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1.  Inhibition of transforming growth factor-β-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis 
British Journal of Cancer  2012;107(1):129-136.
Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment.
We used short hairpin RNA (shRNA) knockdown of TGF-β-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence.
Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells.
These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.
PMCID: PMC3389413  PMID: 22644295
adhesion; invasion; metastasis; fatty acid; TGF-β-activated kinase-1; breast cancer
2.  PI3K/Akt signalling is required for the attachment and spreading, and growth in vivo of metastatic scirrhous gastric carcinoma 
British Journal of Cancer  2012;106(9):1535-1542.
PI3K/Akt (PKB) pathway has been shown in several cell types to be activated by ligands to cell surface integrins, leading to the metastasis of tumour cells. The signalling pathways involved in the metastatic spread of human scirrhous gastric carcinoma cells have not been defined.
The role of the PI3K/Akt pathway in an extensive peritoneal-seeding cell line, OCUM-2MD3 and a parental cell line, OCUM-2M, was investigated by assessing in vitro adhesion and spreading assay, and in vivo peritoneal metastatic model. We also examined the correlation of PI3K/Akt pathway with integrin signals by immunoprecipitations, using cells by transfection with mutant p85 (Δp85).
Adhesiveness and spreading of OCUM-2MD3 cells on collagen type IV was significantly decreased by PI3K inhibitors and expression of mutant p85, but not by inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK). Immunoprecipitation studies indicated that the PI3K/Akt pathway was associated with integrin signalling through Src and vinculin. In an in vivo experimental metastasis model, p85 inhibition reduced peritoneal metastasis of OCUM-2MD3 cells.
PI3K/Akt signalling may be required for integrin-dependent attachment and spreading of scirrhous gastric carcinoma cells, and would be translated into generating better strategies to optimise their use in cancer clinical trials.
PMCID: PMC3341864  PMID: 22531720
PI3 kinase; gastric carcinoma; adhesion; spreading: metastasis; integrin signalling
3.  Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1 
British Journal of Cancer  2011;105(11):1750-1758.
The intake of dietary fatty acids is highly correlated with the risk of various cancers. Linoleic acid (LA) is the most abundant polyunsaturated fat in the western diet, but the mechanism(s) by fatty acids such as LA modulate cancer cells is unclear. In this study, we examined the role of LA in various steps in gastric cancer progression.
The difference in gene expression between LA-treated and untreated OCUM-2MD3 gastric carcinoma cells was examined by mRNA differential display. The involvement of candidate genes was examined by oligo- and plasmid-mediated RNA interference. Biological functions of several of these genes were examined using in vitro assays for invasion, angiogenesis, apoptosis, cell viability, and matrix digestion. Angiogenesis in vivo was measured by CD-31 immunohistochemistry and microvessel density scoring.
LA enhanced the plasminogen activator inhibitor 1 (PAI-1) mRNA and protein expression, which are controlled by PAI-1 mRNA-binding protein. LA-stimulated invasion depended on PAI-1. LA also enhanced angiogenesis by suppression of angiostatin, also through PAI-1. LA did not alter cell growth in culture, but increased dietary LA-enhanced tumour growth in an animal model.
Our findings suggest that dietary LA impacts multiple steps in cancer invasion and angiogenesis, and that reducing LA in the diet may help slow cancer progression.
PMCID: PMC3242595  PMID: 22015554
gastric carcinoma; linoleic acid; plasminogen activator inhibitor 1; angiostatin; invasion
4.  Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice 
British Journal of Cancer  2010;103(8):1182-1191.
Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma.
We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo.
Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53% HLA: 89% VHLA: 100% P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model.
Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.
PMCID: PMC2967057  PMID: 20842125
gastric carcinoma; dietary fatty acid; cyclooxygenase; metastasis; invasion
8.  Psychosocial aspects of the functional gastrointestinal disorders 
Gut  1999;45(Suppl 2):II25-II30.
