involucrin and Keratosis

Symmetrical acrokeratoderma (SAK) is characterized by brown to black hyperkeratotic patches on acral regions. Although epidermal hyperkeratosis and acanthosis are consistent pathological changes, the nature of epidermal hyperplasia is unknown.. To evaluate epidermal proliferation and differentiation and melanocytic density in skin lesions of SAK.. Expression of keratin 10 (K10), K14, K16, involucrin, filaggrin, Ki-67, and Melan-A was detected by immunohistochemistry in eight patients with SAK, seven patients with ichthyosis vulgaris (IV) and six healthy controls (HCs).. Expression of K14, K16, involucrin and filaggrin was upregulated in patients with SAK compared with patients with IV and the HCs (P < 0.01-0.05), but K10 expression was similar for the three groups (P > 0.05). Numbers of Ki-67+ and Melan-A+ cells were higher in patients with SAK than in patients with IV and the HCs (P < 0.05).. These results demonstrate that excessive keratinocyte proliferation and abnormal differentiation contribute to epidermal hyperplasia, while melanocytic proliferation is responsible for the pigmented lesions in SAK.

Topics: Adolescent; Adult; Cell Differentiation; Cell Proliferation; Epidermal Cells; Epidermis; Female; Filaggrin Proteins; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratinocytes; Keratins; Keratosis; Ki-67 Antigen; Male; Melanocytes; Protein Precursors; Skin; Up-Regulation; Young Adult

Desmoglein 2 (Dsg2), a component of the desmosomal cell-cell adhesion structure, has been linked to invasion and metastasis in squamous cell carcinomas. However, it is unknown whether--and if so how--Dsg2 contributes to the malignant phenotype of keratinocytes. In this study, we addressed the consequences of Dsg2 overexpression under control of the involucrin promoter (Inv-Dsg2) in the epidermis of transgenic mice. These mice exhibited epidermal hyperkeratosis with slightly disrupted early and late differentiation markers, but intact epidermal barrier function. However, Inv-Dsg2 transgene expression was associated with extensive epidermal hyperplasia and increased keratinocyte proliferation in basal and suprabasal epidermal strata. Cultured Inv-Dsg2 keratinocytes showed enhanced cell survival in the anchorage-independent state that was critically dependent on EGF receptor activation and NF-kappaB activity. Consistent with the hyperproliferative and apoptosis-resistant phenotype of Inv-Dsg2 transgenic keratinocytes, we observed enhanced activation of multiple growth and survival pathways, including PI 3-kinase/AKT, MEK-MAPK, STAT3 and NF-kappaB, in the transgenic skin in situ. Finally, Inv-Dsg2 transgenic mice developed intraepidermal skin lesions resembling precancerous papillomas and were more susceptible to chemically induced carcinogenesis. In summary, overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors in vivo.

Topics: Animals; Apoptosis; Cell Adhesion; Cell Differentiation; Cell Proliferation; Cell Survival; Desmoglein 2; Epidermis; Immunoblotting; Immunohistochemistry; Keratinocytes; Keratosis; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Phenotype; Protein Precursors; Signal Transduction

A new patient with CHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, and limb defects), the thirtieth in the literature, was observed for over three years. Initially, the right-sided lesion spared the breast area. At 10 months of age the trunk lesion extended to cover the entire area of the right chest. At age 20 months the patient developed linear, bandlike, keratotic, brown-black lesions on her left thigh that subsided within six weeks, leaving a slight hyperpigmentation. This patient was studied by routine histologic methods as well as with markers of keratinization and electron microscopy. In hematoxylin and eosinstained sections, parakeratosis and orthokeratosis alternated. In some parakeratotic areas, large granular cells, and in others, ghost granular cells, were present. The latter showed basophilic cytoplasm, and palestaining or vacuolated nucleus and were seen either above the normal granular layer or without it. Although regional variations existed, basal cell-type keratins as recognized by AE1 continued to be expressed in suprabasal layers. Filaggrin- and involucrin-positive layers were expanded, particularly the latter, down to the lower prickle cell layer. Ultrastructurally, numerous lamellar or membranous structures were found in upper layers of the epidermis, both intracellulary and intercellularly. Normal cementsomes coexisted with these abnormal lamellar structures, and it was thought that the latter represent modified cementsomes because the discharge of those from the cell periphery was often detected.

