Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg ؊1 ) every 2 days for 18 -38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant downregulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.The growth of human cancer cells is often dependent or facilitated by the overexpression of receptor tyrosine kinase, such as the EGFR, 2 that provide a growth advantage to the growing and infiltrating neoplasms (1). To prevent the dire consequences of uncontrolled activation of EGFR, a number of negative feedback mechanisms, both extracellular and intracellular, have evolved (2, 3). The prominent role of the EGFR as a crucial relay station among various inputs from the environment and cellular responses has raised the significance of this signaling-transducing receptor to a new level and offers new possibilities for therapeutic intervention (4). We have previously shown that decorin, a secreted small leucine-rich proteoglycan (5, 6), is capable of suppressing the growth of tumor cells with various histogenetic backgrounds (7, 8) by directly interacting with the EGFR (9 -11). Decorin evokes a protracted down-regulation of EGFR tyrosine kinase (12) and other members of the ErbB family of receptor tyrosine kinase (13) and causes an attenuation of the EGFR-mediated mobilization of intracellular calcium (12). Decorin induces expression of the endogenous cyclin-dependent kinase inhibitor p21 WAF1 (14, 15) and a subsequent arrest of the cells in the G 1 phase of the cell cycle (7). These growthsuppressive properties of the soluble decorin and its protein core can also affect murine tumor cells (8) and normal human cells, such as endothelial cells (16) and macrophages (17). A number of observations point toward a key role for decorin in the cont...
Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.
The evolution of positron emission tomography (PET) imaging for small animals has led to the development of dedicated PET scanner designs with high resolution and sensitivity. The animal PET scanner achieves these goals for imaging small animals such as mice and rats. The scanner uses a pixelated Anger-logic detector for discriminating 2 x 2 x 10 mm3 crystals with 19-mm-diameter photomultiplier tubes. With a 19.7-cm ring diameter, the scanner has an axial length of 11.9 cm and operates exclusively in three-dimensional imaging mode, leading to very high sensitivity. Measurements show that the scanner design achieves a spatial resolution of 1.9 mm at the center of the field-of-view. Initially designed with gadolinium orthosilicate but changed to lutetium- yttrium orthosilicate, the scanner now achieves a sensitivity of 3.6% for a point source at the center of the field-of-view with an energy window of 250-665 keV. Iterative image reconstruction, together with accurate data corrections for scatter, random, and attenuation, are incorporated to achieve high-quality images and quantitative data. These results are demonstrated through our contrast recovery measurements as well as sample animal studies.
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