title: Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche.
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.
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Chronic Diseases, Center for Diseases Control and Prevention of Yangpu District, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Liye
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, Zhejiang University School of Public Health, Hangzhou, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Colorectal Surgery, The 1st Affilaited Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chuangang
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D005472:Fluorouracil
keywords: colorectal carcinoma; drug-resistance; fibroblast; periostin; prognosis