Topics: Arm; Epidermis; Female; Filaggrin Proteins; Follow-Up Studies; Humans; Hyperpigmentation; Ichthyosiform Erythroderma, Congenital; Infant; Infant, Newborn; Intermediate Filament Proteins; Keratinocytes; Keratins; Keratosis; Leg; Lichenoid Eruptions; Protein Precursors; Syndrome

The present study was conducted to determine the patterns of immunohistochemical characterization of keratin (K) and involucrin in solar keratosis and Bowen's disease in order to clarify the abnormal differentiation or maturation of the tumor cells in these precancerous epithelial dermatoses. Seventeen human anti-cytokeratin antibodies and an anti-involucrin antibody were used to examine 15 cases of solar keratosis and 18 cases of Bowen's disease. Formalin-fixed and paraffin-embedded sections were stained with these antibodies by the avidin-biotin-peroxidase technique. In solar keratosis, keratin and involucrin distribution was similar to that in normal epidermis, whereas in Bowen's disease the keratin distribution varied among individual cases. The dyskeratotic cells in Bowen's disease showed a reduction or loss of staining with these antibodies, and they were occasionally positive for keratin 19. These observations suggest that there is a difference in keratin and involucrin expression between solar keratosis and Bowen's disease and that the atypical cells of Bowen's disease exhibit a diversity of differentiation.

Topics: Aged; Aged, 80 and over; Bowen's Disease; Cell Differentiation; Cellular Senescence; Epidermis; Female; Fixatives; Formaldehyde; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Keratosis; Male; Middle Aged; Paraffin Embedding; Precancerous Conditions; Protein Precursors; Skin Neoplasms; Sunlight

Porokeratoses are known to give rise to squamous and basal cell carcinomas. In this study, we examined 15 lesions of porokeratosis immunohistochemically for evidence of aberrant keratinization using several markers of keratinocyte (KC) maturation and differentiation, including involucrin, filaggrin, cytokeratins, and the growth activation marker psi-3. The staining patterns obtained were compared with several non-premalignant parakeratotic skin lesions including psoriasis, pityriasis rosea, pityriasis rubra pilaris, irritated seborrheic keratosis, atopic dermatitis, seborrheic dermatitis, and verruca vulgaris. The centers of porokeratoses stained in a pattern identical to that observed in other premalignant keratinocytic lesions including actinic keratoses, recessive dystrophic epidermolysis bullosa, and nonhealing wounds. KCs beneath the cornoid lamella (CL) stained in a pattern similar to that observed in squamous cell carcinomas. KCs peripheral to the CL in the epidermis showed a normal staining pattern. The control non-premalignant parakeratotic lesions displayed a variety of staining patterns, but none showed a pattern identical to that observed in porokeratosis. The failure of KCs in porokeratoses to mature and differentiate normally may be related to the increased incidence of carcinomas associated with these lesions.

Topics: Epidermis; Filaggrin Proteins; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratinocytes; Keratins; Keratosis; Protein Precursors; Skin Neoplasms

To elucidate the morphogenesis of cornoid lamellae (CL) in porokeratosis, skin lesions of three cases of disseminated superficial actinic porokeratosis and a case of linear porokeratosis were examined. By N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide staining, SH groups were present in the living layer of the epidermis beneath CL and irregularly disappeared at the bottom of CL, whereas SS linkages appeared in dyskeratotic cells in the living layer and in the irregularly shaped cell membranes of the horny cells. Epidermis beneath CL showed an increased and irregular involucrin expression. Ultrastructurally, the living keratinocytes contained many cytoplasmic vacuoles and had a smaller number of lamellar bodies than normal. Intercellular lamellar sheets were incompletely formed. The dyskeratotic cells and the lower horny cells contained many small vacuoles but formed a marginal band. The horny cells of CL also formed a marginal band and, further, a keratin pattern. CL may be formed by hyperproliferative atypical kertatinocytes which keratinize rapidly and irregularly and show defective desquamation due to the paucity of intercellular lamellar sheets.

Topics: Aged; Epidermis; Female; Histocytochemistry; Humans; Immunohistochemistry; Keratinocytes; Keratosis; Male; Maleimides; Microscopy, Electron; Morphogenesis; Protein Precursors; Sulfhydryl Compounds; Sulfur

