The Oncologist ® Targeting the TGF- 1 Pathway to Prevent Normal Tissue Injury After Cancer Therapy MITCHELL S. ANSCHER Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia, USA Key Words. Transforming growth factor Complications Fibrosis Lung Cancer Disclosures: Mitchell S. Anscher: Consultant/advisory role: Civa Tech. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT With >10,000,000 cancer survivors in the U.S. alone, the late effects of cancer treatment are a significant pub- lic health issue. Over the past 15 years, much work has been done that has led to an improvement in our under- standing of the molecular mechanisms underlying the development of normal tissue injury after cancer ther- apy. In many cases, these injuries are characterized at the histologic level by loss of parenchymal cells, exces- sive fibrosis, and tissue atrophy. Among the many cyto- kines involved in this process, transforming growth factor (TGF)- 1 is thought to play a pivotal role. TGF- 1 has a multitude of functions, including both promoting the formation and inhibiting the breakdown of connective tissue. It also inhibits epithelial cell prolif- eration. TGF- 1 is overexpressed at sites of injury after radiation and chemotherapy. Thus, TGF- 1 represents a logical target for molecular therapies designed to pre- vent or reduce normal tissue injury after cancer ther- apy. Herein, the evidence supporting the critical role of TGF-ß1 in the development of normal tissue injury af- ter cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the TGF-ß1 pathway are presented. The On- cologist 2010;15:350 –359 INTRODUCTION The tolerance of normal tissues and organs limits the amount of chemotherapy and radiation therapy that can be administered to a patient undergoing cancer treatment [1, 2]. In many cases, these doses may be less than what one would give under ideal circumstances in an effort to control a tumor. Consequently, cure of the cancer might not be achievable as a result of limitations imposed by normal tissue tolerance. This is particularly true in cir- cumstances requiring high doses of radiation for tumors lo- cated within or adjacent to sensitive organs, such as the lung. Traditionally, radiation oncologists have been forced to deal with normal tissue tolerance by limiting the dose and/or volume of tissue receiving radiation [3, 4]. With re- cent advances in imaging technology, these dose–volume relationships have received additional attention in an at- tempt to more precisely correlate dose, volume, and the risk for normal tissue injury [2]. These dose–volume relation- Correspondence: Mitchell S. Anscher, M.D., VCU Medical Center, 401 College Street, P.O. Box 980058, Richmond, Virginia 23298- 0058, USA. Telephone: 804-828-7238; Fax: 804-828-7232; e-mail: manscher@mcvh-vcu.edu Received October 28, 2008; accepted for publication April 29, 2009; available online without subscription through the open access option. ©AlphaMed Press 1083-7159/2010/ $30.00/0 doi: 10.1634/theoncologist.2009-S101 The Oncologist 2010;15:350 –359 www.TheOncologist.com