epidermal-growth-factor and Carcinoma--Basal-Cell

The field of cutaneous oncology is exploding with innovative treatment options, specifically in the field of targeted therapy. These advances offer new hope to select patients with high risk skin cancers. In part two of our series on targeted therapy for skin cancer, we focus our attention on squamous cell carcinoma. We begin with the epidermal growth factor receptor inhibitors and branch out into newer areas of active research.

Topics: Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Dermatology; Epidermal Growth Factor; Humans; Molecular Targeted Therapy; Skin Neoplasms

Topics: Adenine; Age Factors; Aged; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Epidermal Growth Factor; Female; Follow-Up Studies; Gene Frequency; Genotype; Guanine; Heart Transplantation; Humans; Italy; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Organ Transplantation; Polymorphism, Single Nucleotide; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Skin Neoplasms; Time Factors

In this study, we examined ErbB1 signaling in human basal and squamous cell carcinomas (BCC and SCC) of the skin in vivo. We used enzyme-linked immunosorbent assay, laser capture microdissection-coupled real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry to assess expression and activation levels of ErbB1 protein, ligands, and potential downstream effectors, in BCC and SCC tumors, stroma, and adjacent epidermis. Although total ErbB1 protein and mRNA were similar in cancerous and normal skin, we found that ErbB1 activation (phospho-Tyr(1068)) was greater in bulk SCC versus BCC or normal skin. In addition, three ErbB1 ligand transcripts (amphiregulin, heparin-binding epidermal growth factor-like growth factor, and transforming growth factor-alpha) were up-regulated in tumor cells of SCC but not BCC. Expression of these ligands was also increased in asymptomatic epidermis adjacent to both SCC and BCC, relative to normal skin. Interestingly, betacellulin transcript levels were inversely regulated compared with the other ligands. Consistently, downstream ErbB1 effectors (Erk1/2 and Akt) were activated in tumor cells of SCC but not of BCC and in adjacent epidermis of both BCC and SCC. These results demonstrate that ErbB1 signaling is hyperactive in tumor cells of SCC but not of BCC and in nearby asymptomatic epidermis of both tumor types. Our results suggest that targeting ErbB1 signaling might be of benefit in the treatment of SCC.

Topics: Amphiregulin; Animals; Betacellulin; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; EGF Family of Proteins; Enzyme Activation; Epidermal Growth Factor; Epiregulin; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Glycoproteins; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Proto-Oncogene Proteins c-akt; RNA, Messenger; Signal Transduction; Skin; Skin Neoplasms; Transforming Growth Factor alpha

Glycogen synthase kinase 3beta (GSK3beta) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3beta was drastically down-regulated in human cutaneous squamous cell carcinomas and basal cell carcinomas. Due to its negative regulation of many oncogenic proteins, we hypothesized that GSK3beta may function as a tumor suppressor during the neoplastic transformation of epidermal cells. We tested this hypothesis using an in vitro model system, JB6 mouse epidermal cells. In response to epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA), the promotion-sensitive JB6 P+ cells initiate neoplastic transformation, whereas the promotion-resistant JB6 P- cells do not. JB6 P- cells expressed much higher levels of GSK3beta than JB6 P+ cells; JB7 cells, the transformed derivatives of JB6, had the least amount of GSK3beta. The activity of GSK3beta is negatively regulated by its phosphorylation at Ser9. EGF and TPA induced strong Ser9 phoshorylation in JB6 P+ cells, but phosphorylation was seen at a much lesser extent in JB6 P- cells. EGF and TPA-stimulated Ser9 phosphorylation was mediated by phosphoinositide-3-kinase (PI3K)/Akt and protein kinase C (PKC) pathways. Inhibition of GSK3beta activation significantly stimulated activator protein-1 (AP-1) activity. Overexpression of wild-type (WT) and S9A mutant GSK3beta in JB6 P+ cells suppressed EGF and TPA-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient (K85R) GSK3beta, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo tumorigenicity. Together, these results indicate that GSK3beta plays an important role in skin tumorigenesis.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Enzyme Activation; Epidermal Growth Factor; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Mice; Mice, Inbred BALB C; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Protein Kinase C; Signal Transduction; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transfection