While some cutaneous squamous cell carcinomas (SCC) arise from predisposing conditions such as burn scars, draining sinuses, and chronic, nonhealing wounds, the vast majority of these tumors arise from actinically damaged epidermis. It has been shown previously that keratinocytes within healing wounds show an "activated" immunophenotype when stained with antibodies to psi-3, involucrin, filaggrin, and cytokeratins. A similar pattern has been seen in keratinocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), in whom the incidence of cutaneous SCC is markedly increased. We tested the hypothesis that actinic keratoses (AK), recognized as precursors in the development of the majority of SCC, would show a similar activated immunophenotype when stained with the antibody panel described above. We examined 10 AK, biopsied from the facies and extremities of ten patients, ages 60 to 80, with antibodies to psi-3, involucrin, filaggrin, and AE1. All lesions examined had an immunostaining pattern indistinguishable from that seen in keratinocytes from patients with RDEB or within healing wounds. There was suprabasilar staining of keratinocytes with antibodies to psi-3 and AE1. Involucrin and filaggrin was expressed by all keratinocytes above the midstratum spinosum. Within the acrosyringia and acrotrichia, the staining pattern was that of the normal epidermis, i.e., AE1 staining of basal keratinocytes, granular layer staining of involucrin and filaggrin, and absence of psi-3 expression. These data suggest that an activated keratinocyte phenotype is a unifying feature in conditions which predispose to development of cutaneous SCC.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Epidermis; Female; Filaggrin Proteins; Humans; Intermediate Filament Proteins; Keratinocytes; Keratins; Keratosis; Male; Middle Aged; Phenotype; Precancerous Conditions; Protein Precursors; Skin Neoplasms; Sunburn

We have studied the expression of involucrin in a variety of keratinization disorders, mostly of genetic origin using an avidin-biotin-peroxidase technique. In normal human epidermis 25% of the living epidermis was labelled. The diseases studied fell into two groups. Diseases with greatly increased involucrin staining including collodion baby (38%), Darier's disease (49%), Flegel's disease (56%), erythrokeratoderma variabilis (60%), epidermal naevus with epidermolytic hyperkeratosis (45%) and congenital bullous (58%) and non-bullous (44%) ichythyosiform erythroderma; and diseases with normal or slightly increased staining, including ichthyosis vulgaris (27%), X-linked ichthyosis (25%), confluent and reticulate papillomatosis (27%) and simple epidermal naevus (28%). These results demonstrate that involucrin expression is altered in some keratinization disorders and suggest that in such conditions cellular functions other than keratin metabolism are also affected.

Topics: Humans; Keratosis; Protein Precursors; Skin

In humans, the skin is a particularly sensitive target for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and certain halogenated analogs. Reported lesions include a thickening of the epidermis (acanthosis), hyperkeratosis, and squamous metaplasia of the epithelial lining of the sebaceous glands. In this report we describe ongoing studies on the actions of TCDD on cultured human epidermal cells. This system has been established as an in vitro model for interfollicular epidermal hyperkeratinization. Treatment of newly confluent cultures with TCDD results in enhanced differentiation as judged by histologic examination of the cultures, a decrease in the number of basal proliferating cells, and an increase in the number of envelope competent (differentiating) cells and terminally differentiated cells with highly cross-linked cornified envelopes. Changes in the differentiation program are preceded by a decrease in epidermal growth factor (EGF) binding. The concentration dependence and stereospecificity for these responses suggest the involvement of the Ah receptor. We propose that TCDD modulates normal patterns of epidermal differentiation through direct actions on proliferating basal cells, modulating the responsiveness of these cells to growth factors such as EGF.

Topics: Cell Differentiation; Cell Line; Cells, Cultured; Clone Cells; Dioxins; Epidermal Cells; Epidermal Growth Factor; Epidermis; Humans; Keratins; Keratosis; Male; Polychlorinated Dibenzodioxins; Protein Precursors; Receptors, Aryl Hydrocarbon; Receptors, Drug

Lesions of solar keratoses and squamous cell carcinoma maintained their histological appearance and an increased tritiated thymidine autoradiographic labelling index after being grafted on to nude mice. However, the values for their mean epidermal thickness and individual cell size appeared to decrease slightly during the 24-week period of study. As judged by the immunolocalization of involucrin antibodies, the grafts maintained a human epidermal antigenic profile. However, immunolocalization studies with HLA antibodies showed only a patchy positivity in the original premalignant lesions and were negative after grafting. These results indicate the potential value of the nude mouse as a model for studying the progress of premalignant and malignant skin lesions in an immunologically privileged non-human site and further indicate that solar keratoses can be maintained independently of systemic donor influences.

Topics: Animals; Antibodies; Carcinoma, Squamous Cell; Female; HLA Antigens; Keratosis; Mice; Mice, Nude; Neoplasm Transplantation; Precancerous Conditions; Protein Precursors; Skin Neoplasms; Thymidine