Department of Neurology and Neuromuscular Disorders, Oita University Faculty of Medicine.

A 76-year-old woman developed weakness and sensory loss in the lower limbs and urinary disturbance in four days. She had a history of operation for the ascending colon cancer and lung metastasis one year ago. Neurological examination revealed flaccid paraplegia, absent Achilles tendon reflex, severe disturbance of superficial and deep sensation below the L3 level, and vesicorectal abnormality. Magnetic resonance imaging (MRI) studies showed an intramedullary T1-iso, T2-low lesion with Gd-DTPA contrast enhancement in conus medullaris at LI level. The laboratory examination revealed the elevated level of serum FDP. D-dimer and TAT. She was diagnosed as hematomyelia, which may be caused by the activation of coagulation and fibrinolysis system. We suggested that the ascending colon cancer and lung metastasis may contribute to the coagulation-fibrinolysis abnormality.

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Department of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan [2] 2ERATO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.

The adenomatous polyposis coli (APC) is a tumor suppressor whose loss of function leads to colon cancer. APC shuttles between the nucleus and cytoplasm, however its role in the nucleus remains elusive. We have found that nuclear APC specifically associates with transcriptionally active chromatin through structural elements located downstream to the region of frequent truncation mutations found in colorectal tumors. We show that a recombinant APC fragment comprising such elements associates in vivo with euchromatin and preferentially binds in vitro to acetylated histone H3. Induction of DNA double-strand breaks (DSB) stimulates accumulation of APC at the damaged DNA chromatin marked by histone H2AX and S139-phosphorylated histone H2AX. A nuclear complex containing the DNA-dependent protein kinase catalytic subunit (DNAPKcs) and APC associates with chromatin in response to DNA DSB. APC knockdown with siRNA decreased the rate of DNA DSB-induced S139 histone H2AX phosphorylation in cells expressing endogenous full-length APC, but not in colon cancer cells with its truncation mutants, whereas ectopic APC expression stimulated the H2AX phosphorylation regardless of the type of endogenous APC. Our data suggest that APC involves in the DSB DNA repair and that truncation mutations impair chromatin-associated functions of APC.Oncogene advance online publication, 5 May 2008; doi:10.1038/onc.2008.127.

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Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan [2] 2Department of Surgery, Shinshu University Graduate School of Medicine, Nagano, Japan.

Reactive oxygen species (ROS)-generating enzyme Nox1 is important in the induction of oncogenic Ras transformation phenotypes, but it is not defined whether Nox1 is involved in Ras-induced upregulation of vascular endothelial growth factor (VEGF), a potent stimulator of tumor angiogenesis. Here we describe that ablation of the Nox1 activity by Nox1 small-interference RNAs (siRNAs) or diphenylene iodonium (DPI) inhibited synthesis of both VEGF proteins and VEGF mRNAs in K-Ras transformed normal rat kidney (KNRK) cells. Nox1siRNAs and DPI suppressed extracellular signal-regulated kinase (ERK)-dependent phosphorylation of a transcription factor Sp1 and Sp1 binding to a VEGF promoter. Furthermore, tumors derived from Nox1siRNA-transfected KNRK cells markedly decreased neovascularization. The Nox1 activity was required for VEGF production in human colon cancer CaCO-2 cells, as in the case of KNRK cells. However, since overexpression of Nox1 in normal rat kidney cells failed to induce VEGF, the Nox1 activity alone was not sufficient to upregulate VEGF expression, which suggests that unlike the previously proposed model, Nox1 may act in concert with other effectors integrated into the Ras network. We propose that Nox1 mediates oncogenic Ras-induced upregulation of VEGF and angiogenesis by activating Sp1 through Ras-ERK-dependent phosphorylation of Sp1.Oncogene advance online publication, 5 May 2008; doi:10.1038/onc.2008.102.

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Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan, akio.saiura@jfcr.or.jp.

PURPOSE: Surgical indications for colon cancer directly invading the pancreas head are controversial. METHODS: Between 1957 and 2007, a total of 12 patients (8 men) underwent pancreaticoduodenectomy combined with right hemicolectomy for colon cancer involving the pancreas head. RESULTS: Mean age was 58 (range, 34-77) years. Fistula formation was observed in five patients (41 percent) preoperatively. Tumor involvement was duodenum only (n = 4), duodenum/pancreas (n = 3), stomach/pancreas (n = 1), duodenum/stomach (n = 2), duodenum/liver (n = 1), and pancreas only (n = 1). Only one postoperative death was encountered. Histologic examination showed malignant invasion to the pancreas head in nine cases (75 percent). Overall one-year, three-year and, five-year survival rates after surgery were 75, 66, and 55 percent, respectively. Five patients (41 percent) survived for more than ten 10 years. CONCLUSIONS: Pancreaticoduodenectomy for advanced colon cancer invading the pancreas or duodenum provides favorable long-term survival.

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Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Aims: This study was designed to evaluate the antiangiogenic properties of emodin and its ability to inhibit tyrosine-kinase-mediated phosphorylation of vascular endothelial growth factor (VEGF) receptors in colon cancer cells. Methods: The effects of emodin on VEGF-receptor (VEGFR) phosphorylation were determined by assaying the tyrosine kinase activity and by Western blot analysis. The antiproliferative and proapoptotic activities of emodin were evaluated by soft agar colony formation, flow cytometric analysis of cell cycle, and by apoptotic assay. Results: Emodin causes a dose-dependent inhibition of VEGFR phosphorylation in colon cancer cells. Treatment with 40 muM of emodin decreased the relative activity of VEGFR-1 to 22.4%, when compared to the control group (assigned a value of 100%); VEGFR-2 and -3 showed a similar reduction in relative activity at 58.5% and 31.6%, respectively (p < 0.01, in each case). Treatment with emodin reduced VEGFR phosphorylation, as evidenced by Western blot analysis. Flow cytometric analysis showed that, upon treatment with emodin, the HCT116 cell cycle was blocked at the G2/M phase. Emodin also increased the apoptosis of HCT116 cells in a dose-dependent manner; treatment with 40 muM emodin increased the apoptotic rate from 8.1% +/- 2.7% in the control group to 27.8% +/- 10.9% in the treated group (p < 0.01). Conclusions: These studies demonstrate that emodin may inhibit cancer-cell growth by blocking VEGFR signaling and indicate that emodin can be used as a potential inhibitor for tumor angiogenesis.

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