Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinomaviacreating a cancer-supportive niche

// Xiaowen Xu 1, * , Wenjun Chang 2, * , Jie Yuan 1, * , Xue Han 3, * , Xiaojie Tan 2 , Yibo Ding 2 , Yanxin Luo 4 , Hui Cai 2 , Yan Liu 2 , Xianhua Gao 1 , Qizhi Liu 1 , Yongwei Yu 5 , Yan Du 2 , Hao Wang 1 , Liye Ma 6 , Jianping Wang 4 , Kun Chen 7 , Yanqing Ding 8 , Chuangang Fu 1 , Guangwen Cao 2 1 Department of Colorectal Surgery, The 1 st Affilaited Hospital, Second Military Medical University, Shanghai, China 2 Department of Epidemiology, Second Military Medical University, Shanghai, China 3 Department of Chronic Diseases, Center for Diseases Control and Prevention of Yangpu District, Shanghai, China 4 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 5 Department of Pathology, The 1 st Affilaited Hospital, Second Military Medical University, Shanghai, China 6 Department of General Surgery, The 1 st Affilaited Hospital, Second Military Medical University, Shanghai, China 7 Department of Epidemiology and Biostatistics, Zhejiang University School of Public Health, Hangzhou, China 8 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Guangwen Cao, e-mail: gcao@smmu.edu.cn Chuangang Fu, e-mail: fugang416@126.com Keywords: colorectal carcinoma, periostin, fibroblast, drug-resistance, prognosis Received: June 19, 2015 Accepted: October 30, 2015 Published: November 09, 2015 ABSTRACT Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues ( P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC.