…”

Cluster Analysis of Early Postnatal Biochemical Markers May Predict Development of Retinopathy of Prematurity

“… 95 There are potential associations to ROP development since it is involved in both vascular homeostasis 96 and neuronal differentiation, 97 and several authors suggest that GAL is an important angiogenetic factor in cancer. 98 , 99 No previous reports are in conflict with our results that ROP development may be associated with elevated GAL levels.…”