Angiogenesis inhibitors confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromises neovascularization and growth of tumors. PLD1 deficiency suppressed activation of AKT and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor (VEGF) in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to and migration on extracellular matrixes and reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred significantly fewer lung metastases. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell:platelet interaction due to impaired activation of platelet αIIbβ3 integrin, which decreased seeding of tumor cells into the lung parenchyma. Treatment with a small molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis, and taken together with prior reports of PLD1 roles in tumor cell intrinsic adaptations to stress, suggest potential utility for PLD1 inhibitors as cancer therapeutics.

Kif18A, a member of the kinesin superfamily of molecular motor proteins, is a microtubule depolymerase and a key regulator of chromosome congregation. Kif18A's role in cancer progression has not been well defined. Our hypothesis is that Kif18A has a role in the progression of colorectal cancer (CRC). To investigate this expression of Kif18A, mRNA was assessed by quantitative real-time PCR in 113 operative specimens of primary CRC. Kif18A was overexpressed and significantly (p < 0.0001) higher in CRC than in normal colon tissue. Kif18A overexpression in CRC significantly correlated with clinicopathologic factors such as tumor stage (p < 0.0001), lymphatic invasion (p 5 0.001), lymph node metastasis (p 5 0.01), venous invasion (p 5 0.002) and peritoneal dissemination (p 5 0.02), suggesting that it has a key role in CRC progression. In multivariate analysis, high Kif18A expression had independent significance for poorer overall survival after resection of CRC (p 5 0.037). To demonstrate Kif18A's role in CRC progression, we performed translational and in situ studies. Using in vitro studies on CRC cell lines, we evaluated Kif18A's role in proliferation, migration and invasion. CRC cells transfected with Kif18A cDNA demonstrated significant enhanced migration (p < 0.01) and invasion (p 5 0.018) compared to mock-transfected cells. When Kif18A was targeted with specific small interfering RNA, CRC cells had significantly reduced proliferation (p < 0.01), migration (p < 0.01) and invasion (p < 0.05). The in vitro and translational studies demonstrated that Kif18A expression is related to events of metastasis and is a significant factor for CRC progression.Colorectal cancer (CRC) is one of the most common solid cancers and is increasing in incidence worldwide.

A strong dependence of tunnel magnetoresistance (TMR) on the crystal orientation of ferromagnetic electrodes was confirmed experimentally. We studied the TMR of Fe/Al2O3/Fe50Co50 tunnel junctions with single-crystal Fe electrodes of different crystal orientations and found that the TMR ratio increased from 13% to 42% at 2K (8% to 26% at room temperature) when the crystal orientation was changed from (100) to (211). Such a TMR anisotropy could be explained in terms of the anisotropic spin polarization of Fe bulk and/or interface electronic states. The importance of the "momentum-filtering" effect of the tunnel barrier was also discussed.

Purpose: CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein α (SIRPA) expression may play a key role in the progression of breast cancer.Experimental Design: Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer.Results: In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients.Conclusions: This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells. Clin Cancer Res; 16(18); 4625-35. ©2010 AACR.The numerous efforts in breast cancer research and care have improved early detection and treatment. However, breast cancer prevalence and mortality remain at a high level every year. The prevention and therapy of breast cancer among Japanese women is a crucial public health concern. The most recent statistics for Japan document over 55,000 cases per year (1), with a mortality surpassing 12,000 per year (2). Even after apparently successful localized treatments, there are long-term risks of recurrence and metastasis. To evaluate the postsurgical risk of recurrence of breast cancer, mammography, echogram, computer tomography, and magnetic resonance imaging are utilized for diagnostic imaging, and carcinoembryonic antigen (CEA), CA15-3, and NCC-ST439 are evaluated in peripheral blood as tumor markers. However, the long-term risk of relapse is largely due to clinically occult microrecurrences and micrometastases that are currently beyond detection by current conventional screening strategies. Therefore, it is important to exploit novel tumor markers that could predict recurrence and metastasis with greater reliability.Kaplan et al. have shown that bone marrow-derived hematopoietic progenitor cells play an important role in the accumulation of premetastatic niches and the promotion of carcinogenesis and metastasis (3). We confirmed their findings by using clinical samples in which h...

