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San Diego, CA, United States

Slattum G.,University of Utah | Gu Y.,University of Utah | Sabbadini R.,LPATH | Rosenblatt J.,University of Utah
Current Biology

SummaryBackground To maintain a protective barrier, epithelia extrude cells destined to die by contracting a band of actin and myosin. Although extrusion can remove cells triggered to die by apoptotic stimuli, to maintain constant cell numbers, epithelia extrude live cells, which later die by anoikis. Because transformed cells may override anoikis and survive after extrusion, the direction of extrusion has important consequences for the extruded cell's fate. As most cells extrude apically, they are typically eliminated through the lumen; however, cells with upregulated survival signals that extrude basally could potentially invade the underlying tissue and migrate to other sites in the body. Results We found that oncogenic K-Ras cells predominantly extrude basally, rather than apically, in a cell-autonomous manner and can survive and proliferate after extrusion. Expression of K-RasV12 downregulates the bioactive lipid sphingosine 1-phosphate (S1P) and its receptor S1P2, both of which are required for apical extrusion. Surprisingly, the S1P biosynthetic pathway is not affected because the S1P precursor, sphingosine kinase, and the degradative enzymes S1P lyase and S1PP phosphatase are not significantly altered. Instead, we found that high levels of autophagy in extruding RasV12 cells leads to S1P degradation. Disruption of autophagy chemically or genetically in K-RasV12 cells rescues S1P localization and apical extrusion. Conclusions Oncogenic K-Ras cells downregulate both S1P and its receptor S1P2 to promote basal extrusion. Because live basally extruding cells can survive and proliferate after extrusion, we propose that basal cell extrusion provides a novel mechanism for cells to exit the epithelium and initiate invasion into the surrounding tissues. © 2014 Elsevier Ltd. Source

The present invention relates to use of anti-S1P agents, for example, humanized monoclonal antibodies, for prevention and/or treatment of pain, including neuropathic pain, hyperalgesia, allodynia, and chemotherapy-induced pain.

Compositions and methods for producing monoclonal antibodies and their derivatives reactive against bioactive lipid targets are described. These compositions include derivatized lipids, each of which comprises a bioactive lipid that having a polar head group and at least one hydrocarbon chain (e.g., a lysolipid such as lysophosphatidic acid or sphingosine-1-phosphate) in which a carbon atom has been derivatized with a pendant reactive group; immunogens made by linking a derivatized lipid to a carrier moiety (e.g., a carrier protein, polyethylene glycol, colloidal gold, alginate, or a silicone bead); monoclonal antibodies and derivatives produced by immunizing an animal with such an immunogen; and therapeutic and diagnostic compositions containing such antibodies and antibody derivatives. Methods for making such derivatized lipids, immunogens, and monoclonal antibodies and derivatives, methods for detecting such antibodies once generated, and therapeutic and diagnostic methods for using such antibodies and derivatives, are also described.

Methods are provided for increasing neuronal differentiation of neuronal stem cells using antibodies that bind lysophosphatidic acid (LPA). Particularly preferred antibodies to LPA are monoclonal antibodies, including humanized monoclonal antibodies to LPA. Such antibodies, and derivatives and variants thereof, can be used in increasing neuronal differentiation, and in treatment and/or prevention of injuries, diseases, or conditions associated with insufficient neuronal differentiation and/or with elevated LPA levels in neural tissues.

The present invention relates to methods that involve administration of an anti-S1 P antibody or antibody fragment or derivative to a subject having or suspected of having an ocular disease or condition, including one involving choroidal neovascularization, in order to achieve a desired effect. Such effects include reducing the size of a choroidal neovascularization lesion in the eye, decreasing or resolving retinal pigment epithelial detachment, decreasing central retinal lesion thickness, and preserving or improving visual acuity. Pharmaceutical compositions comprising an anti-S1 P antibody for ocular administration are also provided. The compositions and methods are particularly useful for treating subjects having age-related macular degeneration, particularly exudative or wet age-related macular degeneration.

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