Active TGF-β1 correlates with myofibroblasts and malignancy in the colorectal adenoma-carcinoma sequence

Transforming growth factor-beta 1 (TGF-beta 1), 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-beta 1 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-beta 1 levels are increased only in carcinomas but not in premalignant adenomas. Furthermore, solely active TGF-beta 1 levels are associated with the stage of the carcinomas and worse patient prognosis. Active TGF-beta 1 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-beta 1 levels, myofibroblast accumulation is not (yet) occurring in these premalignant neoplasias. The correlation between active TGF-beta 1 and SMA expression in tumors indicates that tumor-promoting myofibroblasts might arise as a result of increased TGF-beta 1 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. (Cancer Sci 2009; 100: 663-670)