PubMed · 14645343
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A C Y Li, R P H Thompson. 2003. Basement membrane components.. https://doi.org/10.1136/jcp.56.12.885
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Human breast epithelium and the stroma are separated by a layer of myoepithelial (ME) cells and basement membrane, whose disruption is a prerequisite for tumor invasion. The dissolution of the basement membrane is traditionally attributed primarily to an over-production of proteolytic enzymes by the tumor or the surrounding stromal cells. The results from matrix metalloproteinase inhibitor clinical trials, however, suggest that this "protease-centered" hypothesis is inadequate to completely reflect the molecular mechanisms of tumor invasion. The causes and signs of ME cell layer disruption are currently under-explored. Our studies revealed that a subset of pre- and micro-invasive tumors contained focal disruptions in the ME cell layers. These disruptions were associated with immunohistochemical and genetic alterations in the overlying tumor cells, including the loss of estrogen receptor expression, a higher frequency of loss of heterozygosity, and a higher expression of cell cycle, angiogenesis, and invasion-related genes. Focal ME layer disruptions were also associated with a higher rate of epithelial proliferation and leukocyte infiltration. We propose the novel hypothesis that a localized death of ME cells and immunoreactions that accompany an external environmental insult or internal genetic alterations are triggering factors for ME layer disruptions, basement membrane degradation, and subsequent tumor progression and invasion.
Epidermolysis bullosa (EB), a heterogenous group of genodermatoses, is characterized by fragility and blistering of the skin associated with extracutaneous manifestations. Based on clinical severity, constellation of the phenotypic manifestations, and the level of tissue separation within the cutaneous basement membrane zone (BMZ), EB has been divided into distinct subcategories. Traditionally, these include the simplex, junctional, and dystrophic forms of EB, and recently attention has been drawn to hemidesmosomal variants demonstrating tissue separation at the level of the hemidesmosomes. Specific mutations in ten distinct genes expressed within the cutaneous BMZ have been delineated in >500 families with different variants of EB. The types of mutations, their positions along the affected genes, and their consequences at the mRNA and protein levels provide explanation for the phenotypic variability and genetic heterogeneity of this group of genodermatoses. Elucidation of mutations in different forms of EB has direct translational applications for improved diagnosis and molecularly based classification with prognostic implications as well as for genetic counseling and DNA-based prenatal testing in families with EB.
Hindered convection of macromolecules in gels was studied by measuring the sieving coefficient (theta) of narrow fractions of Ficoll (Stokes-Einstein radius, r(s) = 2.7-5.9 nm) in agarose and agarose-dextran membranes, along with the Darcy permeability (kappa). To provide a wide range of kappa, varying amounts of dextran (volume fractions < or = 0.011) were covalently attached to agarose gels with volume fractions of 0.040 or 0.080. As expected, theta decreased with increasing r(s) or with increasing concentrations of either agarose or dextran. For each molecular size, theta plotted as a function of kappa fell on a single curve for all gel compositions studied. The dependence of theta on kappa and r(s) was predicted well by a hydrodynamic theory based on flow normal to the axes of equally spaced, parallel fibers. Values of the convective hindrance factor (K(c), the ratio of solute to fluid velocity), calculated from Theta and previous equilibrium partitioning data, were unexpectedly large; although K(c) < or = 1.1 in the fiber theory, its apparent value ranged generally from 1.5 to 3. This seemingly anomalous result was explained on the basis of membrane heterogeneity. Convective hindrances in the synthetic gels were quite similar to those in glomerular basement membrane, when compared on the basis of similar solid volume fractions and values of kappa. Overall, the results suggest that convective hindrances can be predicted fairly well from a knowledge of kappa, even in synthetic or biological gels of complex composition.