Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche.

Xiaowen Xu,Hui Cai,Xianhua Gao,Xiaojie Tan,Yan Liu,Kun Chen,Yibo Ding,Guangwen Cao,Hao Wang,Chuangang Fu,Yanxin Luo,Wenjun Chang,Qizhi Liu,Yan Du,Jie Yuan,Xue Han,Jianping Wang,Long Ma ,Yan‐Qing Ding ,Yu Ye

doi:10.18632/oncotarget.5985

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.

Highlights

Colorectal cancer (CRC) is one of the most common malignancies worldwide, with 1.23 million newly diagnosed cases annually [1]
The present study demonstrated that stromal POSTN expression was gradually increased from normal tissues, primary CRC tissues to metastatic CRC tissues (Figure 1), indicating that stromal POSTN expression accumulates consecutively during CRC progression
Medium-score stromal POSTN expression is comparable to the CRC cell-derived gene signature in predicting disease-free survival (DFS) of the same CRC patients in Shanghai cohort; while medium-and high-score stromal POSTN expression is comparable to the CRC cell-derived gene signature in predicting disease-specific survival (DSS) in Guangzhou cohort [8]

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide, with 1.23 million newly diagnosed cases annually [1]. Surgical resection is the primary option for CRC treatment. Circumferential resection margin involvement, obstruction/perforation, rupture during surgery, vascular and perineural invasion, poor differentiation, high-frequency microsatellite instability, mismatch repair deficiency, thymidylate synthase positivity, circulating tumor cells, KRAS mutation, BRAF mutation, and elevated expression of Snail or serpinA1 have been suggested to be prognostic for CRC [2,3,4,5]. Postoperative chemotherapy is the standard of care for stage III CRC patients. Some molecules or signatures expressed in CRC tissues can be predictive [6, 7]. These molecules are potentially prognostic and/or predictive, few of them are clinically applied. Identification of new biomarkers to improve CRC prognosis classification and individualized treatment is urgently needed

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