The functional gastrointestinal disorders (FGID) are the most frequent conditions seen in gastroenterology practice and comprise a major portion of primary care. Psychosocial factors are important in these disorders with regard to: (1) their effects on gut physiology; (2) their modulation of the symptom experience; (3) their influence on illness behavior; (4) their impact on outcome; and (5) the choice of the therapeutic approach. This paper provides a review and consensus of the existing literature by gastroenterologists, psychiatrists, psychologists, physiologists, and health services investigators. Evidence is provided to support the biopsychosocial model as a basis for understanding and treating these disorders, and epidemiological and clinical information on the relations of psychosocial factors to gut physiology, symptom presentation, health behavior, and outcome is offered. Features of motility, personality, abuse history, health concerns, and treatment-seeking differ between patients with FGID and healthy controls, but they are not specific to FGID. They occur in other patients with chronic medical conditions and/or psychiatric disorders. Review of treatment trials indicates clear support for psychotherapeutic treatments, especially in the long term, as well as some evidence for the benefit of antidepressants in FGID, even in the absence of improvements in mood.

Keywords: functional gastrointestinal disorders; psychologic assessment; psychiatric diagnosis; psychosocial factors; health-related quality of life; psychological treatment; psychopharmacological treatment; Rome II
PMCID: PMC1766694  PMID: 10457041
9.  Children's health: a mixed review. 
Environmental Health Perspectives  2000;108(6):A250-A251.
PMCID: PMC1638165  PMID: 10856035
11.  Thirty years of environmental health research--and growing. 
Environmental Health Perspectives  1996;104(10):1010-1011.
PMCID: PMC1469485  PMID: 8930536
12.  Air toxics regulatory issues facing urban settings. 
Environmental Health Perspectives  1996;104(Suppl 5):857-860.
Biomarker research does not exist in isolation. Its usefulness can only be realized when it is translated into prevention strategies to protect public health. In the context of air toxics, these prevention strategies begin with the development of regulatory standards derived from risk assessment schemes. The Clean Air Act Amendments of 1990 list 189 air toxics, including many volatile organics, metals, and pesticides. The National Institute of Environmental Health Sciences (NIEHS), through its affiliation with the National Toxicology Program, has generated toxicity and carcinogenicity data on more than 100 of these air toxics. The NIEHS extramural and intramural research portfolios support a variety of projects that develop and validate biomarkers for use in environmental health science and risk assessment. Biomarkers have a tremendous potential in the areas of regulating air toxics and protecting public health. Risk assessors need data provided by biomarkers of exposure, biomarkers of dose/pharmacokinetics, biomarkers of susceptibility or individual variability, and biomarkers of effects. The greatest benefit would be realized if biomarkers could be employed in four areas of primary and secondary prevention. The first is the use of biomarkers to enhance extrapolation of animal data to human exposure situations in establishing risk standards. The second is the use of biomarkers that assess noncancer, as well as cancer, end points. Important health end points include pulmonary dysfunction, immunotoxicity, and neurotoxicity. Third, biomarkers that serve as early waming signs to detect intermediate effects would enhance our ability to design timely and cost-effective intervention strategies. Finally, biomarkers used to evaluate the effectiveness of intervention strategies, both in clinical and regulatory settings, would enable us to ensure that programs designed to protect public health do, in fact, achieve the desired outcome.
PMCID: PMC1469708  PMID: 8933026
13.  A bad start for socioeconomically disadvantaged children. 
Environmental Health Perspectives  1996;104(5):462-463.
PMCID: PMC1469363  PMID: 8743427
15.  Brain-gut interactions. 
Western Journal of Medicine  1994;160(1):55.
PMCID: PMC1022258  PMID: 8128706
17.  Swainsonine: a new antineoplastic immunomodulator. 
Swainsonine, an indolizidine alkaloid with immunomodulatory activity, has been found to be effective in inhibiting metastatic dissemination and growth of primary tumors of both murine and human origins. The unique ability of swainsonine to exhibit antimetastatic, anti-proliferative, and immunomodulatory activity imparts this drug a promising future in cancer therapy.
