Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin

Abstract

BackgroundCutaneous basal cell carcinoma (BCC) is the commonest cancer worldwide. BCC is locally invasive and the surrounding stromal microenvironment is pivotal for tumourigenesis. Cancer associated fibroblasts (CAFs) in the microenvironment are essential for tumour growth in a variety of neoplasms but their role in BCC is poorly understood.MethodsMaterial included facial BCC and control skin from the peritumoural area and from the buttocks. With next-generation sequencing (NGS) we compared mRNA expression between BCC and peritumoural skin. qRT-PCR, immunohistochemical and immunofluorescent staining were performed to validate the NGS results and to investigate CAF-related cyto-and chemokines.ResultsNGS revealed upregulation of 65 genes in BCC coding for extracellular matrix components pointing at CAF-related matrix remodeling. qRT-PCR showed increased mRNA expression of CAF markers FAP-α, PDGFR-β and prolyl-4-hydroxylase in BCC. Peritumoural skin (but not buttock skin) also exhibited high expression of PDGFR-β and prolyl-4-hydroxylase but not FAP-α. We found a similar pattern for the CAF-associated chemokines CCL17, CCL18, CCL22, CCL25, CXCL12 and IL6 with high expression in BCC and peritumoural skin but absence in buttock skin. Immunofluorescence revealed correlation between FAP-α and PDGFR-β and CXCL12 and CCL17.ConclusionMatrix remodeling is the most prominent molecular feature of BCC. CAFs are present within BCC stroma and associated with increased expression of chemokines involved in tumour progression and immunosuppression (CXCL12, CCL17). Fibroblasts from chronically sun-exposed skin near tumours show gene expression patterns resembling that of CAFs, indicating that stromal fibroblasts in cancer-free surgical BCC margins exhibit a tumour promoting phenotype.Electronic supplementary materialThe online version of this article (doi: 10.1186/s12885-017-3663-0) contains supplementary material, which is available to authorized users.

Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses

“…Cancer‐associated fibroblasts (CAFs) promote cancer cell invasion through the basement membrane, and it has been shown that CAFs facilitate the breaching of the basement membrane in a matrix metalloproteinase‐independent manner . This important role of CAFs has been demonstrated in peritumoral skin of basal cell carcinoma …”

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

“…By contrast, high level of IL6 and IL8 favor macrophage immunosopressive phenotype [103]. Augmented expression of IL6 in the peritumoural skin seems to be related to chronic UVexposure rather than to the presence of neoplastic cells, since IL6 is almost absent within BCC [20]. IL-1α in combination with EGFR inhibitor can induce a T cell-dependent anti-tumor immune response in head and neck squamous cell carcinoma [104].…”

“…The capacity to sustain cancer depends largely by altered secretome, augmented pro-mitogenic peptide, regulation of in ammation and ECM whereas the capacity to inhibit cancer is supposed to predominantly depends on the interaction with the immune system. An increased production of a vast repertoire of growth factors has been reported overlapping amongst distinct tumor types including NMSC [4,[20][21][22][23]. Among these, VEGF, PDGFs, EGF, FGFs, and Wnts drive tumor growth and vasculature [24].…”

Epithelial-Mesenchymal Transition in Skin Cancers: A Review

“…These EMT-related proteins can also be expressed by cells from the tumor stroma, such as cancer-associated fibroblasts (CAFs). Activated CAFs are believed to promote tumor progression and decrease patient survival [40][41][42]. Sasaki 3 Analytical Cellular Pathology expression patterns in cutaneous BCC, SCC, and MM [9].…”