The tumor microenvironment encompasses a complex cellular network that includes cancer-associated fibroblasts, inflammatory cells, neo-vessels, and an extracellular matrix enriched in angiogenic growth factors. Decorin is one of the main components of the tumor stroma, but it is not expressed by cancer cells. Lack of this proteoglycan correlates with down-regulation of E-cadherin and induction of β-catenin signaling. In this study, we investigated the role of a decorin-deficient tumor microenvironment in colon carcinoma progression and metastasis. We utilized an established model of colitis-associated cancer by administering Azoxymethane/Dextran sodium sulfate to adult wild-type and Dcn^−/- mice. We discovered that after 12 weeks, all the animals developed intestinal tumors independently of their genotype. However, the number of intestinal neoplasms was significantly higher in the Dcn^−/− microenvironment vis-à-vis wild-type mice. Mechanistically, we found that under unchallenged basal conditions, the intestinal epithelium of the Dcn^−/− mice showed a significant increase in the protein levels of epithelial-mesenchymal transition associated factors including Snail, Slug, Twist, and MMP2. In comparison, in the colitis-associated cancer evoked in the Dcn^−/− mice, we found that intercellular adhesion molecule 1 (ICAM-1) was also significantly increased, in parallel with epithelial-mesenchymal transition signaling pathway-related factors. Furthermore, a combined Celecoxib/decorin treatment revealed a promising therapeutic efficacy in treating human colorectal cancer cells, in decorin-deficient animals. Collectively, our results shed light on colorectal cancer progression and provide a protein-based therapy, i.e., treatment using recombinant decorin, to target the tumor microenvironment.

肿瘤微环境包含一个复杂的细胞网络，其中包括与癌症相关的成纤维细胞、炎症细胞、新血管和富含血管生成生长因子的细胞外基质。核心蛋白聚糖是肿瘤基质的主要成分之一，但癌细胞不表达。缺乏这种蛋白多糖与 E-钙粘蛋白的下调和 β-连环蛋白信号传导的诱导相关。在这项研究中，我们调查了核心蛋白聚糖缺陷的肿瘤微环境在结肠癌进展和转移中的作用。我们通过对成年野生型和Dcn ^-/-施用氧化偶氮甲烷/葡聚糖硫酸钠来利用已建立的结肠炎相关癌症模型老鼠。我们发现，在 12 周后，所有动物都出现了与其基因型无关的肠道肿瘤。然而，与野生型小鼠相比，Dcn ^-/-微环境中肠道肿瘤的数量明显更高。从机制上讲，我们发现在未受挑战的基础条件下，Dcn ^-/-小鼠的肠上皮显示上皮-间充质转化相关因子（包括 Snail、Slug、Twist 和 MMP2）的蛋白质水平显着增加。相比之下，在Dcn诱发的结肠炎相关癌症中^-/-小鼠，我们发现细胞间粘附分子 1 (ICAM-1) 也显着增加，与上皮 - 间充质转化信号通路相关的因素并行。此外，塞来昔布/decorin 联合治疗揭示了治疗缺乏核心蛋白聚糖的动物的人类结直肠癌细胞的有希望的治疗效果。总的来说，我们的结果揭示了结直肠癌的进展，并提供了一种基于蛋白质的疗法，即使用重组核心蛋白聚糖的治疗，以靶向肿瘤微环境。