Abstract
Scirrhous gastric carcinoma (SGC) has the worst prognosis of all gastric cancers, owing to its rapid expansion by invasion and frequent peritoneal dissemination. Due to the increased proliferation of stromal fibroblasts (SFs) that occurs within SGC lesions and the peritoneal metastatic sites, SFs have been proposed to support the progression of this disease. However, the biological and molecular basis and the pathological role of the intercellular interaction between SGC cells and SFs remain largely unknown. In this study, we investigated the role of SFs in the invasion of the extracellular matrix (ECM) by SGC cells. When SGC cells were cocultured with SFs derived from SGC tissue on three-dimensional (3D) Matrigel, they were attracted together to form large cellular aggregates that invaded within the Matrigel. Time-lapse imaging revealed that this process was associated with extensive contraction and remodeling of the ECM. Immunofluorescence and biochemical analysis showed that SGC cells stimulate phosphorylation of myosin light chain and actomyosin-mediated mechanical remodeling of the ECM by SFs. By utilizing this assay system for inhibitor library screening, we have identified several inhibitors that potently suppress the cooperation between SGC cells and SFs to form the invasive structures. Among them, a Src inhibitor dasatinib impaired the interaction between SGC cells and SFs both in vitro and in vivo and effectively blocked peritoneal dissemination of SGC cells. These results indicate that SFs mediate mechanical remodeling of the ECM by SGC cells, thereby promoting invasion and peritoneal dissemination of SGC.
Highlights
Recent studies have established the importance of the tumor stroma in cancer progression [1,2]
When 44As3 and CaF37 cells were cocultured on 3D Matrigel, they formed large aggregates that consist of a sphere-shaped core and surrounding cells (Fig. 1B)
Stromal fibroblasts (SFs) had some invasive and extracellular matrix (ECM) remodeling activities that were markedly promoted by coculture with Scirrhous gastric carcinoma (SGC) cells
Summary
Recent studies have established the importance of the tumor stroma in cancer progression [1,2]. Stromal fibroblasts (SFs) are major cellular constituents of tumor stroma and often called cancer-associated fibroblasts (CAFs) [3] They have been implicated in the malignant behavior of cancers, such as cell proliferation, ECM remodeling, and angiogenesis [4]. They often display the phenotypes of myofibroblasts, characterized by the expression of a-smooth muscle actin (aSMA) and strong contractility [5]. These characteristics contribute to fibrosis in tumor tissue and to the remodeling and stiffening of the stromal ECM that are favorable for invasion and metastasis of carcinoma cells [6,7]
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