A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1a protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1a protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1a-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1a protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1a protein-dependent manner. In addition, pretreatment of cells with propranolol, a b-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1a protein amount by NE in all of the tested cancer cells. However, treatment with the a1-AR blocker prazosin inhibited NE-induced HIF-1a protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1a protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.Researchers have shown that stress and other behavioral conditions are involved in cancer progression.

Abstract. Histone deacetylases (HDAcs) are associated with the development and progression of cancer, but it is not known which of the HDAc isoforms play important roles in breast cancer metastasis. This study identified the specific HDAC isoforms that are necessary for invasion and/or migration in human breast cancer cell lines. MDA-MB-231 cells were significantly more invasive and expressed higher levels of matrix metalloproteinase-9 (MMp-9) compared to McF-7 cells. We compared the expression of HDAc isoforms between McF-7 and MDA-MB-231 cells and found greater expression of HDAc4, 6 and 8 in MDA-MB-231 cells by rt-pcr and Western blot analyses. In addition, apicidin, a histone deacetylase inhibitor, was shown to attenuate the invasion, migration and MMP-9 expression in MDA-MB-231 cells. Using specific sirnAs directed against HDAc1, 4, 6 and 8, we show that inhibition of HDAc1, 6 and 8, but not HDAc4, are responsible for invasion and MMp-9 expression in MDA-MB-231 cells. We analyzed the invasiveness of McF-7 cells overexpressing HDAc1, 4, 6 or 8 and found that overexpression of HDAc1, 6 or 8 increased invasion and MMp-9 expression. By developing HDAc isoforms as potential biomarkers for breast cancer metastasis, the present study can be extended to developing therapies for breast cancer invasion.

Purpose: Lysophosphatidic acid (LPA) plays an important role in mediating cell proliferation, survival, and tumor invasion and angiogenesis. This bioactive phospholipid at the concentration in ascitic fluid stimulates the growth of malignant ovarian tumors by increasing the expression of vascular endothelial growth factor (VEGF). In the present study, we investigated whether LPA activates hypoxia inducible factor-1 (HIF-1), a key transcriptional complex in tumor progression and metastasis, thereby increasing the expression of VEGF. Experimental Design: Immunoblotting, reverse transcription-PCR, ELISA, immunofluorescence, and chromatin immunoprecipitation assay were used to examine the expression of VEGF and HIF-1α in various cancer cells. Specific HIF-1α small interfering RNA was transfected to various cancer cells to determine the role of HIF-1α in LPA-induced VEGF expression. Results: LPA induced expressions of VEGF and HIF-1α in OVCAR-3, CAOV-3, PC-3, and SK-Hep1 cells but not in SKOV-3 and Hep-3B cells. In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen-activated protein kinase pathways were required for LPA-induced HIF-1α and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells. Immunofluorescence microscopy assay showed translocation of HIF-1α to nucleus by LPA, and chromatin immunoprecipitation assay revealed the binding of HIF-1α to the promoter of VEGF by LPA. Importantly, we found that small interfering RNA–induced reduction of HIF-1α expression significantly attenuated VEGF expression by LPA. Conclusions: Our results show for the first time that LPA induces VEGF via HIF-1α activation and reveal a critical role of HIF-1α in LPA-induced cancer cell proliferation and angiogenesis.

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Periostin (POSTN) interacts with multiple integrins to coordinate a variety of cellular processes, including epithelial-to-mesenchymal transition (EMT) and cell migration. In our previous study, anti-vascular endothelial growth factor A (VEGF-A) therapy was associated with resistance and EMT. The present study sought to determine the role of POSTN in the resistance of glioma stem cells (GSCs) to antiangiogenic therapy. In mouse xenograft models of human glioma, POSTN expression was associated with acquired resistance to anti-VEGF-A therapy and had a synergistic effect with bevacizumab in prolonging survival and decreasing tumor volume. Resistance to anti-VEGF-A therapy regulated by POSTN was associated with increased expression of transforming growth factor beta-1 (TGF beta1) and hypoxia-inducible factor-1 alpha (HIF1 alpha) in GSCs. At the molecular level, POSTN regulated invasion and expression of EMT (caveolin-1) and angiogenesis-related genes (HIF1 alpha and VEGF-A) through activation of signal transducer and activator of transcription 3 (STAT3). Moreover, recombinant POSTN increased GSC invasion. Collectively, our findings suggest that POSTN plays an important role in glioma invasion and resistance to antiangiogenic therapy.