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ABSTRACT: Breast tumors expressing no detectable FGFs (MCF-7) were compared with tumors transfected with FGF4 or FGF1 (FGF4/MCF-7 or FGF1/MCF-7), and with MDA-MB-435, which produce endogenous FGF2. Tumor blood flow was measured by 133Xe diffusion, oxygen distribution was measured by Eppendorf pO2 histography, and vascular density was measured by CD31 staining. Tumors that overexpress angiogenic factors grew at a rate far exceeding that of MCF-7. The FGF producing tumors also had much higher metastatic rates to lung. Tumor blood flow was significantly higher in the two FGF-transfected xenografts compared with the parent MCF7. Median tumor pO2 was also higher, and tumor oxygenation was preserved even for large tumors. The vascular density as determined by CD31 staining, however, was not markedly increased in tumors overexpressing angiogenic factors. We found that angiogenic factors preserve and augment neovascular function, thus facilitating tumor growth and progression.
Advances in experimental medicine and biology 02/2003; 530:593-601. · 1.09 Impact Factor
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ABSTRACT: Isotransplants of murine fibrosarcoma (KHT) cells were inoculated i.m. into the hind limbs of 6-8 week-old female C3H/HeJ mice. Intratumoral injection of FGF1 or VEGF proteins decreased hypoxic marker uptake in murine fibrosarcoma KHT. Reduction of tumor hypoxia did not correlate with mRNA expression of transcription factors in tumors. Likewise, there was no significant alteration in either apoptotic frequency or the mRNA levels of 10 apoptotic-related molecules in FGF1- or VEGF-treated tumors. mRNA expression for MCP-1, IL-1 beta, IL-18, and IL-1Ra, however, were decreased in the tumors following FGF1 or VEGF treatment. Among the normal tissues tested (brain, kidney, liver, spleen, and lung), basal mRNA levels for cytokines and chemokines varied. Intratumoral injection of FGF1 or VEGF (6 daily intra-tumor injections of 6 micrograms/mouse) did not alter most cytokine or chemokine mRNA expression in spleen and lung. In summary, alteration of tumor oxygenation by local administration of angiogenic growth factors may be mediated by cytokine/chemokine production in the tumor.
Advances in experimental medicine and biology 02/2003; 530:603-9. · 1.09 Impact Factor
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ABSTRACT: RTP/DRG/Cap43/Rit42 gene is highly expressed in normal prostate cells, but is weakly expressed in prostate cancer cells. The inducible expression by hypoxia is low in normal prostate cells, but is significantly increased in prostate cancer cells. In this study, we report that radiation and various anti-androgens including hydroflutamide, Casodex, and cyproterone acetate greatly induce RTP/DRG/Cap43/Rit42 mRNA expression in a time- and dose- dependent manner. The effect is observed in both human breast tumor (MCF-7) and in prostate cancer cells (LNCaP), but not in cultured normal prostate epithelial cells. The in vitro growth rate of MCF-7 cells was markedly reduced after stable transfection of the Rit42 gene using a tetracycline-inducible system. A yeast two-hybrid study demonstrated that RTP/DRG/Cap43/Rit42 protein binds with cytochrome C oxidase VIb. In this work, RTP/DRG/Cap43/Rit42 gene expression was found to be induced by hypoxia, implying that its association with cytochrome C oxidases may play an important role in regulation of synthesis and consumption of ATP in tumors. Involvement of this gene in the control of cell growth and metabolism, as well as the high inducibility of the gene in tumor cells by hypoxia, radiation, or anti-androgens suggest that RTP/DRG/Cap43/Rit42 might be a novel stress response protein.
08/2002;
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ABSTRACT: Cutaneous fibrosis after breast cancer radiotherapy is unavoidable, progressive, and irreversible. Currently there is no satisfactory, preventive therapy to ameliorate this process. Overexpression of fibrogenic cytokine TGF beta has been associated with soft tissue fibrosis, and reduction of its production or activation can ameliorate radiation induced normal tissue toxicity. Decorin is a small, leucine-rich proteoglycan, and is thought to be a natural inhibitor of TCF beta. In this study, we investigated whether decorin can reduce or prevent radiation induced acute and chronic damage to cutaneous tissue in mouse model. We showed: (1) Inflammatory changes of the papillary dermis in several mouse strains occurred within two weeks of irradiation.