The deregulation of the sonic hedgehog (shh) signaling pathway in epidermal keratinocytes is a primary event leading to the formation of basal cell carcinoma (BCC). The mechanisms by which this pathway exerts this effect remain largely undefined. We demonstrate that overexpression of shh in HaCaT keratinocytes grown in organotypic cultures induced a basal cell phenotype, as evidenced by their morphology, trans-epithelial staining of cytokeratin 14, and suprabasalar proliferation. Shh also induced keratinocyte infiltration into the underlying collagen matrix. Constitutive shh expression was associated with increased phosphorylation of the epidermal growth factor receptor (EGFR) as well as jnk and raf. Additionally, levels of c-jun and matrix metalloproteinase-9 (MMP-9) protein were elevated in shh-expressing cells. Inhibition of EGFR activity with either the tyrphostin, AG1478, or blocking receptor-ligand interaction with the monoclonal antibody, C-225, blocked matrix infiltration. In contrast, exogenously supplied EGF significantly augmented the invasiveness of the HaCaT cells. These observations provide insight into the impact of deregulated shh on epidermal homeostasis. The findings further suggest that an intact EGF signaling axis cooperates with shh and is a critical mediator of matrix invasion in a tumor type characterized by disrupted shh.

Topics: Carcinoma, Basal Cell; Cell Line; Epidermal Growth Factor; Extracellular Matrix; Gene Expression; Hedgehog Proteins; Humans; Keratinocytes; Organ Culture Techniques; Phenotype; Signal Transduction; Skin Neoplasms; Trans-Activators; Transfection

Dermal fibroblasts from patients with the autosomal dominant cancer-prone disease Basal Cell Nevus Syndrome (BCNS) exhibit a serum dependence, anchorage dependence and in vitro lifespan (about 20 population doublings or less) similar to those of fibroblasts from normal age-, race- and sex-matched controls. Transfection with v-myc or with an activated mouse pro-I gene (which specifies sensitivity to promotion of neoplastic transformation in JB6 mouse epidermal cells) specifically conferred partial immortality on the BCNS fibroblasts by substantially extending their population doubling levels by more than 19 population doublings. This suggests that either v-myc or pro-I gene can cooperate with BCNS gene(s) to produce an extension of lifespan or partial immortality. However, the transfected BCNS fibroblasts that escaped senescence were anchorage-dependent even after exposure to the tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA), epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). These observations indicate that BCNS fibroblasts differ from their normal counterparts in susceptibility to extended growth and may therefore be pre-neoplastic. It is clear that they require more than an activated pro or myc gene for progression to the tumor cell phenotype.

Topics: Adult; Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Cell Division; Cell Survival; Cell Transformation, Neoplastic; Cells, Cultured; DNA; Epidermal Growth Factor; Female; Genetic Engineering; Humans; Male; Phenotype; Tetradecanoylphorbol Acetate

Specific binding of 125I-labeled epidermal growth factor (EGF) was measured in 62 skin tumors of different severity. Within a group of 28 benign tumors, 11 of 15 condylomata acuminata were receptor positive, whereas the investigated mesenchymal tumors and normal skin as a control were receptor negative. 6 of 18 basal cell epitheliomas bound EGF specifically. In the group of precancerous and malignant skin tumors, 7 of 8 squamous cell carcinomas had the highest number of EGF binding sites and a high affinity state, whereas 5 malignant melanomas were receptor negative. The clinical relevance of these findings is not yet clear due to the short follow-up of the patients.

Topics: Binding Sites; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Condylomata Acuminata; Epidermal Growth Factor; ErbB Receptors; Humans; Iodine Radioisotopes; Melanoma; Receptors, Cell Surface; Skin; Skin Diseases; Skin Neoplasms