New Advances on the Functions of Epidermal Growth Factor Receptor and Ceramides in Skin Cell Differentiation, Disorders and Cancers

Abstract

Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed. The alterations in EGFR signaling and ceramide metabolism, which might be involved in the etiopathogenesis of diverse skin disorders and cancers, are described. New progress in understanding of skin organization, which might provide the basis for the design of new transcutaneous drug delivery techniques as well as for the development of new therapies of skin disorders and cancers, are reported.

Stem cell therapy for hereditary breast cancer

“…Inactivation of EGFR (erbB2) might represent a potent strate gy, alone or in combination with other conven tional treatments for numerous aggressive cancer forms [17][18][19]. Among the selective agents target ing EGFR signaling, there are antibodies or anti sense oligonucleotides directed against EGFR or its ligands EGF and TGF , anti ErbB2 antibody trastuzumab (Herceptin) and the selective EGFR tyrosine kinase inhibitors such as AG1478, gefi tinib and erlotinib [17]. These agents may induce the inhibition of the growth, invasiveness, and apoptotic death of diverse cancer cell types by counteracting distinct mitotic cascades, including MAPK, PI3K/Akt, NF κB, phospholipase Cγ, and Shc [19].…”

“…The inactivation of hedgehog signaling by using either SMO signaling element inhibitor, cyclopamine alkaloid, or the anti SHH antibody has been observed to result in vitro and in vivo in a growth inhibition and the apoptotic death of the metastatic cancer cells, whereas normal cells were insensitive to the cytotoxic effects of these agents [17]. In addition, molecular targeting of the canonical Wnt/β catenin signaling elements con stitutes another anticarcinogenic strategy for the treatment of breast cancer [20].…”

“…Similarly, the inhibition of the Notch signaling cascade, which also appears to participate in developing certain cancer types, including acute T cell lymphoblastic leukemia and lymphoma, medulloblastoma, and mucoepidermoid, colorectal, pancreatic, mam mary, ovarian, and lung carcinomas, may also rep resent another targeting approach in the therapeu tic interventions against these hyperproliferative disorders [21]. For instance, the inhibition of the β and γ secretases, whose proteases can cleave the intracellular domain of the Notch transmembrane receptor, thereby permitting its translocation into the nucleus, where it participates in the transcrip tional activation of genes, may notably represent a potent therapeutictarget for these malignant disor ders [17,18].…”

“…The simultaneous inhi bition of diverse hormone and growth factor sig naling pathways, including BRCA1, ER, AR, IGFR, EGFR, hedgehog, Wnt/β catenin, Notch, and/or G protein coupled receptors, as well as VEGFR and PDGFR cascades, which can act in cooperation by stimulating the growth, invasion, and metastatic spread of cancer cells at distant sites during the different stages of cancer progression, may also constitute more effective therapiesagainst the aggressive and highly metastatic cancer forms [15,16]. As a matter of fact, some works have revealed that complex cross talks may occur among the AR, ER α/ER β, EGFR/ErbB2 sig naling cascades in breast cancers [17,18]. The combination of the agents that are able to block these tumorigenic pathways may be more effective to treat these epithelial malignancies as a single antihormonal therapy.…”

“…In this matter, the specific block ade of the SDF 1 CXCR4 axis by using a specific anti SDF 1 antibody, anti CXCR4 antibody, or CXCR4 antagonist (TC14012, TN14003, or AMD3100) has notably been observed to prevent the metastatic spread and interfere with the hom ing of breast and prostate cancer epithelial cells at their target metastatic sites, including lymph nodes, bone, and lungs [16]. The results from pre clinical studies have also indicated that the use of the EGFR inhibitors in combination with COX 2 inhibitor or photodynamic treatment or as chemo and radiosensitizers resulted in more effective chemopreventiveand curative treatments for patients with advanced and metastatic cancer forms [17]. It is noteworthy that the sequence of treatment with the EGFR inhibitor and chemotherapy appears to be a critical factor that should be considered for clinical application.…”