Title
Tissue level, activation and cellular localisation of TGF-beta1 and association with survival in gastric cancer patients
Author
TNO Kwaliteit van Leven
Hawinkels, L.J.A.C.
Verspaget, H.W.
van Duijn, W.
van der Zon, J.M.
Zuidwijk, K.
Kubben, F.J.G.M.
Verheijen, J.H.
Hommes, D.W.
Lamers, C.B.H.W.
Sier, C.F.M.
Publication year
2007
Abstract
Transforming growth factor-beta1 (TGF-beta1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-beta1 activation and localisation of TGF-beta1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-beta1 staining by immunohistochemistry. Active TGF-beta1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-beta1. Active TGF-beta1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-beta1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGF-beta1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGF-beta1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-beta1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-beta1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-beta1 activity levels in gastric cancer. © 2007 Cancer Research.
Subject
Biomedical Research
ELISA
Fibroblast
Immunohistochemistry
Matrix metalloproteinase
Transforming growth factor-beta
Tumour microenvironment
Proteinase
Smooth muscle actin
Transforming growth factor beta1
Urokinase
Adult
Aged
Cancer survival
Comparative study
Correlation analysis
Enzyme activity
Enzyme linked immunosorbent assay
Epithelium cell
Female
Fibroblast
Human
Human tissue
Immunohistochemistry
Major clinical study
Male
Microenvironment
Myofibroblast
Priority journal
Protein expression
Protein function
Protein localization
Smooth muscle
Stomach cancer
Stomach mucosa
Tissue homogenate
Aged
Female
Humans
Immunohistochemistry
Male
Middle Aged
Stomach Neoplasms
Survival Analysis
Transforming Growth Factor beta1
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http://resolver.tudelft.nl/uuid:ed64f4ba-b1e5-46d1-9f72-362ab645901a
DOI
https://doi.org/10.1038/sj.bjc.6603877
TNO identifier
240094
ISSN
0007-0920
Source
British Journal of Cancer, 97 (97), 398-404
Document type
article