Expression of the epidermal stem cell marker p63/CK5 in cutaneous papillomas and cutaneous squamous cell carcinomas of dogs.

Cutaneous papillomas (CPs) and cutaneous squamous cell carcinomas (CSCCs) are usual epidermal tumours in dogs. CPs and CSCCs probably arise from the neoplastic transformation of the keratinocytes within the stem cell compartment, since these cells are the only keratinocytes that would reside long enough to accumulate the number of molecular alterations to drive the progression towards a tumour cell phenotype. However, the role of these cells in common epidermal tumours in dogs is still unknown. Thus, the purpose of this study was to evaluate the immunohistochemical expression pattern of p63 together with CK5, molecular markers of epidermal stem cells, on sections of tissue microarrays constructed from canine samples of CP and CSCC to investigate the contribution of stem cells in those canine tumours. p63/CK5 coexpression was retained in most basal and some suprabasal cells in CPs and CSCCs. In addition, increased coexpression of these molecules was observed in a group of CPs and CSCCs, as a result of a higher p63 expression. These results suggest that the coexpression of p63/CK5 may mark epidermal keratinocytes that possess self-renewal capacity rather than only stem cells, and suggest that transit amplifying cells, and even differentiated keratinocytes, may also contribute to the pathogenesis of epidermal tumours in dogs.

Aberrant Expression of E-cadherin/ß-catenin During Epidermal Tumourigenesis in Dogs.

Clinically relevant epidermal tumours in dogs include cutaneous papillomas (CPs) and cutaneous squamous cell carcinomas (CSCCs). The development of CPs and CSCCs involves dysregulation in expression of E-cadherin/ß-catenin; however, knowledge about the contribution of these molecules to epidermal tumourigenesis in dogs is limited. This study examined the immunohistochemical expression pattern of E-cadherin/ß-catenin in samples of normal canine epidermis, CPs, preneoplastic epidermis and CSCCs, using tissue microarrays, in order to elucidate whether the dysregulated expression of these molecules may contribute to the pathogenesis of clinically relevant epidermal tumours in dogs. We also investigated the correlation between the immunohistochemical expression pattern of E-cadherin/ß-catenin in these tissue microarrays to further evaluate whether the disruption of the adherens junction interactions plays a relevant role in canine epidermal tumourigenesis. In samples of CP and preneoplastic epidermis, the membrane immunoreactivity of E-cadherin/ß-catenin was conserved, while in CSCC, the immunoreactivity of these molecules was significantly reduced, independently of the tumour location. There was significant correlation between the membrane expression of E-cadherin/ß-catenin in CSCC. ß-catenin also showed cytoplasmic and nuclear expression in samples of CP, preneoplastic epidermis and CSCC. These results support the hypothesis that dysregulated expression of E-cadherin/ß-catenin may play a critical role in the pathogenesis of relevant canine epidermal tumours, not only due to the disruption of the intercellular adherens junctions, but also due to the dysregulated activity of the signalling pathways in which these molecules are involved.

Dysregulated Expression of Phosphorylated Epidermal Growth Factor Receptor and Phosphatase and Tensin Homologue in Canine Cutaneous Papillomas and Squamous Cell Carcinomas.

The molecular mechanisms contributing to the development of cutaneous papillomas (CPs) and cutaneous squamous cell carcinomas (CSCCs) are still poorly understood, limiting the ability to identify molecular suitable targets for the development of novel therapies. Persistent activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway is a component of epidermal carcinogenesis in dogs. The present study describes the immunohistochemical expression pattern of two key regulatory molecules involved in the PI3K/Akt/mTOR signalling pathway, phosphorylated epidermal growth factor receptor (pEGFR)Tyr1068 and phosphatase and tensin homologue (PTEN), in samples of normal canine epidermis, CP, preneoplastic epidermis and CSCC using tissue microarrays to determine whether the deregulated activity of these molecules is involved in the pathogenesis of these relevant epidermal tumours of dogs. Expression of pEGFR and PTEN was dysregulated in most samples of CP, preneoplastic epidermis and CSCC. Overexpression of pEGFR, together with decreased expression of PTEN, may facilitate the progression of some canine CPs and CSCCs by deregulation of the key cellular functions in which the PI3K/Akt/mTOR signalling pathway is involved. These findings suggest that the PI3K/Akt/mTOR signalling molecules may be potential therapeutic targets for canine patients with CP and CSCC.

Immunohistochemical expression of selected phosphoproteins of the mTOR signalling pathway in canine cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) represents one of the most common malignant skin tumors in dogs. Research aimed at clarifying how the deregulated activity of signalling pathways contributes to cSCC progression can help to identify molecular suitable targets for the development of novel therapies. The present study describes the immunohistochemical expression pattern of two proteins (pAktSer473 and pS6Ser235/236, the latter combined with Ki-67) involved in the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway in canine specimens of normal epidermis, pre-neoplastic epidermis, and cSCC using tissue microarrays. The results suggest that the PI3K/Akt/mTOR signalling pathway has a low expression in the normal canine epidermis, and that selected molecules involved in this signalling pathway are dysregulated during the canine epidermal carcinogenesis process. These findings provide important evidence that the persistent activation of the PI3K/Akt/mTOR signalling pathway represents one of the key events during cSCC progression in canine patients, pointing to the PI3K/Akt/mTOR pathway as a potential therapeutic target.