[Frontiers in Bioscience 14, 4044-4057, January 1, 2009]

The inflammatory network: bridging senescent stroma and epithelial tumorigenesis

Weiwei Shan, Gong Yang, Jinsong Liu

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Epithelial tumorigenesis: much more than mutations
4. Stromal-epithelial interactions: opening Pandora's Box
5. Cellular senescence: the two-faced player
5.1. Overview of cellular senescence
5.2. A focus on oncogene-induced senescence
5.3. The concept of antagonistic pleiotropy
6. Senescence of the stromal fibroblasts: 'bad neighbors' do exist
6.1. Inducers of senescence in stromal fibroblasts
6.2. Senescent fibroblast-mediated promotion of epithelial tumorigenesis
6.3. Paracrine signalers as molecular effectors
7. Dualistic functions of the pro-inflammatory network
8. Perspectives
9. Acknowledgements
10. References

1. ABSTRACT

Cellular senescence or aging, defined by permanent cell cycle arrest, is well known for its evolutionary advantage in protecting the organism from developing cancer; however, it is also acknowledged that aged stromal cells can significantly expedite epithelial tumorigenesis, although exactly how they function to augment tumor formation remains elusive. Recent evidence suggests that this tumor-promoting effect is likely mediated by diffusible pro-inflammatory molecules synthesized and released by senescent stromal fibroblasts, acting in a paracrine fashion on adjacent tumor epithelium. Mobilization of the inflammatory network by senescent fibroblasts has bifurcated roles on the epithelial and stromal compartments, converging on the promotion of epithelial tumorigenesis. A thorough understanding of the regulatory mechanisms underlying these events may lead to improved approaches in cancer treatment.