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.
Highlights
A number of fibroblasts that had proliferated in the scar tissues highly expressed GREM1 as well as α-smooth muscle actin (α-SMA), demonstrating that GREM1-expressing myofibroblasts may appear under physiological conditions such as wound healing (Fig 1)
We demonstrated that GREM1 is frequently expressed by Cancer-associated fibroblasts (CAFs) in the tumoralstromal interface of invasive skin cancers, whereas the resident fibroblasts in normal skin do Nodular (%) 22 (73) 4 (13) 4 (13) 0 (6) 0 (1) 30 (100)
We observed the appearance of GREM1-positive fibroblasts in scar tissue, showing that GREM1 expression is not confined to cancer-associated stromal cells, but can be a phenotypic marker for activated fibroblasts under physiological conditions
Summary
Expression of GREM1 in skin tumors encircle cancer cells that are invading adjacent normal tissues [1]. CAFs can originate from multiple precursors such as resident fibroblasts, smooth muscle cells, endothelial cells, and bone marrow (BM)-derived mesenchymal stem cells [2, 3]. CAFs secrete a wide spectrum of soluble factors including growth factors, chemokines, and cytokines, and contribute to the growth, migrations, epithelial mesenchymal transitions (EMTs), and metastases of the cancer cells. Molecular markers of CAFs, such as fibroblast activation protein (FAP), C-X-C motif chemokine ligand 12 (CXCL12), and hepatocyte growth factor (HGF) are emerging as selective therapeutic targets in the cancer stroma [4]. A few studies on skin cancers have examined the molecular markers in CAFs for developing novel therapeutic strategies [5, 6]
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