title: Prognostic significance of stromal GREM1 expression in colorectal cancer.
abstract: Cancer-associated fibroblasts are the dominant cell population in the cancer stroma. Gremlin 1 (GREM1), an antagonist of the bone morphogenetic protein pathway, is expressed by cancer-associated fibroblasts in a variety of human cancers. However, its biological significance for cancer patients is largely unknown. We applied RNA in situ hybridization to evaluate the prognostic value of stromal GREM1 expression in a large cohort of 670 colorectal cancers (CRCs). Overall, GREM1 expression in CRCs was lower than that of the matched normal mucosa, and GREM1 expression had a strong positive correlation with BMI1 and inverse correlations with EPHB2 and OLFM4. RNA in situ hybridization localized the GREM expression to smooth muscle cells of the muscularis mucosa and fibroblasts around crypt bases and in the submucosal space of a normal colon. In various colon polyps, epithelial GREM1 expression was exclusively observed in traditional serrated adenomas. In total, 44% of CRCs were positive for stromal GREM1, which was associated with decreased lymphovascular invasion, a lower cancer stage, and nuclear β-catenin staining. Stromal GREM1 was significantly associated with improved recurrence-free and overall survival, although it was not found to be an independent prognostic marker in multivariate analyses. In addition, for locally advanced stage II and III CRC, it was associated with better, stage-independent clinical outcomes. In summary, CRCs are frequently accompanied by GERM1-expressing fibroblasts, which are closely associated with low lymphovascular invasion and a better prognosis, suggesting stromal GREM1 as a potential biomarker and possible candidate for targeted therapy in the treatment of CRCs.
authors.affiliation: Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, 690-767 Republic of Korea.
authors.forename: Bo Gun
authors.initials: BG
authors.lastname: Jang
authors.affiliation: Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, 690-767 Republic of Korea.
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of General Surgery, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, 690-767 Republic of Korea.
authors.forename: Weon Young
authors.initials: WY
authors.lastname: Chang
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea; Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Jeong Mo
authors.initials: JM
authors.lastname: Bae
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Hyeon Jeong
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea; Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Xianyu
authors.initials: X
authors.lastname: Wen
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Seorin
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Nam Yun
authors.initials: NY
authors.lastname: Cho
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea; Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799 Republic of Korea. Electronic address: ghkang@snu.ac.kr.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D018256:Adenomatous Polyps / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016009:Chi-Square Distribution; D003082:Colectomy; D003111:Colonic Polyps / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: Cancer-associated fibroblasts; Colorectal cancers; GREM1; In situ hybridization; Prognosis