The Journal of pathology
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The Journal of pathology · Mar 2006
ReviewRole of the ephrin and Eph receptor tyrosine kinase families in angiogenesis and development of the cardiovascular system.
Angiogenesis is a highly complex orchestrated process that plays a critical role in normal development and in the pathophysiology of multiple disease processes, including tumour neovascularization, ischaemic recovery, and wound healing. In recent years there has been a resurgence of interest in Eph receptors and their ligands, ephrins, as their participation in vasculogenesis and angiogenesis has become apparent. The Eph receptor family is the largest family of receptor tyrosine kinases identified to date. ⋯ These include vascular development, tissue-border formation, cell migration, axon guidance, and synaptic plasticity. The role of Eph receptors and ephrins in the processes of development of the cardiovascular system, angiogenesis, and vascular remodelling has been the subject of intense investigation since they were first identified in 1987. This review addresses the role of this new growth factor receptor tyrosine kinase family in those processes and provides new insights into the way in which Eph receptors and ephrin ligands modulate the angiogenic response and participate in vascular remodelling and vascular boundary formation during development of the cardiovascular system and vascularization of cancer.
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The Journal of pathology · Jan 2006
ReviewViral gene therapy strategies: from basic science to clinical application.
A major impediment to the successful application of gene therapy for the treatment of a range of diseases is not a paucity of therapeutic genes, but the lack of an efficient non-toxic gene delivery system. Having evolved to deliver their genes to target cells, viruses are currently the most effective means of gene delivery and can be manipulated to express therapeutic genes or to replicate specifically in certain cells. Gene therapy is being developed for a range of diseases including inherited monogenic disorders and cardiovascular disease, but it is in the treatment of cancer that this approach has been most evident, resulting in the recent licensing of a gene therapy for the routine treatment of head and neck cancer in China. ⋯ Paramount is the safety of these virus vectors and a greater understanding of the virus-host interaction is key to optimizing the use of these vectors for routine clinical use. Recent developments in the modification of the virus coat allow more targeted approaches and herald the advent of systemic delivery of therapeutic viruses. In the context of cancer, the ability of attenuated viruses to replicate specifically in tumour cells has already yielded some impressive results in clinical trials and bodes well for the future of this approach, particularly when combined with more traditional anti-cancer therapies.
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The Journal of pathology · May 2005
Epidermis promotes dermal fibrosis: role in the pathogenesis of hypertrophic scars.
Hypertrophic scarring is a pathological process characterized by fibroblastic hyperproliferation and by excessive deposition of extracellular matrix components. It has been hypothesized that abnormalities in epidermal-dermal crosstalk explain this pathology. To test this hypothesis, a tissue-engineered model of self-assembled reconstructed skin was used in this study to mimic interactions between dermal and epidermal cells in normal or pathological skin. ⋯ These results correlated with collagen and MMP-1 secretion and with cell proliferation, which were increased when keratinocytes were added, except for the collagen secretion of Hmyo and Fb in the presence of NK. The level of dermal apoptosis was not different when epidermis was added to the dermis (<1% in each category). These observations strongly suggest that hypertrophic scar keratinocytes play a role in the development of pathological fibrosis by influencing the behaviour of dermal cells.
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The Journal of pathology · Mar 2005
Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR.
The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) alpha and beta and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. ⋯ Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.