Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction

Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.

Oligodendrocyte Lineage Marker Expression in eGFP-GFAP Transgenic Mice

Oligodendrocytes, the myelinating cells of the central nervous system, orchestrate several key cellular functions in the brain and spinal cord, including axon insulation, energy transfer to neurons, and, eventually, modulation of immune responses. There is growing interest for obtaining reliable markers that can specifically label oligodendroglia and their progeny. In many studies, anti-CC1 antibodies, presumably recognizing the protein adenomatous polyposis coli (APC), are used to label mature, myelinating oligodendrocytes. However, it has been discussed whether anti-CC1 antibodies could recognize as well, under pathological conditions, other cell populations, particularly astrocytes. In this study, we used transgenic mice in which astrocytes are labeled by the enhanced green fluorescent protein (eGFP) under the control of the human glial fibrillary acidic protein (GFAP) promoter. By detailed co-localization studies we were able to demonstrate that a significant proportion of eGFP-expressing cells co-express markers of the oligodendrocyte lineage, such as the transcription factor Oligodendrocyte Transcription Factor 2 (OLIG2); the NG2 proteoglycan, also known as chrondroitin sulfate proteoglycan 4 (CSPG4); or APC. The current finding that the GFAP promoter drives transgene expression in cells of the oligodendrocyte lineage should be considered when interpreting results from co-localization studies.