PMCID: PMC2571577  PMID: 2509720
18.  Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells. 
Journal of Clinical Investigation  1988;81(3):782-790.
The experimental metastasis of B16-F10 murine melanoma cells is blocked by the anti-cell adhesive pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) derived from the central cell-binding domain of fibronectin. In this report, we show that peptide treatment substantially extends the survival time for mice injected intravenously with B16-F10 cells (8/8 vs. 0/8 mice alive at 150 d), thereby demonstrating the potential efficacy of GRGDS treatment in protection against metastatic colonization. We have also examined the specificity of GRGDS activity by testing a series of related homologues for their effects on experimental metastasis. The overall profile of the relative inhibitory activities of these peptides closely matched their previously established capacity to disrupt adhesion in vitro. Lung retention studies with radiolabeled B16-F10 cells revealed an accelerated rate of cell loss from the lung 0-6 h after coinjection with the active peptide GRGDS. This early effect of GRGDS was consistent with its short circulatory half-life, which was found to be 8 min. Taken together, these results suggest that peptide-mediated inhibition of pulmonary colonization is due to interference with B16-F10 cell adhesion to structures in the target organ. Possible peptide interference in tumor cell-blood cell interactions was examined in order to assess (a) possible biological side-effects of peptide treatment and (b) whether such interactions might be an alternative mechanism for GRGDS-mediated inhibition of pulmonary colonization. GRGDS was found to retain full inhibitory activity when coinjected with B16-F10 cells into mice in which platelet function was impaired by acetylsalicylic acid treatment or into thrombocytopenic mice treated with antiplatelet serum (76-93% inhibition of colony formation). These data suggest that platelet involvement in the effects of the peptide is minimal. Similarly, GRGDS was also found to be a potent inhibitor of experimental metastasis in natural killer (NK) cell-deficient beige mice (86% inhibition), thereby discounting the possibility that GRGDS artifactually enhanced NK cell activity. We conclude as a result of these studies that cell-binding fibronectin peptides are specific inhibitors of experimental metastasis that prolong survival, that they appear to function by blocking the adhesion of B16-F10 cells to structures in the target organ, and that they do not appear to act through side effects on certain metastasis-related blood cell functions. In the future, derivatives of fibronectin peptides may be potentially useful prophylactic agents for interfering with the process of metastasis.
PMCID: PMC442526  PMID: 3343338
19.  D-Alanine-requiring cell wall mutant of Escherichia coli. 
Journal of Bacteriology  1975;122(3):1310-1321.
A mutant of Escherichia coli is described whose cells show a spherical or irregular morphology, associated with leakage of beta-galactosidase and other intracellular proteins. The expression of the morphologic abnormality is most marked when the mutant is grown in rich media and is suppressed by D-alamine, D-serine, D-glutamate, or glycine supplementation. D-Alanine is the most effective amino acid supplement, half maximally supressing this anomalous property at a concentration of 75 mug/ml, as measured by the reduction in beta-galactosidase released from the cells. The mutant is more sensitive to penicillin G, D-methionine, and D-valine and it is relatively resistant to lysozyme. These phenotypic abnormalities are likewise corrected by the above supplementations. The relative rates of peptidoglycan synthesis in mutant and parent, grown under restrictive conditions, were measured both in vivo and in vitro by rates of incorporation of L-[14-D]alanine and uridine-5'-diphosphate-N-acetyl-D-[1-15C-A1-glucosamine, respectively. There is not metabolic block in the biosynthesis of uridine-5'-diphosphate-N-acetyl-muramyl-pentapeptide as shown by enzymic analysis and the lack of accumulation of uridine-5'-diphosphate-N-acetylmuramyl-peptide precursors. These preliminary studies suggest that the mutant possesses a defect in the biosynthesis of peptidoglycan although the exact lesion has not yet been established.
PMCID: PMC246189  PMID: 1097398

Results 1-19 (19)