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Tissue
Transglutaminase Is Expressed as a Host Response to Tumor Invasion and Inhibits
Tumor Growth |
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Zishan A. Haroon,
Thung-Shenq Lai, Joann M. Hettasch, Robert A. Lindberg,Mark W. Dewhirst
and Charles S. Greenberg |
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Departments
of Pathology (ZAH, MWD, CSG), Medicine (T-SL, JMH, CSG), and Radiation Oncology
(RAL, MWD), Duke University Medical Center, Durham, North Carolina |
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SUMMARY: A stable extracellular
matrix (ECM) constitutes an important part of host response mechanism against
tumor growth and invasion. Tissue transglutaminase (TG), a calcium-dependent
enzyme, can cross-link all major ECM proteins to form a stable ECM, because
these cross-links are resistant to proteolytic and mechanical damage. TG
can also enhance stability and strength of the ECM by its ability to facilitate
the activation of transforming growth factor-[beta]. We hypothesized that
TG ECM-promoting abilities form an important part of the host response mechanism
against tumor growth. Increased expression of TG was observed in the ECM
of the host tumor interface of subcutaneously implanted rat mammary adenocarcinoma
R3230 Ac. TG expression was also detected in the endothelial cells and macrophages.
We also detected the cross-link product at the host tumor interface and
within the tumor tissue, showing that TG was active. Western blots showed
TG was degraded into three fragments of 55-, 50-, and 20-kDa forms. When
recombinant wild-type TG was applied to R3230 Ac implanted in rat dorsal
skin flap window chamber, it caused significant growth delay at day 7 compared
with recombinant inactive TG controls. Collagen was detected in increased
amounts in TG treated tumors, suggesting augmentation of production and
stability of the ECM. We conclude that TG forms a distinct part of host
response system against and acts to inhibit tumor growth. |
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