Tumor microenvironment: Modulation by decorin and related molecules harboring leucine‐rich tandem motifs

Abstract

Decorin, the prototype member of the small leucine-rich proteoglycans, resides in the tumor microenvironment and affects the biology of various types of cancer by downregulating the activity of several receptors involved in cell growth and survival. Decorin binds to and modulates the signaling of the epidermal growth factor receptor and other members of the ErbB family of receptor tyrosine kinases. It exerts its antitumor activity by a dual mechanism: via inhibition of these key receptors through their physical downregulation coupled with attenuation of their signaling, and by binding to and sequestering TGFb. Decorin also modulates the insulin-like growth factor receptor and the low-density lipoprotein receptor-related protein 1, which indirectly affects the TGFb receptor pathway. When expressed in tumor xenograft-bearing mice or injected systemically, decorin inhibits both primary tumor growth and metastatic spreading. In this review, we summarize the latest reports on decorin and related molecules that are relevant to cancer and bring forward the idea of decorin as an anticancer therapeutic and possible prognostic marker for patients affected by various types of tumors. We also discuss the role of lumican and LRIG1, a novel cell growth inhibitor homologous to decorin.

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

“…The stroma-associated genes DECORIN and SPARC were significantly upregulated after NAC, and high residual DEC-ORIN was a strong predictor of improved outcome. The positive prognostic value of DECORIN found here in residual disease, as well as previously in primary ER disease (30), could be explained by in vitro studies in which the proteoglycan DECORIN acts as a potent inhibitor of proliferation by interacting with TGFb, EGFR, insulin-like growth factor receptor, and low density lipoprotein receptor-related protein (43). Moreover, DECORIN was chosen to represent an activated stroma in the Farmer metagene, with high levels predictive of resistance to chemotherapy in ER À disease (23).…”

Decorin causes autophagy in endothelial cells via Peg3

“…This signaling could represent an additional anti-angiogenic activity of this molecule that could modulate the biology of several types of cancer by directly affecting the tumor microenvironment (54,55). Moreover, we have shown previously that there is a genetic cooperation between decorin and p53, because double-null mice succumb to a highly aggressive thymic lymphoma within the first 6 mo of postnatal life, whereas p53-null mice live longer and present several types of neoplasia (56).…”

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…Decorin is capable of binding to four different receptor tyrosine kinases (RTKs), including the epidermal growth factor receptor (EGFR), 34 insulin-like growth factor-1 receptor (IGF-IR), [35][36][37][38] Met 39 and vascular endothelial growth factor receptor 2 (VEGFR2), 40 thereby impacting on fibrogenesis, 19 tumor growth and metastatic spreading. 12,41,42 A summary of recent data demonstrating the intricacy of decorin signaling, which links innate immunity, inflammation and tumor growth 16 is provided below.…”