Content area
Full text
About the Authors:
John C. Morris
* E-mail: [email protected] (JCM); [email protected] (JAB)
Current address: Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Vontz Center for Molecular Studies, ML0562, Cincinnati, Ohio, United States of America
Affiliation: Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
Antoinette R. Tan
Affiliation: Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
Thomas E. Olencki
Affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America
Geoffrey I. Shapiro
Affiliation: Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
Bruce J. Dezube
Affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
Michael Reiss
Affiliation: Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
Frank J. Hsu
Affiliation: Genzyme Corporation, Cambridge, Massachusetts, United States of America
Jay A. Berzofsky
* E-mail: [email protected] (JCM); [email protected] (JAB)
Affiliation: Vaccine Branch and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
Donald P. Lawrence
Affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
Introduction
Transforming growth factor-beta (TGFβ) is a pleiotropic cytokine that is a member of a superfamily of ligands that includes bone morphogenetic proteins and activins [1], [2]. Under normal conditions, TGFβ helps to maintain homeostasis and limit the growth of epithelial, endothelial, neuronal, and hematopoietic cell lineages through anti-proliferative and apoptotic responses. In addition, TGFβ exerts potent effects that influence immune function, differentiation, adhesion, extracellular matrix production, cell motility, angiogenesis, and cytokine production [3], [4].
Early in the transition of premalignant lesions into malignant neoplasms, TGFβ can suppress cell growth; however, in advanced cancers these effects are typically lost. Instead, TGFβ will directly promote tumor growth and metastases [2], [4], [5]. Chronic exposure of transformed mouse keratinocytes to TGFβ causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]. TGFβ induces epithelial-to-mesenchymal transition, which is characterized by a morphological change to a spindle cell shape, down-regulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the cytoskeleton, and increased...