title: GREM1 is expressed in the cancer-associated myofibroblasts of basal cell carcinomas.
abstract: Cancer-associated fibroblasts (CAFs) play important roles in cancer progression through their complex interactions with cancer cells. The secreted bone morphogenetic protein antagonist, gremlin1 (GREM1) is expressed by the CAFs of basal cell carcinomas (BCCs), and promotes the growth of cancer cells. In this study, we investigated the expression of GREM1 mRNAs in various benign and malignant skin tumors, including various BCC subtypes. Analysis by RNA in situ hybridization (ISH) revealed that fibroblasts in the scar tissue expressed GREM1 and α-smooth muscle actin (α-SMA), whereas resident fibroblasts in the dermis of the normal skin did not express GREM1. Real-time polymerase chain reaction analysis showed significantly higher GREM1 expression in skin cancers and pilomatricomas (PMCs) than in other benign skin tumors. Tissue microarrays analyzed by RNA ISH for GREM1 expression also demonstrated that 23% of BCCs, 42% of squamous cell carcinomas, 20% of melanomas, and 90% of PMCs were positive for GREM1 expression, whereas trichoepitheliomas, eccrine poromas, hidradenomas, and spiradenomas were negative for GREM1 expression. Most BCCs that were GREM1 expression positive were of desmoplastic or mixed subtypes, and GREM1 expression was localized to activated myofibroblasts at the tumoral-stromal interface. Interestingly, most PMCs harbored GREM1-expressing fibroblasts, probably because of the inflammatory responses caused by foreign body reactions to keratin. Additionally, in BCCs, stromal GREM1 expression had a strong correlation with CD10 expression. In conclusion, GREM1 is frequently expressed by myofibroblasts in scars or in the stroma of basal cell carcinomas, suggesting that GREM1 expression can be a marker for activated myofibroblasts in the cancer stroma or in scar tissue.
authors.affiliation: Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Plastic Surgery, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Shin
authors.affiliation: Department of Dermatology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Min Seok
authors.initials: MS
authors.lastname: Cheon
authors.affiliation: Department of Dermatology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Jae Wang
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Young Sill
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, Jeju, South Korea.
authors.forename: Bo Gun
authors.identifier: http://orcid.org/0000-0003-4683-8338
authors.initials: BG
authors.lastname: Jang
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002921:Cicatrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D000199:Actins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins