title: Active TGF-beta1 correlates with myofibroblasts and  malignancy in the colorectal adenoma-carcinoma  sequence.
abstract: Transforming growth factor-beta1 (TGF-beta1), a cytokine involved in various stages of cancer, is produced as a latent complex and requires processing to become active. We have determined total and active TGF-beta1 levels in homogenates of colorectal neoplasia. In contrast to total TGF-b levels, showing a stepwise increase in the mucosa-adenoma-carcinoma sequence, active TGF-beta1 levels are increased only in carcinomas but not in premalignant adenomas. Furthermore, solely active TGF-beta1 levels are associated with the stage of the carcinomas and worse patient prognosis. Active TGF-beta1 levels correlated significantly with plasminogen activator inhibitor (PAI)-1, alpha-smooth muscle actin (SMA) and several matrix-remodeling proteinases. Interestingly, SMA levels are also significantly increased in colorectal carcinomas but not in adenomas, suggesting that despite the enhanced total TGF-beta1 levels, myofibroblast accumulation is not (yet) occurring in these premalignant neoplasias. The correlation between active TGF-beta1 and SMA expression in tumors indicates that tumor-promoting myofibroblasts might arise as a result of increased TGF-beta1 activation. These data underline the significance of the interaction between malignant cells and (myo)-fibroblasts in the tumor microenvironment, modulating the biologic behavior of colorectal cancer.
authors.affiliation: Leiden University Medical Center, Department of Gastroenterology-Hepatology, Leiden, The Netherlands.
authors.forename: Lukas J A C
authors.initials: LJ
authors.lastname: Hawinkels
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.forename: Johan J
authors.initials: JJ
authors.lastname: van der Reijden
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van der Zon
authors.forename: Jan H
authors.initials: JH
authors.lastname: Verheijen
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Cornelis B H W
authors.initials: CB
authors.lastname: Lamers
authors.forename: Cornelis F M
authors.initials: CF
authors.lastname: Sier
mesh_terms: D000199:Actins / Q000378:metabolism; D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003893:Desmin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D014408:Biomarkers, Tumor; D003893:Desmin; D017395:Plasminogen Activator Inhibitor 1; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D007633:Keratins; D014568:Urokinase-Type Plasminogen Activator