Decorin Protein Core Affects the Global Gene Expression Profile of the Tumor Microenvironment in a Triple-Negative Orthotopic Breast Carcinoma Xenograft Model

Abstract

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.

Decorin causes autophagy in endothelial cells via Peg3

“…The first line of evidence to tie decorin signaling to Peg3 came from the empirical demonstration of Peg3 induction exclusively within the tumor microenvironment following systemic administration of decorin (24). Immunofluorescence studies revealed a dramatic association of Peg3 with subcellular structures resembling autophagosomes.…”

“…Specificity was confirmed by the lack of an autophagic response in the presence of equimolar amounts of biglycan protein core, the closest molecular relative of decorin. Decorin, by signaling via RTK interactions, can ameliorate the overall antitumor properties of the tumor stroma by counteracting malignant development to stymie tumor progression (5,13,24) and angiogenesis (20,23). Typically, these interactions are exclusively antagonistic.…”

“…During preclinical studies focusing on identifying decorininduced genes in vivo, we found that systemic delivery of decorin protein core to mice carrying orthotopic mammary carcinoma xenografts induced expression of a small subset of genes (24). Notably, these genes were induced exclusively in the tumor stroma of mouse origin but not in the mammary carcinomas of human origin (24).…”

“…Notably, these genes were induced exclusively in the tumor stroma of mouse origin but not in the mammary carcinomas of human origin (24). One of the most up-regulated genes was Paternally expressed gene 3 (Peg3), an imprinted putative tumor-suppressor gene frequently silenced by promoter hypermethylation and/or loss of heterozygosity (25)(26)(27)(28)(29)(30).…”

DCN prevent metastasis of HepG2 cells by elevating the expression of TGF β and P15

“…The DCN transfection elevated the phosphorylation level of TGF-βRI in HepG2 cells, without affecting the total TGF-βRI expression. The p15 protein is one of the key downstream factors of TGF-βRI, whose activation may influence cell cycle-associated proteins, further inhibiting the cell proliferation [8]. The current results showed that DCN transfection was able to significantly elevate the expression level of p15.…”