Anscher ships, however, disregard the spatial distribution of dose within an organ and also do not account for biologic hetero- geneity, genetic factors, and underlying comorbidities that could impact an individual patient’s risk for treatment- related complications. Research over the past 15 years has led to a better un- derstanding of the underlying molecular events responsible for the development of normal tissue injury after cancer therapy [5– 8]. Of the many cytokines and growth factors shown to contribute to the injury process, transforming growth factor TGF)- 1 is among the most important [9]. TGF- 1 belongs to a family of secreted polypeptide growth factors subcategorized by function, including its three mammalian isoforms (TGF- 1, TGF- 2, and TGF- 3), bone morphogenic proteins, activins, inhibins, and Mulle- rian inhibiting substance [10, 11]. These proteins have im- portant functions in both normal and disease-related processes, such as cell growth, differentiation, migration, adhesion, angiogenesis, immunity, extracellular matrix synthesis, and epithelial–mesenchymal transition [12–15]. The TGF- family signals through a complex interactome [16] involving multiple pathways. Disruption of the TGF- signaling pathway has been implicated in the cellular acqui- sition of the hallmarks of malignancy [17], that is, failure to respond to growth inhibitory factors, proliferation in the ab- sence of exogenous cues, invasion, metastasis, immortality, loss of apoptosis, stimulation of angiogenesis, and evasion of the immune system. Thus, under normal circumstances, a number of genes coding for proteins in the TGF- signal- ing pathway would be considered tumor suppressor genes. In particular, most malignant cells are resistant to the growth inhibitory effects of TGF- through a variety of dif- ferent mechanisms [18 –20], and, in fact, TGF- has been shown to stimulate the growth of malignant cell lines [21]. Thus, overexpression of TGF- within the tumor microen- vironment could promote the local growth and metastatic potential of many solid tumors [22]. That TGF- can function as both a tumor suppressor and a tumor promotor, depending on the environment in which it operates, points to the com- plexity of the processes in which these proteins participate. The most widely studied of this family of molecules is TGF- 1. A detailed discussion of its role in tumor promotion, progression, and metastasis is beyond the scope of this review. Rather, herein, the role of TGF- 1 in normal tissue injury, par- ticularly the lung, is reviewed and strategies to target TGF- 1 to reduce the risk for normal tissue injury are discussed. EVIDENCE FOR A ROLE FOR TGF- 1 IN CHRONIC NORMAL TISSUE INJURY AFTER CANCER THERAPY Loss of parenchymal cells and an excess of fibrous tissue often characterize late injury after cancer therapy (Fig. 1A, www.TheOncologist.com 351 Figure 1. TGF- expression in radiation-induced lung injury. (A): Radiation (RT)-induced lung injury in a rat model. Fi- scher 344 rats were irradiated to 28 Gy in one fraction to the right hemithorax and sacrificed at 6 weeks or 6 months after RT. Slides were stained with either hematoxylin & eosin (top row) or Masson’s trichrome (bottom row). A nonirradiated control lung (left column) demonstrates the normal honey- comb architecture of the lung. At 6 weeks after irradiation (middle column), one begins to see thickening of the alveolar walls resulting from edema, corresponding to the inflamma- tory phase, but with little fibrosis. At 6 months (right column), there is complete loss of normal alveolar architecture, with ex- tensive fibrosis (green staining in bottom right panel). Re- printed from Stone HB, Coleman CN, Anscher MS et al. Effects of radiation on normal tissue: Consequences and mech- anisms. Lancet Oncol 2003;4:529 –536, with permission from Elsevier. (B): Fischer 344 rats were irradiated to 28 Gy in one fraction to the right hemithorax, sacrificed 6 months after ra- diation, and stained for transforming growth factor (TGF)- 1. There is very little staining for TGF- 1 in the control lung (nonirradiated) in contrast to the irradiated lung, which dem- onstrates greater expression of TGF- 1 in regions of fibrosis. 1B). TGF- 1 plays an important role in both normal and abnormal wound healing [23, 24]. This cytokine is pro- duced in a biologically inert form, bound to a latency asso- ciate peptide to form the small latent TGF- complex, which is secreted from cells and can be activated by several methods, including through exposure to proteases, inte- grins, and free radicals [25–30]. The small latent complex may also be covalently bound to one of several latent TGF- binding proteins to form the large latent complex, which may be sequestered in the extracellular matrix [31]. TGF- 1 is found in many different cell types, but its highest concentration is in platelets. As a result, TGF- 1 is nor- mally released in large quantities from platelets at the site of