The biology of decorin in the tumor microenvironment

Abstract

Decorin is a ubiquitous secreted small-leucine rich proteoglycan associated with all major collagen-rich matrices. Initially described for its roles in maintaining the structural integrity of various organs and in collagen fibrillogenesis, decorin has gained notoriety for its involvement in regulating physiological and pathological processes such as wound healing, inflammation, cell adhesion, and carcinogenesis. Decorin exerts these functions through its ability to bind with high affinity to multiple receptor tyrosine kinases (RTKs). In cancer, decorin has been described as a paracrine tumor repressor and anti-angiogenic molecule. However, a detailed description of its mechanism of action in the tumor microenvironment was unknown. Understanding the role of the tumor stroma in modulating the signaling of cancer cells, tumor angiogenesis, and metastatic spreading is critical and of clinical relevance. This thesis unscrambles the biology of decorin in the tumor microenvironment and describes a new double mechanism of action where decorin alters signaling cascades of both cancer cells and surrounding stromal cells via selective binding to different RTKs, ultimately elucidating its tumor suppressor activity. The key observations of my studies are: [1] the discovery that physical interaction of decorin with the Met receptor on cancer cells causes a protracted downregulation of β-catenin and its downstream effector Myc both at the transcriptional and post-translational levels (chapter 3); [2] the discovery that systemic delivery of soluble decorin in-vivo causes genotypic changes in the stroma of orthotopic breast carcinoma xenografts and the identification of Peg3 as a novel decorin-induced tumor suppressor in the tumor microenvironment (chapter 5); [3] the observation that decorin evokes autophagy in endothelial cells via binding to VEGFR2 and induction of Peg3 (chapter 6). Thus, here I define how decorin dually affects the tumor proper by suppressing Met activity and the tumor vasculature by inducing unrestrained autophagy. Decorin could tie the interplay between extracellular signaling and intracellular catabolic pathways that leads to angiostasis and tumor growth suppression and could be an innovative therapeutic alternative against cancer