Over‐expression of stromal periostin correlates with poor prognosis of cutaneous squamous cell carcinomas

Abstract

Periostin, an extracellular matrix macromolecule implicated in tumorigenesis, serves as a prognostic marker for many cancer types. However, there are no data on periostin expression in cutaneous squamous cell carcinoma (cSCC). This study examined periostin expression in patients with cSCC and explored its clincopathological relationship and prognosis. Using immunohistochemistry and ImageJ analysis, we compared periostin expression in 95 cSCCs across a spectrum of cSCC aggressiveness: cSCC in situ (SCCIS) (n = 25), low‐risk cSCC (LR‐cSCC) (n = 26), high‐risk cSCC (HR‐cSCC) (n = 38), and cSCC in recessive dystrophic epidermolysis bullosa patients (RDEB cSCC) (n = 6). Immunohistochemistry demonstrated periostin expression within the intra‐tumoral stroma but not within tumor cells. Periostin levels significantly (P < 0.001) increased from SCCIS, LR‐cSCC, HR‐cSCC to RDEB SCC. The stroma of most of the cSCCs we evaluated contained cancer‐associated fibroblasts with a myofibroblastic (α ‐SMA‐positive) phenotype. Co‐localization of periostin with α‐SMA, evidence of fibroblast periostin expression, and absence of keratinocyte or tumor cell periostin expression suggest that, in cSCC, periostin is a product of the peritumoral microenvironment and not the tumor cells themselves. Our data indicate that fibroblast periostin expression is highly correlated with the aggressiveness of cSCC, and may thereby provide a molecular marker that will be useful for subtyping and diagnosing cSCCs according to their biological nature.

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…In the most classical view, fibroblasts are responsible for the maintenance of the structural integrity of connective tissues. Similar to other types of fibroblasts, CAFs also produce molecules of ECM, such as collagen, hyaluronic acid, fibronectin, periostin, and tenascin [94][95][96][97][98][99][100][101]. ECM production by CAFs seems to be more extensive than in normal fibroblasts, and it even reflects the severity of the disease.…”

Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers

“…Fibroblasts stimulated by proinflammatory cytokines produce POSTN, a TGF-b-induced extracellular matrix protein [ 31 , 32 ]. POSTN is involved in cell survival, angiogenesis, and metastasis in skin cancers [ 32 ] and is expressed in stromal surrounding tumor cells in various skin cancers, including melanoma [ 24 , 29 , 33 , 34 ], cutaneous squamous cell carcinoma (cSCC) [ 35 , 36 ], basal cell carcinoma (BCC) [ 37 ], dermatofibrosarcoma protuberans (DFSP) [ 38 ], Merkel cell carcinoma (MCC) [ 39 ], and mycosis fungoides [ 40 ]. It could be a stimulator for TAMs in melanoma [ 1 ].…”

“…It could be a stimulator for TAMs in melanoma [ 1 ]. Since TAMs reside in the tumor sites in most of the skin cancers described above [ 18 ] and POSTN modulates TAM functions to induce proinflammatory cytokines and chemokines, as well as angiogenetic factors such as matrix metalloproteinase (MMP) [ 24 , 35 , 36 , 37 , 38 , 39 , 40 ], it is important to evaluate the expression levels of POSTN to predict tumor progression, and even predict the efficacy and immune-related adverse events (irAEs) in skin cancers [ 24 , 41 ].…”

Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex

“…As a result, a local increase in nerve fiber density in the interstitial matrix may account for the development of abnormal itch and pruritus, which constitute frequent complaints of EBS patients (Figure 6). Periostin is upregulated in wound-healing processes and has also been reported to be highly abundant in epidermolysis bullosa with cutaneous squamous cell carcinoma (cSCC) and in the epidermis of patients with atopic dermatitis [198,199]. A recent study demonstrated that the JAK/STAT pathway is a key regulator of periostin secretion in KCs, which induces the involvement of α5β3 integrin receptors in sensory neurons, thus forming a direct link between skin inflammation and the spinal cord's tactile and pain circuitries, in cases of skin pruritus.…”