Phospholipase D (PLD), which produces the lipid messenger phosphatidic acid (PA), has been implicated in superoxide generation and degranulation in neutrophils. The basis for this conclusion is the observation that primary alcohols, which interfere with PLD-catalyzed PA production, inhibit these neutrophil functions. However, off-target effects of primary alcohols cannot be totally excluded. Here, we generated PLD ؊/؊ mice in order to reevaluate the involvement of PLD in and investigate the molecular mechanisms of these neutrophil functions. Surprisingly, N-formyl-methionyl-leucyl-phenylalanine (fMLP) induced these functions in PLD ؊/؊ neutrophils, and these functions were suppressed by ethanol. These results indicate that PLD is dispensable for these neutrophil functions and that ethanol nonspecifically inhibits them, warning against the use of primary alcohols as specific inhibitors of PLD-mediated PA formation. The calcium ionophore ionomycin and the membrane-permeative compound 1-oleoyl-2-acetyl-sn-glycerol (OADG) synergistically induced superoxide generation. On the other hand, ionomycin alone induced degranulation, which was further augmented by OADG. These results demonstrate that conventional protein kinase C (cPKC) is crucial for superoxide generation, and a Ca 2؉ -dependent signaling pathway(s) and cPKC are involved in degranulation in mouse neutrophils.

Abstract. Recently, kinesin motor proteins have been focused on as targets for cancer therapy. Kinesins are microtubule-based motor proteins that mediate diverse functions within the cell, including the transport of vesicles, organelles, chromosomes and protein complexes, as well as the movement of microtubules. In the current study, the expression of kinesin family member 18A (KIF18A), a member of kinesin superfamily, was investigated in breast cancer using immunohistochemistry, and its effect on breast cancer prognosis was examined. KIF18A expression level was significantly associated with lymph node metastasis (P=0.047). In patients with high levels of KIF18A expression, survival was significantly poorer compared to patients with low levels of KIF18A expression (disease-free survival, P=0.030). Multivariate analysis revealed that venous invasion (hazard ratio, 9.22; 95% confidence interval, 3.90-23.66; P<0.001) and KIF18A expression (hazard ratio, 3.20; 95% confidence interval, 1.34-6.09; P=0.010) were independent predictive factors for lymph node metastasis. KIF18A may be a useful predictive marker for lymph node metastasis in breast cancer, which could facilitate curative adjuvant treatment.

Fabrication and electrical characterization of high aspect ratio silicon field emitter arrays Fabrication and characterization of silicon field emitter arrays with focusing electrode by the chemical mechanical polishing processWe fabricated hafnium carbide ͑HfC͒ coated Si field emitter arrays ͑HfC FEAs͒ with an extraction-gate electrode to improve the emission characteristics of Si FEAs. Hafnium carbide thin film was deposited by inductively coupled plasma-assisted magnetron sputtering. The HfC film was characterized by x-ray photoelectron spectroscopy and x-ray diffraction measurement, and was found to be ͑111͒-oriented polycrystalline film. The HfC FEAs exhibited superior performance. An emission of more than 10 mA could be obtained from the 16 000 tip array, which is 20 times higher than that for Si FEAs. The operational voltage for emission of 1 A decreased from 61 to 45 V due to the HfC coating. The long-term emission characteristics were also measured. Si FEAs degraded rapidly even in an ultrahigh vacuum chamber. However, the emission degradation in the HfC FEAs was much slower. The number of active tips was counted using an electrostatic-lens projector, and the results revealed that the HfC FEAs had six times as many tips as the Si FEAs had.

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