BackgroundRecent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models.Principal FindingsWe report that chemotherapeutic drug doxorubicin activates TGFβ signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TβR1-KI was administered in combination with doxorubicin.ConclusionsThese observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.

Transforming growth factor-B (TGF-B) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-B type I receptor kinase inhibitor (TBRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TBRI-I had no effect on their growth but blocked TGF-B-stimulated expression of integrin A v B 3 and cell migration in vitro. Systemic administration of the TBRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TBRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by wholebody EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TBRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-B signaling by systemic administration of the TBRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TBRI-I. (Cancer Res 2006; 66(13): 6714-21)

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Insulin-like growth factor-I (IGF-I) may play an important role in the development of renal hypertrophy. In this study we determined the effect of IGF-I on cultured mesangial cells (MCs) and examined activation of key signaling pathways. IGF-I induced hypertrophy as determined by an increase in cell size and an increase in protein to DNA ratio and increased accumulation of extracellular matrix (ECM) proteins. IGF-I also activated both Erk1/Erk2 MAPK and phosphatidylinositol 3-kinase (PI3K) in MCs. Inhibition of either MAPK or PI3K, however, had no effect on IGF-I-induced hypertrophy or ECM production. Next, we examined the effect of IGF-I on activation of the calcium-dependent phosphatase calcineurin. IGF-I treatment stimulated calcineurin activity and increased the protein levels of calcineurin and the calcineurin binding protein, calmodulin. Cyclosporin A, an inhibitor of calcineurin, blocked both IGF-I-mediated hypertrophy and up-regulation of ECM. In addition, calcineurin resulted in sustained Akt activation, indicating possible cross-talk with other signaling pathways. Finally, IGF-I treatment resulted in the calcineurindependent nuclear localization of NFATc1. Therefore, IGF-I induces hypertrophy and increases ECM accumulation in MCs. IGF-I-mediated hypertrophy is associated with activation of Erk1/Erk2 MAPK and PI3K but does not require either of these pathways. Instead, IGF-I mediates hypertrophy via a calcineurin-dependent pathway.In response to stress or injury, kidney tissue undergoes hypertrophy, and to a lesser extent hyperplasia, resulting in a net gain in the size of the kidney. Glomeruli, the filtering microvascular structures, are particularly susceptible to hypertrophy, which eventuates in fibrosis. At the cellular level, hypertrophy is characterized by cessation of the cell cycle at G 1 , a halt in DNA synthesis, and continued production and/or decreased degradation of cellular proteins (1). The net result is an increase in protein concentration disproportionate to DNA and an increase in the overall size of the cell. In addition to the increase in cell size, expansion of the extracellular matrix (ECM), 1 including fibronectin and collagen type IV, contributes to tissue hypertrophy. Studies in humans and in animal models of renal hypertrophy indicate that early hypertrophy and ECM accumulation are potentially reversible (2). Therefore, understanding the mechanisms that are required for the induction and maintenance of hypertrophy and ECM accumulation by growth factors, hormones, and cytokines may be critical for developing therapies that prevent or reverse renal hypertrophy. The insulin-like growth factor (IGF) system has been implicated in glomerular hypertrophy. In patients with type I diabetes, elevated amounts of IGF-I in the urine are associated with hypertrophy and progression of kidney disease (3). Moreover, endogenous kidney IGF-I levels are elevated within 2-3 days of streptozotocin-induced type I diabetes in rats (4, 5) and IGF-I receptor is up-regulated after prolonged hyperglycemia ...

BackgroundSpontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with the high mortality twofold to sixfold higher than that for ischemic stroke. But the treatment of haematomas within the basal ganglia continues to be a matter of debate among neurologists and neurosurgeons. The purpose of this study is to judge the clinical value of minimally invasive stereotactic puncture therapy (MISPT) on acute ICH.MethodsA prospective controlled study was undertaken. The clinical trial was in compliance with the WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. According to the enrollment criterion, there were 168 acute ICH cases analyzed, of which 90 cases were performed by MISPT ( MISPT group, MG) and 78 cases by Conventional craniotomy (CC group, CG), by means of compare of Glasgow Coma Scale(GCS) score, postoperative complications(PC) and rebleeding incidence(RI), moreover, long-term outcome of 1 year postoperation judged by Glasgow Outcome Scale (GOS), Barthel Index (BI), modified Rankin Scale (mRS) and case fatality(CF).ResultsMG patients showed obvious amelioration in GCS score compared with that of CG. The total incidence of PC in MG decreased obviously compared with that of CG. The incidences of rebleeding in MG and CG were 10.0% and 15.4% respectively. There was no obvious difference between CFs of MG and CG. For three parameters representing long-term outcome, the GOS, BI and mRS in MG were ameliorated significantly than that of CG.ConclusionThese data suggested that the advantage of MISPT was displayed in minute trauma and safety, and seemed to be feasible and to had a trend towards improved long-term outcome.Trial RegistrationThe Australian New Zealand Clinical Trials Registry (ANZCTR), the registration number:ACTRN12610000945022.