Understanding the TGF-β signaling pathway in cholangiocarcinoma to harness its therapeutic potential
Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca)
TGF-β signaling is essential for tissue homeostasis and its dysregulation contributes to the development of diseases. During hepatocarcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to tumor progression once cells escape from its cytostatic effects. Therefore, TGF-β receptor inhibition may have undesired effects on tumor cells that maintain the suppressor response to TGF-β. Additionally, TGF-beta can modulate the response of stromal cells that may contribute to tumor progression and immune evasion. Thus, targeting TGF-β downstream targets that are specifically expressed in cells from the tumor microenvironment may represent a new therapeutic approach to target this pathway.
In this study, by using different in vitro and in vivo approaches and analysis of human samples, we demonstrate that TGF-β signaling is highly active in cholangiocarcinoma tumors across species and exerts a prominent and potent suppressor effect in tumor cells. Thus, use of small inhibitors of TGF-β Receptor I, such as Galunisertib, boosts cholangiocarcinoma progression by promoting tumor cell growth. However, targeting of NOX4, which is downstream of TGF-β and involved in the activation of cancer associated fibroblasts from the tumor microenvironment, halts tumor progression. Thus, focusing on TGF-β downstream targets that are only expressed in stromal cells and involved in the pro-tumorigenic actions of the pathway, may represent an alternative therapeutic strategy.