Bone Marrow Stromal Cell Antigen 2 Promotes Esophageal Squamous Cell Carcinoma Progression by Mediating the Cell-Cell Interaction between Cancer Cells and Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) in the esophageal squamous cell carcinoma (ESCC) microenvironment promote cancer progression through cell-cell interactions with cancer cells. A method has been established to generate CAF-like cells by direct co-culturing human bone marrow-derived mesenchymal stem cells (MSCs), a known source of CAFs, with ESCC cells. Using this method, cDNA microarray analyses were conducted on monocultured and co-cultured ESCCs or MSCs. In this study, bone marrow stromal cell antigen 2 (BST2) was studied, which is remarkably expressed in both ESCC cells and CAF-like cells after co-culture and may contribute to cell-cell interactions. In a public database of single-cell RNA-sequencing data from ESCC tissues, BST2 was markedly expressed in cancer cells and CAFs, and the results strongly suggested an interaction between CAFs and BST2-expressing cancer cells. The co-cultured ESCC cells and CAF-like cells showed enhanced proliferation, migration, and adhesion via the extracellular signal-regulated kinase signaling pathway, and BST2 was involved in these phenotypes. Furthermore, BST2 contributed to adhesion between MSCs and ESCC cells in direct co-culture. Immunohistochemistry demonstrated that high BST2 expression, especially in the cancer stroma, was significantly associated with adverse clinicopathologic factors and poor prognosis in patients with ESCC. In conclusion, BST2 contributes to ESCC progression by facilitating cell-cell interactions between cancer cells and CAFs within the tumor microenvironment.