06/2002;
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ABSTRACT: The effects of angiogenic growth factors on the growth, vascular architecture and the downstream cytokine signaling of sarcomas are unknown. These are of potential great importance since sarcoma, like endothelium, is of mesodermal origin and therefore could grow in response to these factors. Three human sarcomas (leiomyosarcoma SK-LMS-1, liposarcoma SW872 and fibrosarcoma SW684) and one murine fibrosarcoma (KHT) were grown in nude and C3H/He mice, respectively. Tumor structural vessels, perfused vessels and hypoxia were quantified immunohistochemically. Fast-growing murine KHT tumors had a markedly higher number of structural vessels compared with the human sarcomas. In both murine and human sarcomas, approximately half of the total structural vessels were perfused, and the numbers of perfused vessels decreased with increasing tumor volume. In vitro, basal mRNA expression of several angiogenic growth factors and their receptors differed between two of the human sarcoma cell lines, SK-LMS-1 and SW872. Compared with SK-LMS-1, untreated SW872 cells had higher levels of mRNA expression for FGF11, FGF14, angiopoietin, CD105 and VEGFR1. Two sarcoma cell lines were also treated with 10 ng/ml of six angiogenic growth factors (FGF1, FGF2, FGF7, FGF10, VEGF and SCF) for 24 h, and mRNA expression of endogenous FGF family members (FGF1, FGF2, FGF10, FGF11, FGF13 and FGF14) were quantitatively measured using RNase protection at various times following treatments. Again, SW872 cells were more responsive to exogenous growth factor treatment compared with SK-LMS-1 cells in terms of the elevation of endogenous FGF mRNA expression. In the SW872 cells, all of the exogenous angiogenic growth factor treatments, except for VEGF, upregulated endogenous FGF1, FGF2 and FGF14 mRNA expression. The SK-LMS-1 cells, in contrast, only responded to exogenous FGF1, FGF7 and FGF10, but did not respond to VEGF.
Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology 06/2002; 132(1):17-25. · 2.23 Impact Factor
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ABSTRACT: Rheumatoid arthritis is a prevalent example of an inflammatory angiogenic disease, which is mediated by pro-inflammatory and pro-angiogenic cytokines such as tumor necrosis factor (TNF). To evaluate the effect of the potent anti-angiogenic factor endostatin on TNF-induced inflammatory arthritis, we injected an endostatin-expressing lentiviral vector directly into the joints of human TNF-transgenic mice before the onset of disease. Histological analysis of the injected joints 8 weeks later revealed that endostatin reduced blood vessel density within the synovial tissues and an overall mean arthritis index. In vitro and in vivo examination of the potential mechanism by which endostatin inhibited the arthritis revealed that endostatin blocks TNF-induced activation of JNK and JNK-dependent pro-angiogenic gene expression. These data suggest a novel mechanism by which endostatin inhibits angiogenesis, and demonstrates the potential utility of anti-angiogenic gene therapy for treatment of inflammatory arthritis.
Molecular Therapy 06/2002; 5(5 Pt 1):547-54. · 6.87 Impact Factor
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ABSTRACT: Radiation pneumonitis is a distinct clinical entity that differs from other pulmonary symptoms such as allergic pneumonitis, chemical pneumonitis, or pneumonia by various infectious agents. Recent research has supported the mechanism of cellular interaction between lung parenchymal cells and circulating immune cells mediated through a variety of cytokines including proinflammatory cytokines, chemokines, adhesion molecules, and profibrotic cytokines. Identifying reliable biomarkers for radiation pneumonitis will allow us to identify individuals at risk for pneumonitis before or during the early stage of therapy. Prospective blood sampling, scoring of respiratory symptoms, and chest imaging were conducted for patients receiving thoracic radiotherapy for malignancy. Serial plasma specimens were analyzed for circulating cytokine changes before, during, and up to 12 weeks after radiation. Radiation pneumonitis was diagnosed using National Cancer Institute (NCI) common toxicity criteria. Cytokine analysis was assayed for interleukin 1alpha (IL-1alpha), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), E-selectin, L-selectin, transforming growth factor beta1 (TGF-beta1), and basic fibroblast growth factor (bFGF) using enzyme linked immmunosorbant assay (ELISA). Twenty-four patients had clinical follow-up longer than 12 months after radiotherapy. Thirteen had symptomatic pneumonitis (NCI grade 2). The peak incidence of symptoms was between 6 and 13 weeks after radiotherapy. Six patients had only radiographic infiltrates (NCI grade 1). Five patients did not have clinical or radiographic pneumonitis. Both IL-1alpha and IL-6 levels were significantly higher before, during, and after radiotherapy for those who had pneumonitis. The pattern of changes of MCP-1, E-selectin, L-selectin, TGF-beta1, and bFGF varied, but none of these cytokines correlated with radiation pneumonitis. Analysis of a panel of circulating cytokines with different putative functions in radiation pulmonary injury identified IL-1alpha and IL-6 as early circulating cytokine markers for radiation pneumonitis.
Seminars in Radiation Onchology 02/2002; 12(1 Suppl 1):26-33. · 4.03 Impact Factor
