ognizant Communication Corporation

ONCOLOGY RESEARCH
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS

ABSTRACTS
VOLUME 18, NUMBER 4

Oncology Research, Vol. 18, pp. 133-139
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

FXYD3 Expression in Gliomas and its Clinicopathological Significance

Ming-Wei Wang,1,2 Ping Gu,1,2 Zhi-Yong Zhang,3 Zhen-Long Zhu,4 Yuan Geng,1,2 Hany Kayed,5 Hanswalter Zentgraf,6 and Xiao-Feng Sun7

1Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
2Brain Ageing and Cognitive Neuroscience Laboratory, Shijiazhuang, Hebei, China
3Department of Pathology, Tangshan Gongren Hospital, Tangshan, Hebei, China
4Department of Pathology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
5Institute of Clinical Radiology and Nuclear Medicine, University Hospital Mannheim, University of Heidelberg, Heidelberg, Germany
6Applied Tumor Virology, German Cancer Research Center, Heidelberg, Germany
7Department of Oncology, Institute of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden

FXYD3, interacting with Na+/K+-ATPase, is considered a cell surface regulator modulating the function of ion pumps and ion channels. The FXYD3 gene was originally cloned from murine mammary tumors and then from human breast tumors. However, no study of FXYD3 has been carried out in gliomas; therefore, we examined FXYD3 expression in gliomas and its clinicopathological significance. FXYD3 expression was immunohistochemically examined in 71 primary gliomas, along with 37 matched adjacent normal brain samples and 8 recurred gliomas. The frequency of strong FXYD3 expression was higher in the primary tumors in either unmatched (p = 0.046) or matched cases (p = 0.02), compared to normal brain tissue. FXYD3 expression was significantly more increased in females than males (p = 0.01), and in multiple site gliomas than single sites (p = 0.02). There was no difference of FXYD3 expression regarding age, tumor location, size, histological type, and tumor grade (p > 0.05). The results suggest that FXYD3 expression may be involved in glioma development, especially in multiple gliomas and female patients.

Key words: Glioma; FXYD3; Immunohistochemistry

Address correspondence to Xiao-Feng Sun, Prof., M.D., Ph.D., Department of Oncology, Institute of Clinical and Experimental Medicine, University of Linko¨ping, S-581 85, Sweden. Tel: +46 13 222066; Fax: +46 13 223090; E-mail: xiasu@ibk.liu.se




Oncology Research, Vol. 18, pp. 141-151
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Expression Patterns of Aurora Kinase B, Heat Shock Protein 47, and Periostin in Esophageal Squamous Cell Carcinoma

Yong-Jae Kwon,1 Seog Joo Lee,1 Jae Soo Koh,2 Sung Han Kim,3 Young-Joon Kim,4 and Jong Ho Park5

1Department of Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
2Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
3Digital Genomics, Inc., Seoul, Korea
4Department of Biochemistry, Yonsei University, Seoul, Korea
5Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

To elucidate the proteins related to the development and progress of esophageal squamous cell carcinoma (ESCC), we performed gene expression profile analysis of 14 ESCC tissues. We identified 182 genes that were commonly upregulated (p < 10-5) and 54 genes that were downregulated in ESCC tissues (p < 10-6). In order to validate the gene expression profiles, we did semiquantitative RT-PCR analysis and found 11 genes upregulated in greater than 70% of 19 tissue samples. We further examined the protein expression level and the distribution patterns of four genes: aurora kinase B (AURKB), periostin (POSTN), heat shock protein 47 (HSP47), and matrix metalloprotease1 (MMP1). Ultimately, three genes (AURKB, HSP47, POSTN) were verified to be increased at both the mRNA and protein levels. Among them, AURKB and HSP47 were found to increase in the early development stage of ESCC and POSTN might be considered to function in the cell-cell interactions between cancer cell and adjacent stromal cells. Accordingly, these studies may provide valuable information for the identification of the genes that are necessary to study further their functions. Moreover, these genes might be used as potential diagnostic or therapeutic target molecules for ESCC patients.

Key words: Esophageal squamous cell carcinoma (ESCC); Aurora kinase B; Periostin Heat shock protein 47

Address correspondence to Jong Ho Park, Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea. Tel: ?822-970-1240; Fax: ?822-970-2402; E-mail: jhpark@kcch.re.kr or Young-Joon Kim, Department of Biochemistry, College of Science, Yonsei University, 134 Shin-chon dong, seodaemunku, Seoul, Korea. E-mail: yjkim@yonsei.ac.kr




Oncology Research, Vol. 18, pp. 153-162
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Expression of the Fluoropyrimidine-Metabolizing Enzymes in Bladder Cancers as Measured by the Danenberg Tumor Profile

Michio Naoe,1 Yoshio Ogawa,1 Jun Morita,1 Takeshi Shichijo,1 Khozo Fuji,1 Kumiko Takeshita,1 Miki Kushima,2 Shuji Terao,3 Toshiko Yamochi,4 and Hidekazu Ota4

