involucrin and Neoplasms

Clinical and experimental experience indicate that differentiation and malignancy are inversely correlated. However, more recent experimental studies using mouse and human keratinocyte systems have demonstrated that complete or even substantial loss in overall epithelial differentiation is not a prerequisite for malignant growth of cancer cells. Major defects in differentiation are also not a prerequisite for premalignant stages, in particular for cell immortalization, which is considered an early and essential step in the transformation process. Moreover, progressive dedifferentiation, often associated with advanced tumor stages, is also found in immortalized cell lines which are, however, nontumorigenic. On the other hand, malignant cell lines may have maintained a high degree of their normal differentiation program and sensitivity to differentiation modulators. However, to date no transformed keratinocyte cell lines with completely normal differentiation have been observed. Since epidermal keratinization is a very complex process involving many different parameters and is fully expressed only under in vivo conditions, an exact and quantitative comparison of such ill-defined phenomena (differentiation and malignancy) is still problematic. Obviously, both phenomena are under separate control and not causally linked. Nevertheless, a better understanding of factors and mechanisms regulating differentiation and of their disturbance in carcinogenesis would offer new possibilities to design novel tumor therapeutic strategies in the field of differentiation therapy.

Topics: Biomarkers; Carcinoma, Squamous Cell; Cell Differentiation; Cell Survival; Cell Transformation, Neoplastic; Disease Progression; Epidermal Cells; Epithelial Cells; Humans; Keratins; Neoplasm Proteins; Neoplasms; Protein Precursors; Skin Neoplasms; Tumor Cells, Cultured

We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity neurotrophin receptor p75(NTR) and differentially expressed cell adhesion molecules, the beta1 and beta4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the p75(NTR)-positive cell subset is immature relative to the other predominant subpopulations coexpressing beta1 integrin at higher levels. The p75(NTR)-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the p75(NTR)-positive cell subset. These findings strongly implicate p75(NTR) as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Adhesion; Cell Cycle; Cell Division; Cell Membrane; Cell Transformation, Neoplastic; Epithelial Cells; Epithelium; Esophagus; Flow Cytometry; Humans; Immunohistochemistry; Integrin beta1; Integrin beta4; Keratinocytes; Keratins; Neoplasms; Phenotype; Propidium; Protein Precursors; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Subcellular Fractions; Time Factors

When malignant human cells are crossed with diploid human keratinocytes, malignancy, as defined by progressive growth in vivo, is suppressed so long as the hybrid cells continue to produce involucrin, a protein that characterizes terminal differentiation in the keratinocyte. When, on continued cultivation in vitro, the cells lose the ability to produce involucrin, they reacquire the ability to grow progressively in the animal.

Topics: Cell Division; Cell Line; Electrophoresis, Polyacrylamide Gel; Epidermal Cells; Epidermis; Humans; Hybrid Cells; Immunoenzyme Techniques; Keratins; Neoplasms; Protein Precursors

Involucrin is a soluble protein precursor of the cross-linked envelope present in the submembranous zone of human stratum corneum, and subsequently demonstrated in stratified squamous epithelia. The immunoperoxidase technique was used to assess the distribution of involucrin in 107 normal and 318 abnormal tissues. With few exceptions, involucrin was restricted to squamous epithelia, urothelium, some skin appendages and thymic Hassall's corpuscles. In normal squamous epithelium and normal urothelium, staining was most intense in the superficial layers where it was concentrated at the cell periphery and gradually decreased toward the basal layer. This orderly staining pattern was maintained in benign squamous and urothelial lesions and in grade I papillary urothelial carcinomas. Higher grade papillary urothelial carcinomas, infiltrating urothelial and squamous carcinomas, and in situ urothelial and squamous carcinomas demonstrated abnormal staining patterns for involucrin that are described. Foci of squamous differentiation in adenocarcinomas and other epithelial malignancies stained intensely for involucrin. Brenner tumours of the ovary and Walthard rests of the fallopian tube, lesions of uncertain histogenesis but possibly urothelial-related, also stained for involucrin. Results of this study suggest that involucrin is a sensitive and specific marker for squamous and urothelial differentiation, staining patterns for involucrin may be helpful in distinguishing benign from malignant urothelial and squamous lesions, and presence of involucrin may be helpful in determining the histogenesis of selected lesions.

Topics: Carcinoma in Situ; Carcinoma, Squamous Cell; Cell Differentiation; Cell Transformation, Neoplastic; Epithelium; Humans; Immunoenzyme Techniques; Neoplasms; Protein Precursors; Urinary Bladder Neoplasms

Topics: Antibodies, Monoclonal; Cytological Techniques; Cytoskeletal Proteins; Cytoskeleton; Desmoplakins; Desmosomes; Humans; Immunologic Techniques; Membrane Proteins; Molecular Weight; Neoplasms; Protein Precursors