Periostin and Epithelial-Mesenchymal Transition Score as Novel Prognostic Markers for Leiomyosarcoma, Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma

Purpose: Inter-patient clinical variability in soft tissue sarcomas (STS) highlights the need for novel prognostic markers supporting patient risk stratification. As sarcomas might exhibit a more mesenchymal or a more epithelial state, we focused on epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT/MET) for prognostic clues, and selected three histotypes with variable aggressiveness. Experimental Design: The expression of EMT/MET-related factors was measured by qRT-PCR in 55 tumor samples from patients with leiomyosarcoma (LMS), myxofibrosarcoma (MFS) or undifferentiated pleomorphic sarcoma (UPS). The identified marker was further evaluated by immunohistochemistry in 31 LMS and by measuring its circulating levels in 67 patients. The prognostic value of a sarcoma-tailored EMT score was analyzed. Epirubicin chemosensitivity and migration were studied in primary STS cultures. Associations with overall survival (OS) were assessed using Kaplan-Meier and Cox regression methods. Results: High expression of periostin, a mesenchymal matricellular protein, in sarcoma tissues (P=0.0024), its high stromal accumulation in LMS (P=0.0075) and increased circulation (>20 ng/mL, P=0.0008) were associated with reduced OS. High periostin expression (HR 2.9, 95% CI 1.3-6.9, P=0.0134) and circulation (HR 2.6, 1.3-5.1, P=0.0086), and a mesenchymal EMT score (mesenchymal vs transitioning, HR 5.2, 2.1-13.0, P=0.0005) were associated with increased risk in multivariable models. An intrinsic or induced mesenchymal state enhanced chemoresistance and migration in sarcoma cell lines. Conclusions: Although limited to a pilot study, these findings suggest that periostin might contribute prognostic information in LMS, MFS and UPS. Moreover, a transitioning EMT score measured in the tumor might predict a less active and a more chemosensitive disease.