Dynamics of transforming growth factor ß signaling and therapeutic efficacy.

Transforming growth factor ß (TGFß) is a multifunctional cytokine, and its signalling responses are exerted via integrated intracellular pathways and complex regulatory mechanisms. Due to its high potency, TGFß signalling is tightly controlled under normal circumstances, while its dysregulation in cancer favours metastasis. The recognised potential of TGFß as a therapeutic target led to emerging development of anti-TGFß reagents with preclinical success, yet these therapeutics failed to recapitulate their efficacy in experimental settings. In this review, possible reasons for this inconsistency are discussed, addressing the knowledge gap between theoretical and actual behaviours of TGFß signalling. Previous studies on oncogenic cells have demonstrated the spatiotemporal heterogeneity of TGFß signalling intensity. Under feedback mechanisms and exosomal ligand recycling, cancer cells may achieve cyclic TGFß signalling to facilitate dissemination and colonisation. This challenges the current presumption of persistently high TGFß signalling in cancer, pointing to a new direction of research on TGFß-targeted therapeutics.

Effects of EphB4 receptor expression on colorectal cancer cells, tumor growth, vascularization and composition.

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. Increased expression of the molecular target, EphB4 receptor, has been observed in several cancer types. However, studies on the role of EphB4 receptor in CRC have yielded contradictory results. The aim of this study was to investigate the influence of EphB4 expression levels on CRC cell behavior and its contribution to tumor growth and vascularization. METHODS: SW480, LIM2405 and CT26 CRC cell lines were transfected with EphB4 expression vector. High EphB4 expressing cells were compared to low EphB4 expressing empty vector controls. Proliferation and migration assays as well as EphrinB2-Fc cell stimulations were conducted in vitro and subcutaneous xenografts of CRC were analyzed in vivo. RESULTS: High EphB4 expression enhanced migratory ability of these CRC cell lines in vitro and contributed to a significant increase in tumor growth and vascularization in vivo. Tumours induced with high EphB4 expressing SW480 and LIM2405 cells yielded homogenous masses densely packed with cancer cells. EphrinB2-Fc cell stimulations induced cell clustering of high EphB4 expressing SW480 and LIM2405 in vitro. CONCLUSION: These results suggest that with enhanced vascularization and an increase in migratory abilities, the high EphB4 expressing cells may be able to metastasize more readily.