The two faces of transforming growth factor β in carcinogenesis

AB Roberts, LM Wakefield - Proceedings of the National …, 2003 - National Acad Sciences
AB Roberts, LM Wakefield
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
Over the past two decades, the perceived role of transforming growth factor ß (TGF-ß) in
carcinogenesis has undergone more plot twists than an Agatha Christie mystery. The initial
experiments leading to the discovery of TGF-ß and its naming as a ''transforming''growth
factor were based on its ability to induce malignant behavior of normal fibroblasts, leading to
the notion that TGF-ß might be a key factor in uncoupling a cell from normal growth control in
such a way that it could become tumorigenic (1). However, at the time, this presumed …
Over the past two decades, the perceived role of transforming growth factor ß (TGF-ß) in carcinogenesis has undergone more plot twists than an Agatha Christie mystery. The initial experiments leading to the discovery of TGF-ß and its naming as a ‘‘transforming’’growth factor were based on its ability to induce malignant behavior of normal fibroblasts, leading to the notion that TGF-ß might be a key factor in uncoupling a cell from normal growth control in such a way that it could become tumorigenic (1). However, at the time, this presumed function of the protein was difficult to reconcile with its ubiquitous pattern of expression in normal tissues, including its prevalence in human platelets. The next twist in the story came several years later, when it emerged that TGF-ß has profound growth-suppressive effects on many cells, including epithelial cells and lymphoid cells, which form the basis of the majority of human cancers. At this point TGF-ß began to be given serious consideration as a candidate tumor suppressor gene (2). Indeed, data from both experimental model systems and studies of human cancers clearly show that not only the ligand itself but also its downstream elements, including its receptors, and its primary cytoplasmic signal transducers, the Smad proteins, are important for suppressing primary tumorigenesis in many organs (3, 4). While solid credentials were being established for the role of TGF-ß as a good citizen in the battle to maintain cellular order, a darker side was emerging. It is now appreciated that metastasis of many different types of tumor cells actually requires TGF-ß activity and that, in the context of advanced disease, it actually has prooncogenic effects (3, 5). To date, understanding of this complex, dual role of TGF-ß in carcinogenesis has come principally from inference based on the synthesis of studies of the behavior of many different tumor cell lines and many different animal model systems (Fig. 1). But in a recent issue of PNAS Siegel et al.(6) convincingly demonstrated this duality in a single model of mammary cancer that is metastatic to lung, by using bitransgenic mice expressing forms of the Neu oncogene driven by the mouse mammary virus long-terminal repeat (MMTV) and either constitutively activated or dominant negative forms of the TGF-ß receptors similarly directed to the mammary gland. This model system is highly relevant to human breast cancer as amplification of erbb2 her2 neu, encoding an epidermal growth factor receptor family tyrosine kinase, is found in 30% of human breast cancers (7) and changes in expression of both the TGF-ß ligand and response system occur during cancer progression (8–10). The results of Siegel et al.(6) show that activation of TGF-ß signaling delays the appearance of primary mammary tumors, whereas tumors appear earlier in mice in which TGF-ß signaling has been compromised, consistent with a tumor suppressor role of the pathway in the earlier stages of tumorigenesis. In contrast, these same manipulations of TGF-ß signaling have opposite effects on formation of spontaneous lung metastases in the mice. Mice expressing an activated TGF-ß receptor exhibit an increased percentage of metastatic foci that have extravastated from the vasculature, consistent with a prooncogenic effect for TGF-ß in late-stage disease.
This dual-or multifunctionality of TGF-ß has plagued and confused researchers for years. Indeed, it seems that for every presumed function of TGF-ß, an example can be found in which it displays exactly the opposite activity (11). In part, this stems from the fact that, unlike many peptide growth factors that act on a restricted set of target cells, TGF-ß is produced by and can …
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