Role of TGF- in Oncogenesis
Transforming growth factor- (TGF-) is the founding member of a large and growing family of growth factors with regulatory properties of a multitude of cellular processes including cell proliferation, differentiation, motility, adhesion, and death. Given this multifunctional nature of TGF-, it is not surprising that during the past two decades researchers have discovered that TGF- is an important factor involved in the genesis of cancers of various origin. This special issue is dedicated to the emerging role of TGF- in oncogenesis.
The function of TGF- in cancer biology is rather complex since it appears that TGF- acts as a growth inhibitor in the early stages of tumorigenesis but may promote tumor growth at later stages. This is not unexpected, keeping in mind that TGF- acts on virtually every cell type in the body and that tumor growth is a result of a complex tumor-host-interaction. Thus, specificity of signaling can only be achieved by complex processing and signaling events.
Hence, the first review by K. Koli et al. focusses on the cellular and extracellular mechanisms underlying the processing of active TGF- from latent complexes. These mechanisms are under tight control of extracellular matrix (ECM) proteins. Disturbances of these control mechanisms may well contribute to tumor development.
The review by J.N. Rich et al. focusses on the signal transduction pathways initiated by TGF-. Signal transduction through TGF- relies on the coordinate assembly of TGF- receptors and distinct activation patterns of downstream transcription factors, the Smad proteins. Again, the complexity of these pathways reflects the ability of TGF- to modulate a variety of cellular functions, and disruption of distinct signaling components may promote tumor development. Coordinated cell proliferation, differentiation, motility, and death are critical for the development of all organisms. The same mechanisms involved in development often contribute to carcinogenesis. Knock-out studies have revealed a central role for TGF- in mouse development. The review by C.L. Mummery elucidates the role of TGF- in mouse development.
Immune surveillance is important for every organism to control tumor development. During malignant progression, tumors may escape host immunity. This immune-escape may be attributed to factors released by tumor cells, including TGF-. The review by C. Beck et al. analyzes various effects of TGF- on immune surveillance of tumor cells.
There are some organs with constitutively low immune surveillance, including the brain and the eye. Maintainance of this immune privilege has in part been attributed to the action of TGF-. It is tempting to speculate that the microenvironment in these immuneprivileged sites may predispose to tumor development.