PDF file - 1150K, From cancer signature genes to EMCT seed predictions (S1); Immunohistochemistry was used to distinguish NFs and CAFs with antibodies targeting cytokeratin (CK), vimentin (VIM), and alpha-smooth muscle actin (alpha-SMA) (x100) (S2); Expression of TbetaRIII in OSCC cells and CAFs after retroviral transfection (S3); Examination of TbetaRIII and vimentin expression in sections of different types of HSC-2 tumors (S4).
ARTICLE ABSTRACT
The complex interactions between cancer cells and their surrounding stromal microenvironment play important roles in tumor initiation and progression and represent viable targets for therapeutic intervention. Here, we propose a concept of common target perturbation (CTP). CTP acts simultaneously on the same target in both the tumor and its stroma that generates a bilateral disruption for potentially improved cancer therapy. To employ this concept, we designed a systems biology strategy by combining experiment and computation to identify potential common target. Through progressive cycles of identification, TGF-β receptor III (TβRIII) is found as an epithelial–mesenchymal common target in oral squamous cell carcinoma. Simultaneous perturbation of TβRIII in the oral cancerous epithelial cells and their adjacent carcinoma-associated fibroblasts effectively inhibits tumor growth in vivo, and shows superiority to the unilateral perturbation of TβRIII in either cell type alone. This study indicates the strong potential to identify therapeutic targets by considering cancer cells and their adjacent stroma simultaneously. The CTP concept combined with our common target discovery strategy provides a framework for future targeted cancer combinatorial therapies. Cancer Res; 74(8); 2306–15. ©2014 AACR.
