Abstract-Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-␣ (PDGFR␣)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFR␣-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFR␣-p70S6K pathway is an essential regulator for FGF-2-mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.
Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of 'non-smoking-associated lung cancer'. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought 'non-smoking-associated lung cancer' into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or 'non-smoking-associated lung cancer', both clinical trials and investigations are needed.
Abstract-Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-␣ and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state.
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