oa Editorial [Hot Topic: TGF-β As Target in Oncology (Guest Editor: Karl-Hermann Schlingensiepen)]

Recent advances in understanding tumor biology have provided new opportunities to develop effective approaches to treat patients with cancer. Intensive research on molecular pathways influencing genesis and progression of tumors has resulted in a panoply of potential drug targets. However, transforming growth factor beta (TGF-β) has kept a privileged position among cancer targets as it exerts a whole set of effects in malignant cancer progression. Particularly at later stages of tumor progression, many tumors produce excessive amounts of TGF-β. TGF-β supports angiogenesis and promotes cell motility and invasiveness as prerequisites of metastasis. Most importantly, TGF-β potently suppresses antitumor responses, e.g. through its effects on Tcells, B-cells, and antigen presenting cells, allowing tumors to escape from being recognized and eradicated by the immune system. The objective of this Special Issue of Current Pharmaceutical Biotechnology is to provide an overview on TGF-β biology and to reflect the current status of targeting TGF-β in oncology from the perspectives of scientists and clinicians, academics and pharmaceutical companies. At first A. Hinck & M. O'Connor McCourt give a comprehensive overview of recent progresses in characterizing structural features of the interaction of the three mammalian TGF-β isoforms TGF-β1, TGF-β2, TGF-β3 with the TGF-β receptor complex and work out both similarities and differences between the isoforms. H. Ikushima & K. Miyazono then describe the elements of intracellular TGF-β signaling and the multiple factors involved in its regulation. Considering the resulting complex network, it is not surprising that aberrant regulation of this pathway is involved in many diseases. L. van Meeteren, M.-J. Goumans & P. ten Dijke summarize the current understanding of TGF-β signaling in vascular development and angiogenesis, with a focus on recent insights into the role of the TGF-β type I receptor ALK1 and co-receptor endoglin in tumor angiogenesis. J. Buijs, P. Juarez & T. Guise outline the role of TGF-β in bone metastasis and discuss the limitations and opportunities of current treatment approaches. The following contributions review the specific role of TGF-β in various indications. E. Connolly & R. Akhurst work out the complexities of TGF-β action in regulation of two epithelial tumor types, namely squamous cell carcinoma and breast cancer. P. Hau, P. Jachimczak, J. Schlaier & U. Bogdahn highlight the critical role of TGF-β2 in high-grade glioma. The decisive role of this isoform in high-grade glioma patients was recognized early in TGF-β research. TGF-β2 has also an important role in two other indications reviewed in this edition. A. Hilbig & H. Oettle compile current knowledge on TGF-β in pancreatic cancer and A. Busse & U. Keilholz review the effects TGF-β in malignant melanoma with special emphasis on its vital role in immunosuppression. How can TGF-β be targeted? Overall, therapeutic interventions directed against TGF-β can either block excessive TGF-β production, neutralize its activity, or inhibit its receptor signaling. Several approaches are currently being developed. S. Lonning, J. Mannick & J. McPherson put together results of experimental animal and human clinical studies on antibody-mediated neutralization of TGF-β. L. Ling & W.-C. Lee then give an overview on the development of small molecules for the inhibition of TGF-β type I receptor kinase (ALK5) as a means to interrupt TGF-β-signaling. Finally, F. Jaschinski, T. Rothhammer, P. Jachimczak, C. Seitz, A. Schneider & K.-H. Schlingensiepen present the antisense oligodeoxynucleotide trabedersen for the targeted treatment of patients with tumors overproducing TGF-β2. I sincerely hope that this Special Issue provides insightful reading and contributes to raise awareness for TGF-β as a highly attractive therapeutic target in oncology.