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| December 2004 | Inside IOVS | Volume 45/12 |
EpCAM as a Novel Molecular Target in Retinoblastoma
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein overexpressed in a number of cancers. Krishnakumar et al. (p. 4247) investigated the expression of EpCAM in retinoblastoma and found that it was significantly higher in invasive and poorly differentiated tumors. Their findings have potential clinical applications, as anti-EpCAM antibodies may be included in the treatment of retinoblastoma. EpCAM, as a tumor associated antigen (TAA), could be used as a target in immunotherapy using bispecific antibody (BiAb). BiAbs redirect lysis by forming conjugates between cell-surface antigens on tumor cells (TAA) with the CD3-TCR on cytotoxic T lymphocytes (CTLs), hence overriding any MHC-restriction. These results open new possibilities for antibody-based therapies in retinoblastoma.
Novel Functions of CAP37, a Neutrophil Protein, on Corneal Epithelial Cells
CAP37, a molecule which is constitutively expressed in neutrophils, is a multifunctional protein important in the host response to infection and inflammation. It is a natural antibiotic with strong activity for many Gram-negative bacteria. Noteworthy is its potent regulation of host cells including monocytes, microglia and endothelial cells. Pereira et al. (p. 4284) describe a series of novel findings indicating that CAP37 modulates corneal epithelial cell proliferation, migration, and adhesion; three critical events in wound healing. The delineation of the mechanism of action of CAP37 on corneal epithelial cells may provide new insight into the regulation of corneal inflammation and healing.
Stimulation of MMPs by Hyperosmolarity via JNK
Matrix metalloproteinases (MMP) play a vital role in ocular surface inflammation. Li et al. (p. 4302) found that hyperosmotic stress activates the c-Jun NH2-terminal kinase (JNK1 and JNK2) stress-activated protein kinase pathway and stimulates expression and production of gelatinase MMP-9, collagenases MMP-1 and –13, and stromelysin MMP-3 in human corneal epithelial cells exposed to hyperosmolar media. SB202190, an inhibitor of the JNK pathway, and doxycycline, an agent used to treat MMP mediated ocular surface disease, inhibit these hyperosmolarity-induced MMP production and JNK activation. These findings may have relevance and therapeutic potential for stimulated MMPs by the elevated tear osmolarity in dry eye.
Digital Reconstruction of the Optic Nerve Head in Normal and Glaucoma Eyes
Burgoyne et al. (page 4388) produced digital 3D reconstructions of the normal and early glaucoma monkey ONH connective tissues. These demonstrate that at the earliest stage of glaucomatous damage, the connective tissues of the lamina cribrosa and neural canal wall are profoundly and permanently altered. These alterations likely represent connective tissue damage, which should make the ONH more susceptible to further damage at the same or even lower levels of IOP. Finite element models based on clinical 3D reconstructions such as these may eventually lead to a science for predicting the susceptibility of an individual ONH to a given level of IOP.
Ocular Surface Water Permeability in Living Mice
The roles of corneal and conjunctival aquaporins (AQPs 1, 3, and 5) in both membrane and whole tissue water permeation are determined. Levin and Verkman (p. 4423) introduced microperfusion and fluorescence techniques to make comparative measurements between wild-type mice and transgenic mice deficient in AQPs 1, 3, or 5. Both murine cornea and conjunctiva exhibited the capacity to efficiently transport fluid in response to osmotic gradients. The authors formulated a model of tear film ion composition that demonstrates how tear fluid replacement across the ocular surface can reduce tear fluid hyperosmolarity common to all forms of keratoconjunctivitis sicca.
Factors Associated with Poor Graft-Host Integration in Retinal Transplants
Poor graft-host integration is one of the problems limiting restoration of host visual function by transplantation of neural retina. Zhang et al. (p. 4440) examined factors influencing integration between abutting retinal pieces. Normal neural retinas derived from young GFP mice were subretinally transplanted to adult rd1 mice or placed flat or as aggregates overlapping the latter in an organ culture system. The results demonstrate that lack of integration between abutting retinas correlates with the accumulation of glial-associated inhibitory molecules (CD44 and neurocan) at the interface, and indicate that manipulation of the molecular environment at the retinal surfaces may improve graft-host integration.
The Fas-Mediated Apoptosis Pathway in Retinal Detachment
Zacks et al. (p. 4563) demonstrate the activation of the Fas-mediated apoptosis pathway and its relation to the intrinsic apoptosis pathway during retinal detachment. They further show that the inhibition of the Fas pathway results in decreased intrinsic pathway activity. This work suggests that there may be a direct site for inhibition of photoreceptor cell death in diseases where there is a component of retinal detachment (which includes exudative macular degeneration). This potential therapeutic target might allow for the preservation of retinal elements while the underlying disease is being treated with improved visual outcomes.
Protein Kinase CK2 and Retinal Neovascularization
Ljubimov et al. (p. 4583) show that a ubiquitous and pleiotropic protein kinase CK2 (formerly, casein kinase 2) plays a role in retinal angiogenesis and neovascularization. Inhibitors of CK2 decreased tube formation, proliferation, migration, and secondary sprouting of retinal endothelial cells. They were also able to counteract the action of four angiogenic growth factors in the above assays. In a mouse model of oxygen-induced retinopathy, specific CK2 inhibitors significantly reduced retinal neovascularization. This demonstration of CK2 involvement in angiogenesis indicates that CK2 inhibitors, many of which are plant-derived, may emerge as a new class of antiangiogenic agents.
Tumor Formation after Subretinal Engraftment of Embryonic Stem Cells in Mice
Embryonic stem (ES) cells from the preimplantation blastocyst are increasingly discussed as a cell source for the treatment of degenerative disorders including those of the retina. However, care has to be taken in carrying out these therapeutical approaches. Arnhold et al. (p. 4251) transplanted neurally selected ES cells into the subretinal space of wild type and rhodopsin knockout mice. This resulted in severe teratoma formation. Thus, their findings indicate that even a thorough selection procedure resulting in a nearly pure population of neural precursor cells cannot eliminate the risk of an ectopic differentiation and a consecutive tumor formation.
Characterizing Intraocular Pressure in Zebrafish
Link et al. (p. 4415) have established a servo-null based technique for measuring intraocular pressure (IOP) in zebrafish. In their analysis, multiple inbred strains were characterized, and a hypopigmented mutant with elevated IOP was identified. This work lays the foundation for studying the complex genetics of elevated intraocular pressure and its relationship to glaucoma within the genetically powerful zebrafish model.
Iris Pigment Epithelial Transplantation: A Treatment for Age-Related Macular Degeneration?
Combined choroidal new vessel removal and iris pigment epithelial cell (IPE) transplantation has been advocated as a treatment for age-related macular degeneration (AMD). Itaya et al. (p. 4520) examined the behavior of human IPE on aged submacular human Bruch's membrane in organ culture using scanning electron microscopy. They found that freshly harvested IPE were unable to attach and resurface Bruch's membrane. Cultured IPE resurfaced Bruch's membrane initially, but the cells were extremely flat with many cells dying. While cultured IPE grafts may be a better option for autologous transplantation, they may not be able to differentiate and survive long-term in AMD eyes.
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