Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth.
Administration of active TG2 to two different in vitro angiogenesis assays resulted in the accumulation of a complex extracellular matrix (ECM) leading to the suppression of endothelial tube formation without causing cell death. Matrix accumulation was accompanied by a decreased rate of ECM turnover, with increased resistance to matrix metalloproteinase-1. Intratumor injection of TG2 into mice bearing CT26 colon carcinoma tumors demonstrated a reduction in tumor growth, and in some cases tumor regression. In TG2 knockout mice, tumor progression was increased and survival rate reduced compared to wild-type mice. In wild-type mice, an increased presence of TG2 was detectable in the host tissue around the tumor. Analysis of CT26 tumors injected with TG2 revealed fibrotic-like tissue containing increased collagen, TG2-mediated crosslink and reduced organized vasculature. TG2-mediated modulation of cell behavior via changes in the ECM may provide a new approach to solid tumor therapy.
Jones
R A
RA
School of Biomedical and Natural Sciences, Nottingham Trent University, Nottingham NG11 8NS, UK.
Kotsakis
P
P
Johnson
T S
TS
Chau
D Y S
DY
Ali
S
S
Melino
G
G
Griffin
M
M
D000818:Animals; D016923:Cell Death; D018920:Coculture Techniques; D003094:Collagen / Q000096:biosynthesis; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014183:Transplantation, Heterologous
C000717609:Tgm2 protein, rat; D003094:Collagen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D020781:Matrix Metalloproteinase 1; D019204:GTP-Binding Proteins