Stromal POSTN Enhances Motility of Both Cancer and Stromal Cells and Predicts Poor Survival in Colorectal Cancer

SIMPLE SUMMARY: Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. The present study revealed that patients with stromal periostin (POSTN)-positive colorectal cancer (CRC) with peritoneal and distant organ metastasis had a significantly worse 5-year survival rate. Furthermore, significant associations between stromal POSTN and complete loss of p53 were identified. POSTN was also associated with decorin and fibroblast-activation protein expression, indicating gene expression status and/or phenotypes similar to CAF-A. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK, AKT, or STAT3 activation. Co-culture assays demonstrated communication between CRC cells and fibroblasts, enhancing STAT3 and phospho-STAT3 expression in fibroblasts. On the basis of our experiments, we speculated that stromal POSTN accelerated metastasis via enhanced stromal remodeling capacity and activated migration of both tumor and stromal cells. POSTN-modulating therapies may be candidate treatments for patients with CRC. ABSTRACT: Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. To uncover clinicopathological importance of periostin (POSTN) expression in colorectal cancer (CRC), the present study immunohistochemically examined its expression status. Furthermore, to reveal its mechanisms involved, molecular experiments were performed. In CRC tissues, 44% of the cases (119/269) exhibited POSTN expression in the CAFs. In contrast, CRC cells expressed POSTN at almost undetectable levels. Survival analyses identified that patients with POSTN-positive CRC had a significantly worse 5-year survival rate (63.2% vs. 81.2%; p = 0.011). Univariate analyses revealed that POSTN positivity was associated with peritoneal (p = 0.0031) and distant organ metastasis (p < 0.001). Furthermore, immunohistochemical analyses identified a significant association between POSTN and p53 complete loss status in CRC cells. Decorin and fibroblast activation protein expression in CAFs was also associated with POSTN. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK and AKT or STAT3 activation, and co-culture assays demonstrated the communication between CRC cells and fibroblasts, which enhanced STAT3 activation in fibroblasts. On the basis of our results, we speculated that stromal POSTN accelerated metastasis via stromal remodeling capacity and activated the migration of both tumor and stromal cells.