1Division of Urology, Showa University, Tokyo, Japan
2Division of Hospital Pathology, Showa University Hospital, Tokyo, Japan
3Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan
4Division of Pathology, Showa University, Tokyo, Japan

5-Fluorouracil (5-FU) and its prodrugs are used to treat various cancers. Response to 5-FU-based chemotherapy and expression of 5-FU-related enzymes differ among cancers. The objective of the present study was to investigate the relationship between the expression of 5-FU-related enzymes and clinicopathologic factorsin bladder cancer. Formalin-fixed, paraffin-embedded sections of 44 bladder cancers and 27 normal bladders were included in this study. After laser capture microdissection, "Danenberg tumor profile," was performed for the measurement of 5-FU-related enzymes. There was no significant difference between dihydropyrimidine hydrogenase (DPD) mRNA expression in bladder cancer and in normal bladder. On the contrary, mRNA expressions of orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP) in bladder cancer were higher than those in normal bladder. Compared with previously reported DPD mRNA expressions in other types of cancer, DPD mRNA expression in bladder cancer wasrelatively low. The 5-FU-related enzymatic condition of bladder cancer is favorable for 5-FU.

Key words: Bladder cancer; 5-Fluorouracil (5-FU); Dihydropyrimidine dehydrogenase (DPD); Orotate phosphoribosyltransferase (OPRT); Thymidylate synthase (TS); Thymidine phosphorylase (TP)

Address correspondence to Michio Naoe, Department of Urology, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, Japan. Tel: +81-3-3784-8560; Fax: +81-3-3784-1400; E-mail: naoe@east.cts.ne.jp




Oncology Research, Vol. 18, pp. 163-171
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Antitumor Effects and Cytotoxicity of Recombinant Plant Nucleases

Jaroslav Matousek,1 Tomás Podzimek,1,2 Pavla Poucková,3 Jan Stehlík,1 Jirí Skvor,4 Josef Soucek,5 and Josef Matousek6

1Biology Centre, Academy of Sciences of the Czech Republic v.v.i., Institute of Plant Molecular Biology, 370 05 Ceské Bud?jovice, Czech Republic
2Department of Biochemistry and Microbiology, Institute of Chemical Technology Prague, 166 28 Prague, Czech Republic
3Institute of Biophysics and Informatics, 1st Medical Faculty of the Charles University, 128 00 Prague, Czech Republic
4Laboratory of Genetics, Department of Anthropology, Faculty of Science of the Charles University, 128 20 Prague, Czech Republic
5Institute of Hematology and Blood Transfusion, 128 00 Prague, Czech Republic
6Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 277 21 Lib?chov, Czech Republic

Recombinant plant nucleases R-TBN1 and R-HBN1 were isolated to homogeneity and examined for their antitumor effects and cytotoxicity. Although antiproliferative effects of both recombinant nucleases were not significant on the ML-2 cell culture in vitro, the nucleases were strongly cytostatic in vivo after their administration intravenously as stabilized conjugates with polyethylene glycol (PEG). Recombinant nucleases were as effective against melanoma tumors as previously studied pine pollen (PN) and mung bean nucleases and their effects were reached at about 10 times lower concentrations compared to the use of bovine seminal RNase (BS-RNase). Because the recombinant nucleases R-HBN1 and R-TBN1 share only 67.4% amino acid identity and showed only partial immunochemical cross-reactivity, their similar anticancerogenic effects can be mainly explained by their catalytical similarity. Both recombinant nucleases showed lower degree of aspermatogenesis compared to BS-RNAse and PN nuclease. Unlike BS-RNase, aspermatogenesis induced by both recombinant nucleases could not be prevented by the homologous antibody complexes. Owing to relatively low cytotoxicity on the one hand, and high efficiency at low protein levels on the other, recombinant plant nucleases R-HBN1 and R-TBN1 appear to be stable biochemical agents that can be targeted as potential antitumor cytostatics.

Key words: Anticarcinogenic and antiproliferative nucleases; Human melanoma; Tumor xenografts; Spermatogenesis; Nicotiana benthamina; Plant infiltration; L. esculentum; H. lupulus

Address correspondence to Josef Matous?ek, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 277 21 Lib?chov, Czech Republic. Tel: 00420 315639539; Fax: 00420 315639510; E mail: matousek@iapg.cas.cz




Oncology Research, Vol. 18, pp. 173-184
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Bioactive Lipids Lysophosphatidic Acid and Sphingosine 1-Phosphate Mediate Breast Cancer Cell Biological Functions Through Distinct Mechanisms

Ahmed Boucharaba,1 Benoit Guillet,2 Farid Menaa,3 Mohamed Hneino,4,5,8 Andre J. van Wijnen,6 Clézardin Philippe,7,8,9 and Peyruchaud Oliver7,8,9

1Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
2Département d'hématologie, Hôpital Universitaire de Renne, Renne, France
3Department of Cancer Cell Biology, Sidney Kimmel Cancer Center, San Diego, CA, USA
4INSERM, ER122/EA4173, Lyon, France
5Faculté de Médecine Rockefeller, Lyon, France
6University of Massachusetts, Worcester, MA, USA
7INSERM, U664, Lyon, France
8Université Claude Bernard Lyon 1, Villeurbanne, France
9Faculté de Me´decine Laennec, Lyon, France

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are structurally related bioactive lipids with growth factor-like activities. LPA and S1P are naturally produced in vivo by blood platelets upon platelet aggregation and at least in vitro by fibroblasts, adipocytes, and multiple types of tumor cells. Breast cancer cells respond to LPA and S1P. However, their specific actions on breast cancer cell biological functions remain unclear. We therefore conducted an in vitro side-by-side study of these two lipids on breast cancer cells. LPA mediates human breast cancer MDA-BO2 cell proliferation, migration, and invasion through activation of a Gai/ERK1/2-dependent signaling pathway, whereas activation of Gai/PI3K predominates upon S1P stimulation. In MDA-BO2 cells, LPA but not S1P activities were dependent on active type 1 insulin-like growth factor and epithelial growth factor receptors. LPA and S1P act directly on endothelial cells to induce angiogenesis. We demonstrate that LPA and S1P have indirect angiogenic properties as judged by induced secretion of angiogenic factors by breast cancer cells primed with these lysophospholipids. S1P, but not LPA, controlled the expression of VEGF-A by breast cancer cells, while LPA, but not S1P, controlled the expression of GM-CSF, Gro-a, MCP-1, and IL-6. According to the secretion of these paracrine osteoclastic factors, LPA, but not S1P, stimulates breast cancer cell-induced osteoclastogenesis. These findings suggest that, in vivo, LPA and S1P can coordinate their action on tumor and surrounding cells to induce breast cancer progression both at primary and bone metastatic sites.

Key words: Lysophosphatidic acid (LPA); Sphingosine 1-phosphate (S1P); Breast cancer cells; Proliferation; Migration; Invasion; Angiogenesis; Osteoclastogenesis

Address correspondence to Peyruchaud Olivier, INSERM U.664, Faculté de Médecine Laennec, rue Guillaume Paradin, 69372 Lyon cedex 08, France. Tel: (33) 4 78 78 57 38; Fax: (33) 4 78 77 87 72; E-mail: peyruchaud@lyon.inserm.fr




Oncology Research, Vol. 18, pp. 185-192
0965-0407/09 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Status of p16INK4a and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

Mohammed Attaleb,1 Wail El hamadani,1 Meriem Khyatti,2 Laila Benbacer,1 Nadia Benchekroun,3 Abdellatif Benider,3 Mariam Amrani,4 and Mohammed El Mzibri1

1Unité de Biologie et recherche Médicale, Centre National de l'Energie, des Sciences et Techniques Nucléaires (CNESTEN), Rabat, Morocco
2Laboratoire d'Oncologie, Institut Pasteur du Maroc, Casablanca, Morocco
3Centre d'Oncologie, Centre Hospitalier Universitaire Ibn Rochd, Casablanca, Morocco
4Service d'Anatomie Pathologique, Institut National d'Oncologie, Rabat, Morocco

Aberrant methylation of tumor suppressor gene promoters has been extensively investigated in cervical cancer. Transcriptional silencing, as a main consequence of hypermethylation of CpG islands, is the predominant mechanism of p16INK4a and E-cadherin gene inactivation in malignant epithelial tumors. This study was conducted to evaluate the promoter methylation status of p16INK4a and E-cadherin genes in 22 specimens of cervical carcinomas, four cervical cancer cell lines (HeLa, SiHa, Caski, C33A), and 20 human papillomavirus negative specimens, obtained from normal cervical swabs, using the methylation-specific PCR approach. Hypermethylation of the 5´ CpG island of the p16INK4a and E-cadherin genes were found in 13 (59.1%) and 10 (45.5%) of 22 cervical cancer samples, respectively. Furthermore, our findings did not show any correlation between promoter methylation of p16INK4a and E-cadherin genes and clinicopathological parameters, including HPV infection, phenotypic distribution, and stage of the disease. However, hypermethylation of E-cadherin gene promoter appears to be age related in cervical cancer, whereas the frequency of aberrant methylation of p16INK4a gene promoter is unchanged according to the age of patients. Thus, caution must be made to use these markers in the diagnosis of cervical cancer. However, dietary or pharmaceutical agents that can inhibit these epigenetic events may prevent or delay the development of cervical cancer.

Key words: Cervical cancer; E-cadherin; Hypermethylation; p16INK4a

Address correspondence to Mohammad El Mzibri, Unité de Biologie et Recherche Médicale, Centre National de l'Energie, des Sciences et des Techniques Nucle´aires, B.P. 1382 RP, 10001 Rabat, Morocco. Tel: +212-37-71.27.51; Fax: +212-37-71.18.46; E-mail: mzibri@yahoo.com or elmzibri@cnesten.org.ma