Decorin is a stromal-derived prototype member of the small leucine-rich proteoglycan gene family. In addition to its functions as a regulator of collagen fibrillogenesis and TGFb activity, soluble decorin acts as a pan-receptor tyrosine kinase (RTK) inhibitor. Decorin binds to various RTKs, including EGFR, HER2, HGFR/Met, VEGFR2, TLR and IGFR. Although the molecular mechanism for the action of decorin on these receptors is not entirely elucidated; overall, decorin evokes transient activation of these receptors with suppression of downstream signaling cascades culminating in growth inhibition, followed by their physical downregulation via caveosomal internalization and degradation. In the case of Met, decorin leads to decreased b-catenin signaling pathway and growth suppression. As most of these RTKs are responsible for providing a growth advantage to cancer cells, the result of decorin treatment is oncosuppression. Another decorin-driven mechanism to restrict cancer growth and dissemination is by impeding angiogenesis via VEGFR2 and the concurrent activation of protracted endothelial cell autophagy. In this review, we will dissect the multiple roles of decorin in cancer biology and its potential use as a next-generation protein-based adjuvant therapy to combat cancer.

Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As a member of the small leucine-rich proteoglycan gene family, decorin has single-handedly pioneered the connection between extracellular matrix signaling and autophagy regulation. Soluble decorin evokes protracted endothelial cell autophagy via Peg3 and breast carcinoma cell mitophagy via mitostatin by interacting with VEGFR2 or the MET receptor tyrosine kinase, respectively. In this paper, we give a mechanistic perspective of the vital factors underlying the nutrient-independent, SLRP-dependent programs utilized for autophagic and/or mitophagic progression in breast cancer. Future protein therapies based on decorin (or fellow proteoglycan members) will represent a quantum leap forward in transforming autophagic progression into a powerful tool to control intracellular cell catabolism from the outside.

CD11c+CD86+), CD4 T helper (CD3+CD4+), and CD8 cytotoxic cells (CD3+CD8+). Results: Experiments demonstrated significant efficacy of SAHA and Reolysin treatment in vitro and in the immunocompetent mouse model. Combination therapy exhibited a synergistic anti-tumor effect with a significant increased survival of mice compared to any of the agents alone. The Jam1 receptor was upregulated on tumor cells allowing enhanced reovirus uptake. There was marked and significant reduction in circulating B cells in combination treated mice versus all other groups. Activated NK cells were decreased in the combination group. T cells and dendritic cells (CD11c+MHCII+) were reduced in the SAHA groups. SAHA model withdrawal experiments show a significant synergistic response and immune system rebound after SAHA cessation. Conclusion: This data demonstrates that combination of reovirus plus SAHA therapy has significant activity in the treatment of SCCHN, even in an immunocompetent model. Immune inhibition due to SAHA as well as increased Jam1 receptor expression on tumor cells results in a synergistic effect of the combination therapy. Immune system rebound likely plays a significant role in the long-term anti-tumor response. This strong preclinical evidence supports the translation of this combination to phase-I clinical trials.